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Ak B, Akısü M, Durmaz A, Yalaz M, Terek D, Sönmezler E, Oktay Y, Akın H, Aykut A. Expanding the genetic spectrum of short rib polydactyly syndrome: Novel DYNC2H1 variants and functional insights. Bone 2025; 197:117511. [PMID: 40339774 DOI: 10.1016/j.bone.2025.117511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/28/2025] [Accepted: 05/02/2025] [Indexed: 05/10/2025]
Abstract
INTRODUCTION Short rib polydactyly syndrome (SRPS), with or without polydactyly, also known as Verma-Naumoff/Saldino-Noonan syndrome, is a type of skeletal ciliopathy. Initially, variants in the IFT80 gene were implicated; however, approximately half of the SRPS cases are associated with variants in the DYNC2H1 gene. Additionally, digenic variants involving DYNC2H1 and NEK1 can contribute to the syndrome. MATERIALS AND METHODS This case report describes a male patient presenting with characteristic SRPS features, including a constricted thorax and shortened limbs. Exome sequencing was performed to identify causative variants, followed by functional analyses to assess the pathogenicity of the identified variants, including a synonymous variant. RESULTS Exome sequencing identified compound heterozygous variants in the DYNC2H1 gene: a novel missense variant c.6439G>T p.(Asp2147Tyr) and a synonymous variant c.6477G>A p.(Gln2159=). Functional analyses confirmed that the synonymous variant triggers nonsense-mediated decay of the affected allele. CONCLUSION This study expands the spectrum of DYNC2H1 variants associated with SRPS and emphasizes the importance of functional analyses in genetic diagnostics. Demonstrating pathogenicity for a synonymous variant highlights the necessity for comprehensive variant assessments to improve diagnostic accuracy and enable early intervention. These findings have significant implications for molecular diagnostics and personalized therapy strategies in skeletal ciliopathies.
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Affiliation(s)
- Bilgesu Ak
- Department of Medical Genetics, Ege University Hospital, Izmir, Turkey
| | - Mete Akısü
- Department of Neonatology, Ege University Hospital, Izmir, Turkey.
| | - Asude Durmaz
- Department of Medical Genetics, Ege University Hospital, Izmir, Turkey.
| | - Mehmet Yalaz
- Department of Neonatology, Ege University Hospital, Izmir, Turkey.
| | - Demet Terek
- Department of Neonatology, Ege University Hospital, Izmir, Turkey.
| | | | - Yavuz Oktay
- Izmir Biomedicine and Genome Center, Izmir, Turkey.
| | - Haluk Akın
- Department of Medical Genetics, Ege University Hospital, Izmir, Turkey.
| | - Ayça Aykut
- Department of Medical Genetics, Ege University Hospital, Izmir, Turkey.
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Ghanty I, Perez-Palma E, Villaman C, Stobo D, Symonds J, Zuberi S, Lal D, Brunklaus A. SCN9A should not be considered an epilepsy gene; Refuting a gene-disease association. Epilepsia 2025. [PMID: 40492992 DOI: 10.1111/epi.18474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 05/11/2025] [Accepted: 05/12/2025] [Indexed: 06/12/2025]
Abstract
OBJECTIVE The SCN9A gene is primarily expressed in nociceptive pathways within the peripheral nervous system, and pathogenic variants are associated with human pain disorders. In recent years, several studies have proposed SCN9A as a monogenic cause of epilepsy. Our objective was to critically appraise the SCN9A-epilepsy gene-disease relationship. METHODS We assessed "epilepsy-associated" SCN9A variants from four sources: (1) the literature up to December 2023 (n = 27), (2) epilepsy patients referred for genetic testing at a regional service in Glasgow, UK over a 5-year period (n = 30), (3) the Human Genetics Mutation Database (n = 25), and (4) ClinVar (n = 1546). The latter two are genome-wide variant databases, accepting submissions from genetic laboratories and research groups. We checked whether each SCN9A variant is present in the Genome Aggregation Database (gnomAD) V4 (a reference population database for variant interpretation), and classified its pathogenicity based on the American College of Molecular Genetics and Genomics/Association of Molecular Pathologists guidelines. RESULTS Only three SCN9A variants were classified as "likely pathogenic," of which two were identified in healthy individuals in gnomAD. A total of 1540 of the 1546 SCN9A variants in ClinVar labeled as being associated with epilepsy were also reported in association with hereditary sensory and autonomic neuropathy. No further clinical data were provided in 1482 of these submissions. SIGNIFICANCE There is no convincing genetic evidence to support SCN9A as a causative epilepsy gene. As such, the inclusion of SCN9A in epilepsy genetic testing panels should be reassessed. Research centers and genetic testing laboratories should be rigorous and consistent in their submissions to variant databases.
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Affiliation(s)
- Ismael Ghanty
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
- Leeds Children's Hospital, Leeds, UK
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Eduardo Perez-Palma
- Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Camilo Villaman
- Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Daniel Stobo
- West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK
| | - Joseph Symonds
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
| | - Sameer Zuberi
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
| | | | - Andreas Brunklaus
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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Wen B, Shi S, Long Y, Dang Y, Tian W. PhenoDP: leveraging deep learning for phenotype-based case reporting, disease ranking, and symptom recommendation. Genome Med 2025; 17:67. [PMID: 40481598 PMCID: PMC12143081 DOI: 10.1186/s13073-025-01496-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Current phenotype-based diagnostic tools often struggle with accurate disease prioritization due to incomplete phenotypic data and the complexity of rare disease presentations. Additionally, they lack the ability to generate patient-centered clinical insights or recommend further symptoms for differential diagnosis. METHODS We developed PhenoDP, a deep learning-based toolkit with three modules: Summarizer, Ranker, and Recommender. The Summarizer fine-tuned a distilled large language model to create clinical summaries from a patient's Human Phenotype Ontology (HPO) terms. The Ranker prioritizes diseases by combining information content-based, phi-based, and semantic-based similarity measures. The Recommender employs contrastive learning to recommend additional HPO terms for enhanced diagnostic accuracy. RESULTS PhenoDP's Summarizer produces more clinically coherent and patient-centered summaries than the general-purpose language model FlanT5. The Ranker achieves state-of-the-art diagnostic performance, consistently outperforming existing phenotype-based methods across both simulated and real-world datasets. The Recommender also outperformed GPT-4o and PhenoTips in improving diagnostic accuracy when its suggested terms were incorporated into different ranking pipelines. CONCLUSIONS PhenoDP enhances Mendelian disease diagnosis through deep learning, offering precise summarization, ranking, and symptom recommendation. Its superior performance and open-source design make it a valuable clinical tool, with potential to accelerate diagnosis and improve patient outcomes. PhenoDP is freely available at https://github.com/TianLab-Bioinfo/PhenoDP .
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Affiliation(s)
- Baole Wen
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Computational Biology, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, China
| | - Sheng Shi
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Computational Biology, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, China
| | - Yi Long
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yanan Dang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Computational Biology, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, China
| | - Weidong Tian
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Computational Biology, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai, 200438, China.
- Children's Hospital of Fudan University, Shanghai, 201102, China.
- Children's Hospital of Shandong University, Jinan, Shandong, 250022, China.
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Zhang M, Qiu H, Han Z, Ma Y, Hou J, Yuan J, Jia H, Zhou M, Lu H, Wu Y. Topical transdermal administration of lenalidomide nanosuspensions-based hydrogels against melanoma: In vitro and in vivo studies. Int J Pharm X 2025; 9:100316. [PMID: 39898009 PMCID: PMC11787432 DOI: 10.1016/j.ijpx.2025.100316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/09/2025] [Accepted: 01/13/2025] [Indexed: 02/04/2025] Open
Abstract
Percutaneous neoadjuvant therapy has proven effective in diminishing tumor size and the surgical intervention area, which couldeffectively mitigate the risk of tumor recurrence and enhance immunotherapy efficacy. Lenalidomide, an approved medication orally used to treat myeloma, was loaded into nanosuspensions-based hydrogels (Len-NBHs) for transdermal administration as a percutaneous neoadjuvant therapy. This study was designed to investigate the inhibitory effect and mechanism of Len-NBHs on melanoma. Network pharmacology and transcriptomic analyses identified key targets and signaling pathways. The effects of lenalidomide on melanoma were further verified through Western blotting, immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction,using both in vitro cell experiments and in vivo melanoma mouse models. Lenalidomide could induce melanoma cells apoptosis, disrupt cell cycle progression, impede cell migration and invasion, and modify tumor microenvironment (TME). Mechanistically, lenalidomide reversed the abnormal activation of the PI3K-AKT signaling pathway and the overexpression of CD93, while also recruiting CD8+ T cells, CD4+ T cells, and dendritic cells to infiltrate the tumor site. Transdermal administration of Len-NBHs represents a promising adjuvant therapy for the treatment of malignant melanoma. Preoperative administration of Len-NBHs can inhibit the outward spread of melanoma, reduce tumor size, thereby decreasing the surgical excision area and improving patient survival rates and prognosis.
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Affiliation(s)
| | | | - Zheyi Han
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Yazhong Ma
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Jingjing Hou
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Jingwei Yuan
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Haiyan Jia
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Menglu Zhou
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Hongjie Lu
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Yan Wu
- Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
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Gholami M, Hamidi AK, Naghshband Z, Asadi M, Amoli MM. Whole exome sequencing revealed new variants and haplotypes associated with monogenic obesity. J Diabetes Metab Disord 2025; 24:23. [PMID: 39712340 PMCID: PMC11662120 DOI: 10.1007/s40200-024-01507-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/01/2024] [Indexed: 12/24/2024]
Abstract
OBJECTIVES This study aims to identify new variants and haplotypes associated with monogenic obesity by analyzing known obesity genes in whole exome sequencing (WES) data. METHODS The monogenic obesity-associated genes were identified by using the National Institutes of Health (NIH) Genetic Testing Registry (GTR) monogenic obesity panels. WES was performed on (n = 49) extremely obese (children under 5 with weight-for-height greater than 3 standard deviations (SD) above the World Health Organization (WHO) Child Growth Standards median) and (n = 50) control nonobese (25 > body mass index (BMI) < 30) subjects without a history of childhood obesity, and also Iranome WES data of healthy subjects (n = 800). RESULTS Seventy-four genes were included in WES analyses. After Bonferroni correction, the T allele of rs2275155 on SDCCAG8 was significantly associated with the increased risk of obesity for allelic and co-dominant models (p˂0.05). Also, a significant association was observed for the T allele of rs116167439 on CEP19 and the T allele of rs201676524 a rare variant on ADCY3; for allelic, dominant, overdominant, and co-dominant models (p˂0.05). In the haplotype association study, TC (on CEP19), CATA (on SDCCAG8), CAA, CTA, CAAA, and TTGA (on ADCY3) haplotypes showed significant associations with monogenic obesity (p < 0.05). CONCLUSIONS This study suggested that the T allele of two common variants rs2275155 and rs116167439, also rare variant rs201676524 are associated with an increased risk of monogenic obesity. The significant haplotype associations indicate these variants may be in linkage with causative rare variants and should be considered in future studies. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s40200-024-01507-2.
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Affiliation(s)
- Morteza Gholami
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Armita Kakavand Hamidi
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Naghshband
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojgan Asadi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa M. Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Sun P, Song J, Liu Y, Li X, Zhang Y, Zhou Y, Gong W. Investigating the Mechanisms of Lycii fructus in Treating Nonalcoholic Fatty Liver Disease and Diabetes Comorbidity Through Network Pharmacology and Molecular Dynamics. Food Sci Nutr 2025; 13:e70256. [PMID: 40433113 PMCID: PMC12106045 DOI: 10.1002/fsn3.70256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 02/27/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are prevalent metabolic disorders that frequently coexist, yet their shared molecular mechanisms remain poorly understood, and current therapies often yield suboptimal outcomes. Lycium barbarum L. (Lycii fructus, LF), a traditional medicinal herb, has demonstrated clinical efficacy in treating both conditions, but its mechanism of action in comorbidity management remains unclear. Active LF compounds were identified via the TCMSP database, with potential targets predicted using Swiss Target Prediction and PharmMapper. Disease-associated proteins for NAFLD and DM were curated from OMIM, GeneCards, DisGeNET, UniProt, DrugBank, and TTD. A protein-protein interaction (PPI) network was constructed from these targets, and GO and KEGG pathway analyses were performed using the DAVID platform. Key targets were further refined through network module analysis via Metascape. Drug-likeness of bioactive compounds was assessed using SwissADME and ADMETlab 2.0. Molecular docking and dynamics simulations validated interactions between core targets and LF compounds. Mendelian randomization (MR) analysis tested causal relationships between core genes and disease phenotypes. We identified 58 shared therapeutic targets for NAFLD-DM comorbidity, including HSP90AA1, ESR1, MMP9, EGFR, AKT1, and CASP3. GO analysis implicated LF in blood pressure regulation and glucose-stimulated insulin secretion. KEGG pathways highlighted modulation of MAPK, PI3K-Akt, FoxO, and mTOR signaling. 24-methylenelanost-8-enol and cryptoxanthin monoepoxide emerged as core bioactive compounds with favorable drug-likeness. Molecular docking confirmed strong binding of 24-methylenelanost-8-enol to HSP90AA1 and cryptoxanthin monoepoxide to MMP9, further supported by dynamics simulations. MR analysis revealed a significant causal role for CASP3 in both NAFLD and DM, aligning with network pharmacology predictions. LF's therapeutic effects on NAFLD-DM comorbidity likely arise from terpenoid and cryptoxanthin mediated modulation of apoptosis and inflammation pathway. This study identifies shared molecular networks, proposes candidate mechanisms for LF's efficacy, and provides a framework for targeting multifactorial metabolic diseases.
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Affiliation(s)
- Peng Sun
- Science and Technology CenterNingxia Medical UniversityYinchuanChina
- Ningxia Hui Autonomous Region Institute of Medical SciencesYinchuanChina
- Public Health SchoolNingxia Medical UniversityYinchuanChina
| | - Jiahui Song
- Science and Technology CenterNingxia Medical UniversityYinchuanChina
- Ningxia Hui Autonomous Region Institute of Medical SciencesYinchuanChina
| | - Yang Liu
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Xiujing Li
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Yiming Zhang
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Yuxing Zhou
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Wei Gong
- Public Health SchoolNingxia Medical UniversityYinchuanChina
- Key Laboratory of Environmental Factors and Chronic Disease ControlNingxia Medical UniversityYinchuanChina
- School of Medical Information and EngineeringNingxia Medical UniversityYinchuanChina
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Yang Y, Yu K, Gao S, Yu S, Xiong D, Qin C, Chen H, Tang J, Tang N, Zhu H. Alzheimer's disease knowledge graph enhances knowledge discovery and disease prediction. Comput Biol Med 2025; 192:110285. [PMID: 40306017 PMCID: PMC12103266 DOI: 10.1016/j.compbiomed.2025.110285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 03/26/2025] [Accepted: 04/24/2025] [Indexed: 05/02/2025]
Abstract
OBJECTIVE To construct an Alzheimer's Disease Knowledge Graph (ADKG) by extracting and integrating relationships among Alzheimer's disease (AD), genes, variants, chemicals, drugs, and other diseases from biomedical literature, aiming to identify existing treatments, potential targets, and diagnostic methods for AD. METHODS We annotated 800 PubMed abstracts (ADERC corpus) with 20,886 entities and 4935 relationships, augmented via GPT-4. A SpERT model (SciBERT-based) trained on this data extracted relations from PubMed abstracts, supported by biomedical databases and entity linking refined via abbreviation resolution/string matching. The resulting knowledge graph trained embedding models to predict novel relationships. ADKG's utility was validated by integrating it with UK Biobank data for predictive modeling. RESULTS The ADKG contained 3,199,276 entity mentions and 633,733 triplets, linking >5K unique entities and capturing complex AD-related interactions. Its graph embedding models produced evidence-supported predictions, enabling testable hypotheses. In UK Biobank predictive modeling, ADKG-enhanced models achieved higher AUROC of 0.928 comparing to 0.903 without ADKG enhancement. CONCLUSION By synthesizing literature-derived insights into a computable framework, ADKG bridges molecular mechanisms to clinical phenotypes, advancing precision medicine in Alzheimer's research. Its structured data and predictive utility underscore its potential to accelerate therapeutic discovery and risk stratification.
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Affiliation(s)
- Yue Yang
- Department of Biostatistics, University of North Carolina at Chapel Hill, USA
| | | | - Shan Gao
- Department of Mathematics and Statistics, Yunnan University, China
| | - Sheng Yu
- Center for Statistics Science, Tsinghua University, China
| | - Di Xiong
- Department of Mathematics, Shanghai University, China
| | - Chuanyang Qin
- Department of Mathematics and Statistics, Yunnan University, China
| | - Huiyuan Chen
- Department of Mathematics and Statistics, Yunnan University, China
| | - Jiarui Tang
- Department of Biostatistics, University of North Carolina at Chapel Hill, USA
| | - Niansheng Tang
- Department of Mathematics and Statistics, Yunnan University, China
| | - Hongtu Zhu
- Department of Biostatistics, University of North Carolina at Chapel Hill, USA.
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Cao Q, Cai C, Wang C, Li L, Liu J, Zhang J, Rong M, Ren J, Han Y, Zhang J, Han X. Zengmian Yiliu formula suppresses cell cycle in immune-rich ovarian cancer patient-derived organoids. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156721. [PMID: 40215819 DOI: 10.1016/j.phymed.2025.156721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 03/18/2025] [Accepted: 04/01/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Ovarian cancer, often diagnosed at advanced stages, has a 5-year survival rate below 50%, indicating a critical need for innovative treatments. The Zengmian Yiliu (ZMYL) formula, a Traditional Chinese Medicine (TCM) prescription, has shown potential in enhancing chemotherapy efficacy and improving patients' quality of life, PURPOSE: To investigate the effects of the ZMYL formula on ovarian cancer organoids, focusing on its impact on organoid phenotypes and underlying mechanisms, and to explore its potential as an immunotherapeutic agent. METHODS Ovarian cancer organoids were established from surgical tissues and treated with the ZMYL formula at varying concentrations. Network pharmacology was utilized to predict the formula's therapeutic targets and pathways, and molecular docking was conducted to validate ingredient-target interactions. Phenotypic changes were monitored, and RNA sequencing was performed post-treatment to analyze gene expression alterations. RESULTS A total of 34 overlapping targets of 10 compounds in the ZMYL formula and ovarian cancer were predicted by Network pharmacology analysis. The ZMYL formula induced dose-dependent morphological changes in organoids, including a reduction in size and structural sparsity at higher concentrations. RNA sequencing revealed significant modulation of cell cycle and immune response pathways, with a particular focus on immunomodulatory effects. The formula's treatment targeted key genes involved in these processes, reshaping the tumor's molecular landscape. CONCLUSIONS This study establishes ZMYL's capacity to simultaneously target oncogenic drivers (e.g., cell cycle regulators) and immune checkpoints (e.g., CXCL10-mediated T cell recruitment) in ovarian cancer organoids. Unlike conventional monotherapy-focused approaches, ZMYL's multi-component mechanism offers a synergistic framework for integrating TCM with modern immunotherapies. These findings provide a foundation for future clinical evaluation of ZMYL as a precision medicine strategy to enhance treatment efficacy and mitigate chemoresistance in ovarian cancer.
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Affiliation(s)
- Qi Cao
- Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China
| | | | - Chen Wang
- Shanghai LiSheng Biotech, Shanghai, China
| | - Lanyang Li
- Shanghai LiSheng Biotech, Shanghai, China
| | - Jiping Liu
- Shanghai LiSheng Biotech, Shanghai, China
| | - Jian Zhang
- Shanghai LiSheng Biotech, Shanghai, China
| | | | - Jiaqi Ren
- Shanghai LiSheng Biotech, Shanghai, China
| | - Yanyan Han
- Shanghai LiSheng Biotech, Shanghai, China
| | - Jie Zhang
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Xuhui District, Shanghai, China.
| | - Xinxin Han
- Shanghai LiSheng Biotech, Shanghai, China; Organ Regeneration X Lab, LiSheng East China Institute of Biotechnology, Peking University, Jiangsu, China.
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Marques JP, Soares CA, Carvalho AL, Estrela‐Silva S, Santos LC, Ramos L, Silva E. Portuguese Society of Ophthalmology and Portuguese Society of Human Genetics Joint Clinical Practice Guidelines for Genetic Testing in Inherited Retinal Dystrophies. Clin Genet 2025; 107:600-611. [PMID: 39745089 PMCID: PMC12050251 DOI: 10.1111/cge.14691] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/30/2024] [Accepted: 12/18/2024] [Indexed: 05/06/2025]
Abstract
The Portuguese Society of Ophthalmology and the Portuguese Society of Human Genetics developed clinical practice guidelines to streamline genetic testing for inherited retinal dystrophies (IRDs), underlining the critical role of molecular diagnosis in enhancing patient care. Genetic testing is pivotal in diagnosis, genetic counselling, prognosis and access to clinical trials, and new gene-specific therapies. These guidelines recommend genetic testing in all IRD patients and provide a detailed assessment of available testing methods, ensuring that genetic counselling is integrated into ophthalmic care. Essential to this process is the inclusion of at least one genetic counselling session to effectively communicate and discuss implications of test results with patients and families/carers. Key recommendations include cascade testing to identify at-risk family members and standardisation of variant classification according to international criteria to ensure consistency in diagnosis and care. Ophthalmological follow-up is generally prescribed at intervals of 1-2 years for adults and 6 months for paediatric patients, to monitor disease progression and complications. Paediatric considerations are addressed, reflecting the complexities and ethical concerns associated with testing minors. These guidelines aim to elevate diagnostic accuracy, guide therapeutic decisions and ultimately improve patient outcomes, marking a significant advance in the genetic management of IRDs.
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Affiliation(s)
- João Pedro Marques
- Departament of OphthalmologyHospitais da Universidade de Coimbra (HUC), Unidade Local de Saúde (ULS) Coimbra, E.P.E.CoimbraPortugal
- Clinical and Academic Centre of Coimbra (CACC)CoimbraPortugal
- Clínica Universitária de Oftalmologia, Faculdade de MedicinaUniversidade de Coimbra (FMUC)CoimbraPortugal
| | - Célia Azevedo Soares
- Medical Genetics DepartmentCentro de Genética Médica Dr. Jacinto Magalhães, Unidade Local de Saúde (ULS) Sto António, E.P.E.PortoPortugal
- Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas Abel Salazar (UMIB/ICBAS) and Laboratory for Integrative and Translational Research in Population Health (ITR)Universidade Do PortoPortoPortugal
- Departamento de Ciências MédicasUniversidade de AveiroAveiroPortugal
- i3S – Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
| | - Ana Luísa Carvalho
- Clinical and Academic Centre of Coimbra (CACC)CoimbraPortugal
- Department of Medical GeneticsHospital Pediátrico de Coimbra, Unidade Local de Saúde (ULS) Coimbra, E.P.E.CoimbraPortugal
- Clínica Universitária de Genética MédicaFaculdade de Medicina, Universidade de Coimbra (FMUC)CoimbraPortugal
| | - Sérgio Estrela‐Silva
- Departament of OphthalmologyUnidade Local de Saúde (ULS) São João, E.P.E.PortoPortugal
| | - Luísa Coutinho Santos
- Instituto de Oftalmologia Dr. Gama PintoUnidade Local de Saúde (ULS) São José, E.P.E.LisboaPortugal
| | - Lina Ramos
- Department of Medical GeneticsHospital Pediátrico de Coimbra, Unidade Local de Saúde (ULS) Coimbra, E.P.E.CoimbraPortugal
- Clínica Universitária de Genética MédicaFaculdade de Medicina, Universidade de Coimbra (FMUC)CoimbraPortugal
| | - Eduardo Silva
- Centro de Responsabilidade Integrado de Oftalmologia Pediátrica (CRI‐OftaPed), Hospital Dona EstefâniaUnidade Saúde Local (ULS) São José, E.P.E.LisboaPortugal
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He J, Wong LY, Chen S, Zhang SJ, Chen W, Bai JX, Wang L, Wang XQ, Li SMA, Li Q, Fu XQ, Yu ZL. Inhibition of the PI3K/AKT signaling pathway contributes to the anti-renal cell carcinoma effects of deoxyelephantopin. Biomed Pharmacother 2025; 187:118136. [PMID: 40344699 DOI: 10.1016/j.biopha.2025.118136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/17/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025] Open
Abstract
Renal cell carcinoma (RCC) is the most common kidney cancer. Despite advances in treatment, current therapeutic strategies are often limited by side effects, drug resistance, and low response rates, necessitating alternatives for RCC treatment. Deoxyelephantopin (DEO), a sesquiterpene lactone from Elephantopi Herba, has demonstrated anticancer properties in multiple cancer models; however, its effects on RCC remain unknown. This study aimed to investigate the anti-RCC effects of DEO and its underlying molecular mechanisms. Human RCC cell lines (786-O, Caki-1, A498) and a murine RCC cell line (RENCA) were used for in vitro assays. Results revealed that DEO dose-dependently inhibited cell viability and colony formation in 786-O, Caki-1, A498, and RENCA cells, while also inducing apoptosis in 786-O and Caki-1 cells. A RENCA allograft mouse model was used for in vivo assays. DEO significantly suppressed tumor growth without causing notable changes in body weight, organ coefficients, or serum biochemical markers (ALT, AST, BUN, Cr). Network pharmacology analysis predicted the PI3K/AKT signaling pathway as a key mediator of DEO's anti-RCC effects. Western blotting showed that DEO downregulated the expression of EGFR, p-EGFR (Tyr1068), PI3K p110α, p-Akt (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), 4E-BP1, p-4E-BP1 (Thr37/46), HIF-1α, and Bcl-2. Overactivation of AKT attenuated DEO's inhibitory effects on cell viability in 786-O cells. In conclusion, this study is the first to demonstrate that DEO exerts anti-RCC effects in both cellular and animal models, primarily through inhibition of the PI3K/AKT pathway. These findings suggest that DEO holds promise as a lead compound for RCC management.
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Affiliation(s)
- Jinjin He
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Lut Yi Wong
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Si Chen
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Shi-Jia Zhang
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Wei Chen
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Jing-Xuan Bai
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Li Wang
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Xiao-Qi Wang
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Sze-Man Amy Li
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong
| | - Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Xiu-Qiong Fu
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
| | - Zhi-Ling Yu
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China.
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11
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Honarmand H, Bonyadi M, Barzegar M. Genetic insights into progressive myoclonic epilepsies: A case study of KCTD7 mutation in an Iranian-Azeri-Turkish family. Epilepsy Behav Rep 2025; 30:100757. [PMID: 40123863 PMCID: PMC11925558 DOI: 10.1016/j.ebr.2025.100757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/25/2025] Open
Abstract
Progressive Myoclonic Epilepsies (PMEs) are a rare and heterogeneous group of epileptic disorders often with progressive neurologic deterioration. The intensity of the clinical features varies depending on the underlying genetic etiology. This study aims to identify the genetic mutation associated with PME in a family belonging to the Iranian-Azeri-Turkish ethnic population. A 5-year-old boy and his 8-year-old sister, presenting with PME-related electroclinical features such as myoclonic seizures and progressive cognitive and motor decline, underwent comprehensive clinical evaluations, including pedigree analysis, laboratory tests, and EEG assessments, followed by Whole-Exome Sequencing (WES) to identify potential disease-causing mutations. We identified a novel homozygous mutation (c.14C > T) in the KCTD7 gene in both siblings, confirmed through Sanger sequencing. This mutation was not observed in a cohort of 430 healthy individuals from the same Iranian-Azeri-Turkish ethnic background, providing strong evidence for its pathogenic role. This finding advances our understanding of the genetic basis and phenotypic diversity of PMEs, but further research is needed to elucidate how KCTD7 mutations contribute to epilepsy and neurodegeneration.
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Affiliation(s)
- Haneieh Honarmand
- Animal Biology Dept., Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mortaza Bonyadi
- Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Barzegar
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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12
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Li X, Liu X, Cai M, Wei S, Wang R, Xu N, Qu J, Wang Y. Investigation of the mechanism of Dan Zhi Qing'e Formula for treating menopausal hot flashes using UHPLC-Q-TOF MS and network pharmacology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04277-7. [PMID: 40434420 DOI: 10.1007/s00210-025-04277-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 05/07/2025] [Indexed: 05/29/2025]
Abstract
This study aims to investigate the material basis and underlying mechanisms of action of the Dan Zhi Qing'e Formula in the treatment of menopausal hot flashes. The composition analysis of the Dan Zhi Qing'e Formula was conducted using UHPLC-Q-TOF MS, facilitated by MassLynx V4.1 software. Subsequently, Cytoscape 3.10.1 was employed to merge the data with information from Swiss, GeneCards, and OMIM databases to identify the active components and primary targets. GO and KEGG analyses were performed to elucidate the potential mechanisms of action. Finally, the molecular docking technique was applied to validate the results. A total of 118 components, 73 blood-absorbed components, and 89 potential targets were identified. Seven key targets were obtained, which were aldose reductase (AKR1B1, UniProtKB: P15121), carbonic anhydrase 4 (CA4, UniProtKB: P22748), carbonic anhydrase 2 (CA2, UniProtKB: P00918), acetylcholinesterase (ACHE, UniProtKB: P22303), estrogen receptor beta (ESR2, UniProtKB: Q92731), cytochrome P450 19A1 (CYP19A1, UniProtKB: P11511), and matrix metalloproteinase-2 (MMP2, UniProtKB: P08253). Molecular docking studies indicate that these core components exhibit strong affinity for the identified targets. These targets contribute to the tonic function of the liver and kidneys through hormone response. The findings provide a scientific foundation for further in-depth research into the therapeutic mechanisms of Dan Zhi Qing'e Formula for menopausal hot flashes.
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Affiliation(s)
- Xinyu Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, West Zone Tuanbo New City, Jinghai District, Tianjin, 301617, China
| | - Xinyu Liu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, West Zone Tuanbo New City, Jinghai District, Tianjin, 301617, China
| | - Minghui Cai
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, NO. 88 Changling Road, Xiqing District, Tianjin, 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Shuang Wei
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, West Zone Tuanbo New City, Jinghai District, Tianjin, 301617, China
| | - Rui Wang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, West Zone Tuanbo New City, Jinghai District, Tianjin, 301617, China
| | - Nanjian Xu
- Department of Spine Surgery, No.6 Hospital in Ningbo, 1059# Zhongshan East Road, Ningbo, 315040, Zhejiang Province, People's Republic of China.
| | - Jingtian Qu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, NO. 88 Changling Road, Xiqing District, Tianjin, 300381, China.
| | - Yuming Wang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, West Zone Tuanbo New City, Jinghai District, Tianjin, 301617, China.
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13
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Li X, Chen M, Wei D, Wei P, Jiang Y, Chen J, Duan X, Wang Z, Zhang Y, Bai D, Jia H, Jin G. Study on the Mechanism of Dihydromyricetin in Alleviating Depressive-Like Behavior in Rats Based on Network Pharmacology. Neurochem Res 2025; 50:171. [PMID: 40418429 DOI: 10.1007/s11064-025-04419-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/27/2025]
Abstract
Depression is a chronic and recurrent neuropsychiatric disorder with complex pathophysiology. Dihydromyricetin (DMY), a bioactive flavonoid compound isolated from Ampelopsis grossedentata (commonly known as rattan tea), has demonstrated multiple pharmacological properties including anti-inflammatory, antioxidant, antitumor, and antimicrobial activities. In the present study, a well-established rodent model of depression was generated through chronic unpredictable mild stress (CUMS) paradigm combined with social isolation. Following eight weeks of DMY intervention, comprehensive behavioral assessments were conducted to validate both the successful establishment of the depression model and the therapeutic efficacy of DMY treatment. We employed network pharmacology approaches to systematically predict potential antidepressant targets of DMY. Further mechanistic investigations were performed to elucidate the underlying molecular pathways, providing novel perspectives for developing innovative antidepressant therapeutics.Integrating network pharmacology prediction with molecular biology validation, our findings revealed that DMY exerts significant antidepressant-like effects through suppression of the advanced glycosylation end products (AGEs)-RAGE signaling pathway, activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant defense system, and upregulation of synaptic plasticity-related proteins including postsynaptic density protein 95 (PSD95) and synaptophysin (SYP). These results suggest that DMY may represent a promising natural therapeutic candidate for depression treatment.
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Affiliation(s)
- Xue Li
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Miaoqi Chen
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Decheng Wei
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Pengsheng Wei
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Yanzong Jiang
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Jiaqi Chen
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Xiaomeng Duan
- School of Traditional Chinese Medicine, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Zitong Wang
- School of Pharmacy, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Yuchuan Zhang
- Basic Medical School, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China
| | - Dafeng Bai
- The Eleventh People's Hospital of Shenyang, No. 31 Haitang Street, Shenyang, China.
| | - Hui Jia
- School of Traditional Chinese Medicine, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China.
- Key Laboratory of Behavioral and Cognitive Neuroscience of Liaoning Province, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China.
| | - Ge Jin
- School of Traditional Chinese Medicine, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China.
- Key Laboratory of Behavioral and Cognitive Neuroscience of Liaoning Province, Shenyang Medical College, 146 Huanghe North Street, Yuhong District, Shenyang, 110034, Liaoning, China.
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14
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Bellaart A, Brambila A, Xu J, Mendez Diaz F, Deep A, Anzola J, Meitinger F, Ohta M, Corbett KD, Desai A, Oegema K. TRIM37 prevents ectopic spindle pole assembly by peptide motif recognition and substrate-dependent oligomerization. Nat Struct Mol Biol 2025:10.1038/s41594-025-01562-0. [PMID: 40415024 DOI: 10.1038/s41594-025-01562-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 04/10/2025] [Indexed: 05/27/2025]
Abstract
Tightly controlled duplication of centrosomes, the primary microtubule-organizing centers of animal cells, ensures bipolarity of the mitotic spindle and accurate chromosome segregation. The RING-B-box-coiled coil ubiquitin ligase tripartite motif-containing protein 37 (TRIM37), whose loss is associated with elevated chromosome missegregation and the tumor-prone human developmental disorder Mulibrey nanism, prevents the formation of ectopic spindle poles assembling around structured condensates that contain the centrosomal protein centrobin. Here, we show that TRIM37's tumor necrosis factor receptor-associated factor (TRAF) domain, which is unique in the extended TRIM family, engages peptide motifs in centrobin to suppress condensate formation. TRIM family proteins form antiparallel coiled-coil dimers with RING-B-box domains at each end. Oligomerization resulting from RING-RING interactions and conformational regulation through B-box 2-B-box 2 interfaces are essential for TRIM37 to suppress centrobin condensate formation. These results indicate that, similar to antiviral TRIM ligases, TRIM37 activation is coupled to detection of oligomerized substrates, facilitated by recognition of specific motifs in the substrate, to enforce ubiquitination-mediated clearance of ectopic centrosomal protein assemblies.
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Affiliation(s)
- Andrew Bellaart
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Amanda Brambila
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Jiawei Xu
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Francisco Mendez Diaz
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Amar Deep
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - John Anzola
- Ludwig Institute for Cancer Research, La Jolla, CA, USA
| | - Franz Meitinger
- Ludwig Institute for Cancer Research, La Jolla, CA, USA
- Okinawa Institute of Science and Technology, Onna, Japan
| | - Midori Ohta
- Ludwig Institute for Cancer Research, La Jolla, CA, USA
- Okinawa Institute of Science and Technology, Onna, Japan
| | - Kevin D Corbett
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Arshad Desai
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
| | - Karen Oegema
- Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
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15
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Xiu J, Yang H, Shen X, Xing Y, Li W, Han W. Exploring Hidden Dangers: Predicting Mycotoxin-like Toxicity and Mapping Toxicological Networks in Hepatocellular Carcinoma. J Chem Inf Model 2025. [PMID: 40393043 DOI: 10.1021/acs.jcim.5c00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Mycotoxins are potent triggers of hepatocellular carcinoma (HCC) due to their intricate interplay with cellular macromolecules and signaling pathways. This study integrates machine learning and biomolecular analyses to elucidate the mechanisms underlying mycotoxin-induced hepatocarcinogenesis. Using a data set of 1767 mycotoxins and 1706 non-mycotoxin fungal metabolites, we evaluated 51 machine learning models. The KPGT model achieved optimal performance with an ROC-AUC of 0.979 and balanced accuracy of 0.930. Clustering analysis identified six distinct mycotoxin clusters with unique structural features. Network toxicology analysis revealed distinct protein-protein interaction patterns across different mycotoxin clusters, identifying key regulatory proteins including EGFR, SRC, and ESR1. GO enrichment analysis uncovered cluster-specific effects on protein complexes and macromolecular assemblies, particularly in membrane organization and vesicular transport. KEGG pathway analysis demonstrated systematic perturbation of major signaling cascades, with each mycotoxin cluster distinctly modulating protein kinase networks and receptor tyrosine kinase pathways. Molecular docking analyses validated these interactions, with binding affinities ranging from -9.6 to -4.7 kcal/mol. Notably, cluster 5 showed strong binding to SRC (-9.6 kcal/mol), EGFR (-9.5 kcal/mol), and ESR1 (-7.8 kcal/mol), providing structural insights into toxin-macromolecule recognition. These findings enhance our understanding of mycotoxin-protein interactions in HCC development and suggest potential therapeutic strategies targeting these macromolecular interfaces.
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Affiliation(s)
- Jian Xiu
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Hengzheng Yang
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Xiaoli Shen
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yuenan Xing
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Wannan Li
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Weiwei Han
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
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16
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Sharma Y, Good DJ. Case Study: Genetic and In Silico Analysis of Familial Pancreatitis. Genes (Basel) 2025; 16:603. [PMID: 40428425 PMCID: PMC12110861 DOI: 10.3390/genes16050603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2025] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Chronic pancreatitis (CP) is a progressive inflammatory condition of the pancreas that leads to irreversible changes in pancreatic structure. The pancreatic α and β cells secrete hormones such as insulin and glucagon into the bloodstream. The pancreatic acinar cells secrete digestive enzymes that break down macromolecules. When these digestive enzymes do not function properly, maldigestion, malabsorption, and malnutrition may result. Presented here is a case study of an individual newly diagnosed with chronic pancreatitis, along with a genetic analysis of his son and an in-silico analysis of two of the variant proteins. METHODS This study was conducted using human subjects, namely, the proband (father) and his son. Medical genetic testing of the proband (father) identified the presence of two variants in the cystic fibrosis transmembrane receptor gene (CFTR): variant rs213950, resulting in a single amino acid change (p. Val470Met), and variant rs74767530, a nonsense variant (Arg1162Ter) with known pathogenicity for cystic fibrosis. Medical testing also revealed an additional missense variant, rs515726209 (Ala73Thr), in the CTRC gene. Cheek cell DNA was collected from both the proband and his son to determine the inheritance pattern and identify any additional variants. A variant in the human leukocyte antigen (rs7454108), which results in the HLA-DQ8 haplotype, was examined in both the proband and his son due to its known association with autoimmune disease, a condition also linked to chronic pancreatitis. In silico tools were subsequently used to examine the impact of the identified variants on protein function. RESULTS Heterozygosity for all variants originally identified through medical genetic testing was confirmed in the proband and was absent in the son. Both the proband and his son were found to have the DRB1*0301 (common) haplotype for the HLA locus. However, the proband was also found to carry a linked noncoding variant, rs2647088, which was absent in the son. In silico analysis of variant rs213950 (Val470Met) in CFTR and rs515726209 (Ala73Thr) in CTRC revealed distinct changes in predicted ligand binding for both proteins, which may affect protein function and contribute to the development of CP. CONCLUSIONS This case study of a proband and his son provides additional evidence for a polygenic inheritance pattern in CP. The results also highlight new information on the role of the variants on protein function, suggesting additional testing of ligand binding for these variants should be done to confirm the functional impairments.
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Affiliation(s)
- Yash Sharma
- Department of Biochemistry, Virginia Tech, Blacksburg, VA 24060, USA;
| | - Deborah J. Good
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA 24060, USA
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17
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Sun C, Gao X, Sha S, Wang S, Shan Y, Li L, Xing C, Guan H, Du H. Berberine alleviates Alzheimer's disease by activating autophagy and inhibiting ferroptosis through the JNK-p38MAPK signaling pathway. Int Immunopharmacol 2025; 155:114550. [PMID: 40215776 DOI: 10.1016/j.intimp.2025.114550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 03/19/2025] [Accepted: 03/22/2025] [Indexed: 04/29/2025]
Abstract
INTRODUCTION Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposition, phosphorylated Tau protein aggregation, inflammation, and neuronal damage. Neuronal autophagy plays an important role in ameliorating central nervous system diseases such as AD. As an emerging form of iron-dependent cell death, ferroptosis has attracted great attention in the field of neurodegenerative diseases. Berberine (BBR), a natural alkaloid, has demonstrated excellent in inflammation reduction, inhibition of Aβ production, and neuroprotection, making it a potential candidate for AD treatment. However, the mechanisms of autophagy and ferroptosis in BBR treatment of AD have not been elucidated. OBJECTIVES This study aimed to investigate the potential of BBR in alleviating AD and evaluate its molecular mechanism through a combination of network pharmacology and biological experiments. METHODS We assessed alterations in Aβ plaques, neurons, neuroinflammation, and autophagy-related markers in the mice brain using immunofluorescence staining. Network pharmacology and molecular docking were used to analyze the potential targets and signaling pathways of BBR in the treatment of AD. Morris Water Maze (MWM) and new object recognition (NOR) experiments were used to test the spatial memory ability of mice. In addition, we validated the relationship between JNK-P38MAPK, autophagy, ferroptosis, and BBR treatment in 5xFAD mice and A β-induced SH-SY5Y cell models. RESULTS The results of immunofluorescence staining showed that BBR effectively mitigated Aβ plaque deposition, ameliorated neuronal damage and neuroinflammation. The autophagy-related markers Beclin1 and LC3B were upregulated and P62 was downregulated after BBR treatment. The expression levels of ROS and lipid peroxide MDA decreased significantly after BBR treatment. qPCR results showed that the expression levels of ferroptosis-related genes TFR1, ASCL4, DMT1, and IREB2 were decreased, while the expression levels of FTH1 and SLC7A11 increased after BBR treatment. Behavioral experiments showed that BBR treatment enhanced spatial memory impairment in 5xFAD mice. Network pharmacological and in vitro analyses demonstrated that BBR activated autophagy and inhibited ferroptosis by inhibiting the JNK-P38MAPK signaling pathway. Following treatment with an autophagy inhibitor on SH-SY5Y cells, autophagy was markedly suppressed, and ferroptosis was induced. CONCLUSION In summary, we found that BBR alleviates AD by inhibiting the JNK-P38MAPK pathway to enhance autophagy and inhibit ferroptosis, further reducing Aβ plaque deposition, inhibiting inflammatory response, and improving neuronal damage.
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Affiliation(s)
- Chunbin Sun
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Xiaoyu Gao
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Shuang Sha
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Si Wang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Yubang Shan
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Luping Li
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Cencan Xing
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083,China.
| | - Hongyan Guan
- China Testing & Certification International Group Co., Ltd., Beijing 100024, China.
| | - Hongwu Du
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083,China.
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18
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Lv Q, Chen L, Du Y, Yang P, Chen Q, Qin F, Zhang H, Li Y. Network pharmacology and in vitro experiments based strategy to explore the effects of Jujuboside A on the proliferation and migration ability of glioma cells. Brain Res 2025; 1855:149570. [PMID: 40090447 DOI: 10.1016/j.brainres.2025.149570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVE This study predicted and verified the effects of Jujuboside A (JuA) on the proliferation and migration ability of glioma cells to developing new therapies for glioma treatment. METHODS The druggability of JuA was determined by using cheminformatics. Network pharmacology was used to analyse common targets, biological function and metabolic pathways of JuA against glioma. The core targets of JuA against glioma were validated by using molecular docking. The biological functions of JuA were verified by in vitro experiments. RESULTS Cheminformatics results showed that JuA is possible to be a drug. Network pharmacology revealed 294 shared targets between JuA and glioma, which were associated with proliferation, migration, and multiple signalling pathways. A total of 16 core targets related to the signalling pathways were verified by molecular docking. The in vitro experiments showed that JuA could inhibit cell proliferation and migration, decrease cell numbers and alter cell morphology. CONCLUSION The results of network pharmacology and in vitro experiments indicate that JuA has significant toxic effects on glioma cells, and can play a therapeutic role in treating glioma by inhibiting the proliferation and migration of glioma cells.
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Affiliation(s)
- Quanzhou Lv
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Lin Chen
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Yuan Du
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Peng Yang
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Quanying Chen
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Fayu Qin
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Hongxia Zhang
- Pharmaceutical School, Jilin Medical University, Jilin, Jilin 132013, China
| | - Yan Li
- Basic Medical School, Jilin Medical University, Jilin, Jilin 132013, China.
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Yang F, Luo G, Liu MN, Liu P, Wu D, Chen HL, Li S, Yang SJ, Dong L. Network pharmacology and experimental validation to investigate the mechanism of action of Zhilong Huoxue Tongyu capsule in the prevention and treatment of diabetic cardiomyopathy. PLoS One 2025; 20:e0323745. [PMID: 40373162 DOI: 10.1371/journal.pone.0323745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/12/2025] [Indexed: 05/17/2025] Open
Abstract
BACKGROUND Diabetes cardiomyopathy (DCM) is a prevalent complication of diabetes, characterized by a multifaceted pathogenesis. Zhilong Huoxue Tongyu Capsule (ZL), a traditional Chinese medicine, is extensively employed for the treatment of cardiovascular diseases. Thus, this study aimed to comprehensively explore the mechanism of action of ZL on DCM. METHOD Network pharmacology approaches were applied to predict the potential pathways and targets of ZL on DCM. Then, a DCM model mouse was constructed and divided into a control group, DCM group, DCM + ZL group, SB203580 group, and DCM + R group. The DCM + ZL group was administered 6.24g/kg/d ZL via gavage, the SB203580 group was given 1 mg/kg/d SB203580 (p38MAPK inhibitor) via intraperitoneal injection, the DCM + R group received 4 mg/kg/d rosiglitazone via gavage, and the control group and DCM group were given equal volume of physiological saline by gavage. The intervention period lasted for 6 weeks to verify these key targets. RESULT Network pharmacology analyses identified 45 active ingredients in ZL linked to 719 potential targets, forming an herbal compound-target network. Screening of databases revealed 1032 DCM-related targets, with MAPK14, TNF, FOS, AKT1, and IL-10 emerging as key hub genes from PPI network analysis. Additionally, enrichment analysis indicated that the candidate targets were enriched in response to the MAPK signaling pathway. Finally, in vivo studies in DCM mice demonstrated that ZL significantly mitigated myocardial fibrosis and down-regulated the expression of p-P38MAPK, TNF-α, α-SMA, and Collagen-I proteins in myocardial tissue. CONCLUSION Our results collectively indicated that ZL can effectively ameliorate diabetes cardiomyopathy, possibly by modulating the P38MAPK signaling pathway.
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Affiliation(s)
- Fang Yang
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Gang Luo
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Meng-Nan Liu
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Ping Liu
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Dan Wu
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Hao-Ling Chen
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Shan Li
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Si-Jin Yang
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Li Dong
- National Traditional Chinese Medicine Clinical Research Base and Cardiology department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
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20
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Zhang Q, Yang L, Li C, Zhang Y, Li R, Jia F, Wang L, Ma X, Yao K, Tian H, Zhuo C. Exploring the potential antidepressant mechanisms of ibuprofen and celecoxib based on network pharmacology and molecular docking. J Affect Disord 2025; 377:136-147. [PMID: 39986574 DOI: 10.1016/j.jad.2025.02.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Evidence has shown that ibuprofen and celecoxib are effective in improving depressive symptoms, but their mechanisms of action are unclear. In this study, we aimed to determine the relationship between these two drugs and depressive disorder (DD) and elucidate potential mechanisms of action. METHODS Relevant targets for ibuprofen, celecoxib, and DD were obtained and screened from multiple online drug and disease public databases. A protein-protein interaction network was obtained. The Centiscape and CytoHubba plug-ins were applied to screen for core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed. Molecular docking was performed to predict the binding of ibuprofen and celecoxib to core targets. Examined the differences in core target protein expression between DD patients (DDs, n = 18) and healthy controls (HCs, n = 16) as a further experimental validation of the network pharmacology results. RESULTS In total, 220 potential targets for ibuprofen and 316 potential targets for celecoxib were identified and associated with DD. The antidepressant effects of both drugs involve many key targets in pathways such as "pathways in cancer" and "neuroactive ligand-receptor interaction," including ALB, BCL2, MAPK3, SRC, STAT3, EGFR, and PPARG. The binding affinity of ALB with ibuprofen is the strongest, and it is connected only by hydrophobic interactions. Celecoxib exhibits higher affinity at multiple targets such as SRC, EGFR, and PPARG, with stronger and more specific intermolecular interactions, including salt bridges and halogen bonds. Clinical trials have found that serum ALB expression in DDs is significantly lower than that in HCs (t = 6.653, p < 0.001), further confirming the potential role of ibuprofen in DD. CONCLUSIONS Ibuprofen and celecoxib primarily exert their antidepressant effects through targets and pathways related to inflammation, neural signaling, and cancer, with celecoxib showing a stronger potential antidepressant effect. The expression difference of the core target ALB between depression and healthy individuals further supports the potential effect of the drug on DD. Our findings propose new treatment strategies, support the link between inflammation and depression, and encourage reassessing existing medications for depression.
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Affiliation(s)
- Qiuyu Zhang
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Lei Yang
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Chao Li
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Ying Zhang
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Ranli Li
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Feng Jia
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Lina Wang
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Xiaoyan Ma
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Kaifang Yao
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Hongjun Tian
- Animal Imaging Center (AIC) of Tianjin Fourth Center Hospital, Tianjin Medical University Affiliated Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin 300140, China
| | - Chuanjun Zhuo
- Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, Tianjin 300222, China; Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin 300222, China.
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Sun H, Hao X, Liu H, Zhang S, Han J, Zhang Y, Liu T, Yang X, Wang H, Fan J, Guan Y, Peng N, Xie J, Xia H, Ji X, Xu Y, Zhang J, Wang J, Lan F, Zhang H, Gu X, He Y. Rare damaging variants in the sex differences of congenital heart disease: an exome sequencing study. EBioMedicine 2025; 116:105736. [PMID: 40347836 DOI: 10.1016/j.ebiom.2025.105736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Congenital heart disease (CHD) exhibits a marked male predominance in birth prevalence, yet the genetic mechanisms underlying this sex disparity remain poorly understood. This study investigates the contribution of rare damaging variants on autosomes and the X chromosome to sex differences in foetal CHD. METHODS Parents of foetuses with CHD were recruited for the study. Rare damaging variants were identified by analysing whole-exome sequencing data from foetus-parental trios, and their contributions to sex differences were estimated through case-control studies. Functional enrichment analysis was conducted to assess functional differences in genetic variants between sexes. FINDINGS 820 foetal probands with CHD were recruited, including 487 males and 333 females. We identified a significant enrichment of X-linked rare damaging variants, primarily driven by maternally inherited hemizygous variants (MIHVs) in male probands (OR = 1·84, P < 0·05), which accounted for 7·2% of male cases in our cohort. These variants were not found to be enriched in female probands. Additionally, X-linked rare damaging de novo variants (DNVs) were not enriched in either male or female probands (female probands: 1·8% versus female controls: 0·7%, P = 0·6789; no DNVs observed in males). Gene-level variant burden analysis revealed three X-linked CHD candidate genes: DCX, CACNA1F, and MAP3K15. Autosomal rare variants did not show significant differences in variant burdens between sexes. Notably, male probands showed specific functional enrichments in cilia-related pathways for autosomal recessive variants, as well as in chromatin remodelling and nervous system development pathways for autosomal DNVs. INTERPRETATION Male and female foetal CHD have significantly different genetic landscapes. The enrichment of X-linked rare damaging MIHVs in males provides a genetic explanation for the higher prevalence of CHD in males. This finding highlights the importance of incorporating sex-stratified approaches in clinical diagnostics and research. FUNDING Natural Science Foundation of China and Key research and development project of Hebei Province.
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Affiliation(s)
- Hairui Sun
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Xiaoyan Hao
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Hankui Liu
- BGI-genomics, BGI-Shenzhen, Shenzhen, 518083, China
| | - Siyao Zhang
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Jiancheng Han
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Ye Zhang
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Tingting Liu
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Xian Yang
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Hairui Wang
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Jiaqi Fan
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Yuxuan Guan
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Ni Peng
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Jiaoyang Xie
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
| | - Hongmei Xia
- Department of Ultrasound, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Xueqin Ji
- Department of Ultrasound, Ningxia Women's and Children's Hospital, Beijing University First Hospital (Ningxia Hui Autonomous Region Maternal and Child Health Hospital), Yinchuan, 750004, China
| | - Yan Xu
- Rizhao People's Hospital, Shandong, 276827, China
| | | | - Jianbin Wang
- School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Feng Lan
- Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China
| | - Hongjia Zhang
- Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China
| | - Xiaoyan Gu
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China.
| | - Yihua He
- Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China.
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Eisfeldt J, Ek M, Nordenskjöld M, Lindstrand A. Toward clinical long-read genome sequencing for rare diseases. Nat Genet 2025:10.1038/s41588-025-02160-y. [PMID: 40335760 DOI: 10.1038/s41588-025-02160-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/11/2025] [Indexed: 05/09/2025]
Abstract
Genetic diagnostics is driven by technological advances, forming a tight interface between research, clinic and industry, which enables rapid implementation of new technologies. Short-read genome and exome sequencing, the current state of the art in clinical genetics, can detect a broad spectrum of genetic variants across the genome. However, despite these advancements, more than half of individuals with rare diseases remain undiagnosed after genomic investigations. Long-read whole-genome sequencing (LR-WGS) is a promising technology that identifies previously difficult-to-detect variants while also enabling phasing and methylation analysis and has the potential of generating complete personal assemblies. To pave the way for clinical use of LR-WGS, the clinical genomic community must establish standardized protocols and quality parameters while also developing innovative tools for data analysis and interpretation. In this Perspective, we explore the key challenges and benefits in integrating LR-WGS into routine clinical diagnostics.
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Affiliation(s)
- Jesper Eisfeldt
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
- Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden
| | - Marlene Ek
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
| | - Magnus Nordenskjöld
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Lindstrand
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden.
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Fortunato F, De Fiores R, Sammarra I, Bonacci MC, Caligiuri ME, Sturniolo M, Martino I, Gambardella A. Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study. Epilepsia 2025. [PMID: 40323733 DOI: 10.1111/epi.18442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/18/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025]
Abstract
We aim to determine whether epilepsy can be considered part of the arginine:glycine amidinotransferase (AGAT) deficiency syndrome phenotype and to identify its associated electroclinical signatures. We reviewed clinical data from our center, identifying individuals with AGAT deficiency. Each individual underwent a dedicated epilepsy assessment with electroencephalography and 3-T brain magnetic resonance imaging (MRI). Additionally, 30 age- and sex-matched healthy controls (18 females, 28.2 ± 3.7 years old) were recruited for advanced MRI analysis. A family with four affected members carrying homozygous AGAT c.446>A:p.Trp149* variant was identified. Two individuals had focal epilepsy with sensory seizures characterized by a prominent "tingling" sensation. Three experienced febrile seizures plus and marked temperature sensitivity. Corpus callosum dysmorphisms were observed in three cases. Despite creatine supplementation, cortical thickness was significantly reduced across multiple brain regions compared to controls, as indicated by Z-scores. A brain map of AGAT mRNA expression revealed lower expression in the parieto-occipital areas. Our findings suggest that focal epilepsy with sensory seizures and temperature-related seizures may be part of the AGAT deficiency spectrum. Furthermore, significant brain atrophy was demonstrated, despite creatine supplementation. The sensory-predominant epilepsy phenotype aligns with observed atrophy and AGAT-mRNA regional expression patterns, supporting its biological plausibility.
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Affiliation(s)
- Francesco Fortunato
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
| | - Roberta De Fiores
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
| | - Ilaria Sammarra
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
| | - Maria Celeste Bonacci
- Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Græcia University, Catanzaro, Italy
| | - Maria Eugenia Caligiuri
- Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Græcia University, Catanzaro, Italy
| | - Miriam Sturniolo
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
| | - Iolanda Martino
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
| | - Antonio Gambardella
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
- Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Græcia University, Catanzaro, Italy
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Qi J, Wang Y, Chen H, Wu K, Zhou P, Dou Y, Xiong B, Zhou W. Advancing the Identification of Bioactive Molecules and the Construction of a Synergistic Drug Delivery System in Combating Lung Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407802. [PMID: 40091443 PMCID: PMC12079430 DOI: 10.1002/advs.202407802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 02/17/2025] [Indexed: 03/19/2025]
Abstract
In recent years, pneumonia caused by multiple viruses has posed a significant threat to public health, particularly affecting vulnerable populations such as the elderly and immunocompromised individuals. Current treatments primarily focused on antiviral medications, lacking "miracle cure" and innovative approaches for the pathological damage caused by viruses. Since 2019, Traditional Chinese Medicine (TCM) has shown remarkable efficacy in treating coronavirus disease 2019 (COVID-19). However, the application is hindered by intricate mechanisms, variable quality, and slow onset. Clinically, Ge-Gen Decoction (GGD) effectively reduced the severity in patients with viral infections. Taking COVID-19 as a case, the bioactive ingredients from GGD: glabridin (GLA) and puerarin (PUE) are identified. Interestingly, it was discovered that PUE can self-assemble into a 3D hydrogel structure upon heating and cooling, namely PUE@gel. This process mirrored the formation of gel-like precipitates in GGD post-decoction. Motivated by this phenomenon, a decoction-mimicking drug delivery system, glabridin─puerarin self-assembled hydrogel (GLA-PUE@gel) was constructed, which exhibits strong anti-inflammatory and antioxidant properties, comparable to GGD at the same dosage. Additionally, PUE that has a high biosafety threshold can competitively bind to angiotensin converting enzyme 2 (ACE2) on host cells, preventing SARS-CoV-2 from invading. This study offered a promising approach for treating virus-induced lung injury.
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Affiliation(s)
- Jianhong Qi
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Yanxia Wang
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Huan Chen
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Kaitian Wu
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Pei Zhou
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Yue Dou
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Bingqi Xiong
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
| | - Wei Zhou
- Department of PharmaceuticsChina Pharmaceutical University#24 Tong Jia Xiang, Gulou DistrictNanjing210009China
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He H, Jin X, Ding X, Jiang H, Wang X, Chen Y, Zhu J. Unraveling the Anti-Tumor Effects and Molecular Mechanisms of Hairyvein Agrimonia Herb in Gastric Cancer Through Network Pharmacology and Experimental Validation. Cancer Rep (Hoboken) 2025; 8:e70169. [PMID: 40391580 PMCID: PMC12089993 DOI: 10.1002/cnr2.70169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/24/2024] [Accepted: 02/14/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Stomach cancer has become one of the most common types of cancer, with its mortality rate ranking third in the world. Currently, the main treatments for gastric cancer are surgery, radiation therapy, and chemotherapy. Although current treatments can effectively prevent postoperative metastasis and recurrence of gastric cancer, they may also bring various adverse reactions in the gastrointestinal tract and side effects such as bone marrow suppression. Years of research have confirmed that traditional Chinese medicine treatment for gastric and other cancers has distinct characteristics and advantages. Combined treatment can increase the tumor inhibition rate, reduce the side effects of radiation and chemotherapy, improve patients' quality of life, and prolong the survival prognosis. AIMS This study explores the anti-tumor effect and specific molecular mechanism of Hairyvein Agrimonia Herb on gastric cancer. METHODS AND RESULTS The combination of network pharmacology technology and various experimental techniques, including in vitro cell verification, was carried out throughout the whole study. The results show that five active components in the Hairyvein Agrimonia Herb can act on 160 carcinogenic targets in gastric cancer. String correlation analysis, Cytoscape network topology analysis, core target screening, protein molecule docking, immunohistochemical expression levels, and survival immune correlation analysis revealed that the carcinogenic genes JUN, HIF1A, and PTGS2 may be the primary drug targets for Hairyvein Agrimonia Herb in treating gastric cancer. The active component quercetin shows the best inhibitory effect on the docking of the PTGS2 protein. Furthermore, the prognostic models constructed by the carcinogenic genes JUN, HIF1A, and PTGS2 are significantly correlated with the survival time of gastric cancer patients. CONCLUSION This study provides a new ethical basis and research direction for understanding the mechanism of action of Hairyvein Agrimonia Herb in treating gastric cancer.
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Affiliation(s)
- Hequn He
- Emergency DepartmentThe First Hospital of Haishu DistrictNingbo City
| | - Xiaohui Jin
- Emergency DepartmentThe First Hospital of Haishu DistrictNingbo City
| | - Xiaoyun Ding
- Gastroenterology DepartmentThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Haizhong Jiang
- Gastroenterology DepartmentThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Xuguang Wang
- Emergency DepartmentThe First Hospital of Haishu DistrictNingbo City
| | - Yi Chen
- Emergency DepartmentThe First Hospital of Haishu DistrictNingbo City
| | - Jiyun Zhu
- Hepatopancreatobiliary Surgery DepartmentThe First Affiliated Hospital of Ningbo UniversityNingboChina
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Radjasandirane R, Diharce J, Gelly JC, de Brevern AG. Insights for variant clinical interpretation based on a benchmark of 65 variant effect predictors. Genomics 2025; 117:111036. [PMID: 40127826 DOI: 10.1016/j.ygeno.2025.111036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/20/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
Single amino acid substitutions in protein sequences are generally harmless, but a certain number of these changes can lead to disease. Accurately predicting the effect of genetic variants is crucial for clinicians as it accelerates the diagnosis of patients with missense variants associated with health problems. Many computational tools have been developed to predict the pathogenicity of genetic variants with various approaches. Analysing the performance of these different computational tools is crucial to provide guidance to both future users and especially clinicians. In this study, a large-scale investigation of 65 tools was conducted. Variants from both clinical and functional contexts were used, incorporating data from the ClinVar database and bibliographic sources. The analysis showed that AlphaMissense often performed very well and was in fact one of the best options among the existing tools. In addition, as expected, meta-predictors perform well on average. Tools using evolutionary information showed the best performance for functional variants. These results also highlighted some heterogeneity in the difficulty of predicting some specific variants while others are always well categorized. Strikingly, the majority of variants from the ClinVar database appear to be easy to predict, while variants from other sources of data are more challenging. This raises questions about the use of ClinVar and the dataset used to validate tools accuracy. In addition, these results show that this variant predictability can be divided into three distinct classes: easy, moderate and hard to predict. We analyzed the parameters leading to these differences and showed that the classes are related to structural and functional information.
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Affiliation(s)
- Ragousandirane Radjasandirane
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics team, F-75015 Paris, France
| | - Julien Diharce
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics team, F-75015 Paris, France
| | - Jean-Christophe Gelly
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics team, F-75015 Paris, France
| | - Alexandre G de Brevern
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics team, F-75015 Paris, France.
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Pandey H, Sharma J, Kumar S, Mohan N, Jain V, Dhua AK, Yadav DK, Dubey AK, Choudhury P, Goel P. Chromosomal Microarray Analysis in Spina Bifida: Genetic Heterogeneity and Its Clinical Implications. J Indian Assoc Pediatr Surg 2025; 30:290-295. [PMID: 40406313 PMCID: PMC12094595 DOI: 10.4103/jiaps.jiaps_217_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/26/2024] [Accepted: 12/10/2024] [Indexed: 05/26/2025] Open
Abstract
Background The etiology of spina bifida is multifactorial; the phenotype is the end result of both genetic and environmental influences. While whole exome sequencing has identified several pathogenic variants in Indian cohorts, the role of chromosomal imbalances and long contiguous stretches of homozygosity (LCSHs) remains largely unexplored in this population. Chromosomal microarray analysis (CMA) is an important tool that provides insights into such genetic aberrations, making it significant for evaluating patients with spina bifida. Objective To identify LCSHs and chromosomal imbalances in three spina bifida patients through CMA analysis as a pilot investigation. Materials and Methods Genomic DNA was isolated from three spina bifida patients (P1: 10-year-old female, P2: 1-year-old male, and P3: 2.8-year-old male) and subjected to CMA using the Affymetrix 750K high-density array platform. The submicroscopic chromosomal imbalances and LCSHs were cross-referenced with public databases (Database of Genomic Variants, ClinVar, and OMIM) to evaluate their clinical significance. Functional annotations of the affected genes were performed to understand their role in neural tube development. Results CMA revealed significant LCSH on chromosomes 2, 3, and 7 involving the genes SOX11, WNT7A, FZD9, SEMA3A, and VHL, all of which are involved in neural tube closure. Mosaic Klinefelter syndrome (25.9% mosaicism) was identified in the second patient while the third patient had a normal genetic profile. The detection of significant genetic variations in two of three cases underscores the potential utility of CMA in spina bifida patients. Conclusions This study has generated valuable insights into the complex genetic landscape underlying the multifactorial etiopathogenesis of spina bifida. The findings not only underscore the importance of an integrated approach but also support the cause of a platform for large-scale investigations in the Indian population.
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Affiliation(s)
- Himani Pandey
- Laboratory Head, Redcliffe Laboratories, Noida, Uttar Pradesh, India
| | - Jyoti Sharma
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sourabh Kumar
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Nakul Mohan
- Laboratory Head, Redcliffe Laboratories, Noida, Uttar Pradesh, India
| | - Vishesh Jain
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Anjan Kumar Dhua
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Devendra Kumar Yadav
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Kumar Dubey
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Prativa Choudhury
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prabudh Goel
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
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Yan Z, Zhang L, Ma T, Yuan Y, Kang Y, Liu S, Chen B, Li K, Xiao M, Xie Y. SuoquanYishen formula improves renal cellular senescence by inhibiting YTHDF1-Rubicon axis to promote autophagy in diabetic kidney disease. Front Pharmacol 2025; 16:1543277. [PMID: 40371338 PMCID: PMC12075247 DOI: 10.3389/fphar.2025.1543277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/14/2025] [Indexed: 05/16/2025] Open
Abstract
SuoquanYishen formula (SQYSF), a traditional Chinese herbal prescription for treating diabetic kidney disease (DKD), has demonstrated clinical efficacy in lowering blood glucose and alleviating renal damage. Emerging evidence implicates cellular senescence as a critical contributor to DKD progression. This study aimed to elucidate the mechanism by which SQYSF improves renal cellular senescence using both in vivo (db/db mice) and in vitro (high glucose-induced HK-2 cells) DKD models, with interventions involving SQYSF aqueous extract and SQYSF-containing serum. We screened 59 chemical compounds by UHPLC-QTOF-MS and used network pharmacology approach to discover that autophagy and cellular senescence are important pathways for pharmacological treatment of disease. Experimental validation demonstrated that senescence and damage occurred in the kidneys of db/db mice and HK-2 cells under high glucose environment, and SQYSF ameliorated these abnormal changes. Then, we also found that SQYSF enhanced autophagy in renal tissues and cells, whereas co-treatment with the autophagy inhibitor Bafilomycin A1 abolished SQYSF's anti-senescence effects. Notably, DKD progression was associated with elevated Rubicon expression at mRNA and protein levels, accompanied by increased m6A modification. While SQYSF effectively downregulated Rubicon mRNA and protein expression, it did not influence m6A modification levels. Further investigation identified that SQYSF was able to target to reduce YTHDF1 expression level. Overexpression of YTHDF1 in HK-2 cells increased Rubicon mRNA stability and protein expression, while concurrently reversing SQYSF-induced autophagy enhancement and senescence amelioration. These results suggest that SQYSF exerts its role in ameliorating renal cellular senescence in DKD by targeting to reduce the expression level of YTHDF1, which inhibits the level of Rubicon mRNA and protein translation, and thus promotes autophagy. Our results reveal the active components and mechanisms of SQYSF for the treatment of DKD, which may provide useful information to guide the clinical application of SQYSF as well as the therapeutic pathway for DKD.
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Affiliation(s)
- Zijie Yan
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
| | - Lin Zhang
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
| | - Tianpeng Ma
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
| | - Yong Yuan
- Sanya Hospital of Traditional Chinese Medicine, Sanya, Hainan, China
| | - Yu Kang
- Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Shuman Liu
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
| | - BoCen Chen
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Kai Li
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
| | - Man Xiao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
- Hainan Provincial Key Laboratory for human reproductive medicine and Genetic Research & Hainan Provincial Clinical Research Center for Thalassemia & Key Laboratory of Reproductive Health Diseases Research and Translation, Ministry of Education, Hainan Medical University, Haikou, Hainan, China
| | - Yiqiang Xie
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, China
- The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
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Hong J, Guo Z, Huang X, Wu P, Chen X, Liu X, Yang J, Lai Y. Pharmacological mechanisms of probenecid for SARS-CoV-2 and RSV co-infection: findings of system pharmacology, molecular docking, molecular dynamics simulation, and structure-activity relationship. Front Microbiol 2025; 16:1552603. [PMID: 40371107 PMCID: PMC12075369 DOI: 10.3389/fmicb.2025.1552603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/10/2025] [Indexed: 05/16/2025] Open
Abstract
Background The clinical consequences of the co-infection with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) are not optimistic. Nevertheless, there is currently no approved therapeutic regimen specifically targeting SARS-CoV-2/RSV co-infection, with existing monotherapies showing limited efficacy. According to recent studies, probenecid has both anti-SARS-CoV-2 and anti-RSV effects. Therefore, as one probable molecular candidate for the co-infection with SARS-CoV-2 and RSV, probenecid was researched in this exploration. Methods Using systems pharmacology and bioinformatics, we characterized the targets associated with probenecid for the treatment of SARS-CoV-2/RSV co-infection, focusing on their biological functions, mechanisms and binding activities. To further validate these findings, we conducted molecular docking, MD simulations, electrostatic potential mapping, and SAR analysis to explore the binding interactions between probenecid and the identified core targets. Results We identified 141 targets that overlapped with the co-infection and probenecid, and used these shared targets to construct a protein-protein interaction (PPI) network. Subsequently, we obtained the top 16 hub targets of probenecid for SARS-CoV-2/RSV co-infection, namely, AKT1, ALB, EGFR, CASP3, CTNNB1, SRC, HSP90AA1, and so on. According to the enrichment analysis, probenecid might affect inflammation, immunity, oxidative stress, and virus defenses; Toll-like receptor, TNF, IL-17, NOD-like receptor, cytokine-cytokine receptor, among others. Additionally, based on molecular docking analysis, probenecid is effectively bound to the targets related to the SARS-CoV-2/RSV co-infection. Meanwhile, according to molecular dynamics (MD) simulations and structure-activity relationship (SAR) analysis, we speculated that SRC and HSP90AA1 are more likely to be the target proteins of probenecid than the other proteins. Conclusion Our findings from systems pharmacology and bioinformatics analysis indicate that immune and inflammatory responses play a pivotal role in the therapeutic effects of probenecid. Infectious disease-related pathways also contribute significantly to its effectiveness in treating SARS-CoV-2/RSV co-infection. Further validation was conducted through molecular docking, MD simulations, electrostatic potential mapping, and SAR analysis. These analyses suggest that SRC and HSP90AA1 are the potential binding targets of probenecid. This study provides valuable preliminary insights into the molecular mechanisms of probenecid. It establishes a strong foundation for future research to explore its potential as a therapeutic strategy for SARS-CoV-2/RSV co-infection.
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Affiliation(s)
- Junbin Hong
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhendong Guo
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - XiaoMei Huang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peng Wu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinying Chen
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoyi Liu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinghua Yang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanni Lai
- School of Medicine and Health, Shunde Polytechnic, Foshan, China
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30
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Lu Q, Tian W, Cheng Y, Chen Z, Cao Y, Zhao H, Tong Z, Chang Y, Zhou Y. Metabolomics and network pharmacology reveal the anti-inflammatory core substances and mechanisms of a new cultivar of high-polyphenol lettuce. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025. [PMID: 40298069 DOI: 10.1002/jsfa.14270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Diet plays a significant role in mitigating inflammation, with lettuce and its polyphenols showing potential for improving inflammatory conditions. However, research on the material basis and mechanisms of action remains unclear. RESULTS This study investigated the primary components and anti-inflammatory effects of the new lettuce cultivar Binfen-1, which is rich in polyphenols and may offer enhanced health benefits. There were 65 metabolites with significant changes in Binfen-1 by metabolomics, comprising mainly polyphenols. Meanwhile, the high-polyphenol lettuce extract (HPLE) from Binfen-1 demonstrated superior antioxidant and anti-inflammatory effects in vitro. Moreover, HPLE showed a significant improvement in mice with dextran sodium sulfate-induced ulcerative colitis. By integrating network pharmacology with high-performance liquid chromatographic quantitative results, isoquercitrin and chlorogenic acid were identified as the core active substances in HPLE, and the PI3K-Akt, MAPK, and JAK-STAT pathways were the key anti-inflammatory pathways for HPLE, supported by mRNA validation and molecular docking predictions. CONCLUSION The core anti-inflammatory substances in HPLE were isoquercitrin and chlorogenic acid, with the key anti-inflammatory pathways being the PI3K-Akt, MAPK, and JAK-STAT pathways. These findings substantially propel the understanding of the therapeutic potential of lettuce in the treatment of inflammatory diseases. © 2025 Society of Chemical Industry.
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Affiliation(s)
- Qianshan Lu
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Wenxuan Tian
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yanzhe Cheng
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Zitian Chen
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yu Cao
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Haiying Zhao
- Zhejiang Jiameishan Plant Technology Co., Shanghai, People's Republic of China
| | - Zhou Tong
- Zhejiang Jiameishan Plant Technology Co., Shanghai, People's Republic of China
| | - Yaning Chang
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yingjun Zhou
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, People's Republic of China
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Niu Q, Zhang T. Synergistic mechanism of olaparib and cisplatin on breast cancer elucidated by network pharmacology. Sci Rep 2025; 15:14800. [PMID: 40295796 PMCID: PMC12038030 DOI: 10.1038/s41598-025-99741-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/22/2025] [Indexed: 04/30/2025] Open
Abstract
Cisplatin is an important chemotherapeutic agent is widely used to treat breast cancer and olaparib is the most studied PARP inhibitor to date. To explore the combinational anti-cancer potential and synergistic mechanism of Olaparib and cisplatin in breast cancer using network pharmacology. Drugs targets were drawn from PharmMapper, DrugBank, BATMAN-TCM, DrugCentral, STITCH, Swiss Institude of Bioinformatics and Comparative Toxigenomics Database (CTD). Breast cancer targets were extracted from OMIM, KEGG, GeneCards and DrugBank. The protein-protein interaction (PPI) network was created using the STRING database. Core targets were selected by incorporating PPI networks using Cytoscape 3.9.1. GO and KEGG analyses were performed to investigate common targets of Olaparib and cisplatin in breast cancer. The drug-disease-target network contained 82 nodes and 901 edges. The common targets obtained from Olaparib, cisplatin and breast cancer were identified, including ATK, p53, caspase-3, HSP90AA1, IL-6, IL-1β, ANXA5, SIRT1, caspase-9 and PARP. Core targets were primarily related to response to reactive oxygen species, regulation of apoptotic signaling pathway, regulation of DNA metabolic process, and regulation of cell activation. The KEGG pathway analysis revealed that Olaparib and cisplatin may affect breast cancer through platinum drug resistance and longevity regulating pathway. Furthermore, Olaparib combined with cisplatin downregulated the expression of caspase-3 and caspase-9 proteins and upregulated p53, PARP, and SIRT1 protein levels in MCF-7 cells. Functionally, the cooperative effect of Olaparib and cisplatin reduced the applied concentration of cisplatin and enhanced the anticancer effect, emphasizing the importance of combination therapy to overcome side effects and significantly improve the anticancer efficacy of cisplatin.
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Affiliation(s)
- Qiang Niu
- Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Tao Zhang
- Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, 266001, Shandong Province, China.
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32
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Bai T, Hu Y, Zhou J, Luo L, Liu Y, Yu C. Therapeutic effects and potential mechanisms of caffeine on obese polycystic ovary syndrome: bioinformatic analysis and experimental validation. Sci Rep 2025; 15:14640. [PMID: 40287474 PMCID: PMC12033246 DOI: 10.1038/s41598-025-93890-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 03/10/2025] [Indexed: 04/29/2025] Open
Abstract
The risk of PCOS is significantly increased in obese women, and studies have shown that weight loss can improve symptoms of PCOS. Coffee has been shown to be effective in reducing body weight. In this study, we focused on the SLC16A6 gene using bioinformatics and searched for coffee and its monomers using reverse network pharmacology. The gene expression omnibus (GEO) database was searched to screen for differentially expressed genes (DEGs) in PCOS patients. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were then performed. The effects of caffeine on body weight, estrous cycle, ovarian pathology, serum insulin concentration and insulin resistance index, and SLC16A6 transporter gene expression in ovarian tissue of obese PCOS rats were monitored. The common differentially expressed gene SLC16A6 was identified in this study, and animal experiments confirmed the efficacy of caffeine in the treatment of obese PCOS rats. Caffeine can effectively improve the symptoms of obese PCOS rats. The mechanism by which caffeine can treat obese patients with PCOS is related to increasing the expression of the SLC16A6 gene.
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Affiliation(s)
- Tonglin Bai
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
| | - Yue Hu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Naval Medical University, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
| | - Jing Zhou
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China
| | - Ling Luo
- Department of Military and Physical Education Department, Naval Medical University, Shanghai, 200433, China
| | - Yuhuan Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Naval Medical University, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
| | - Chaoqin Yu
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
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Wang C, Huang W, Chen Q, Yang C, Zhu H, Chen X, He Q, Yu X. Exploring the mechanism of Cynanchum paniculatum (Bunge) Kitag's therapeutic strategy for rheumatoid arthritis: integrating network pharmacology, molecular docking and in vivo experiments. J Biomol Struct Dyn 2025:1-15. [PMID: 40269643 DOI: 10.1080/07391102.2025.2494840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 04/04/2024] [Indexed: 04/25/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by joint swelling, cartilage degradation, and joint deformity. The traditional Chinese herb Cynanchum paniculatum (Bunge) Kitag has been utilized in the management of RA, but the underlying mechanisms are unknown. This study utilized network pharmacology analysis to identify 26 active compounds associated with RA treatment and elucidate their interactions with 23 critical targets linked to RA. Subsequently, molecular docking studies revealed eight compounds with the capacity to bind to multiple key targets, with butyl isobutyl phthalate and geranyl acetone emerging as the most promising candidates based on their drug-likeness properties. To validate these findings, a rat model of adjuvant-induced arthritis was employed. Oral administration of geranyl acetone led to a significant reduction in paw swelling and pro-inflammatory markers, including TNF-α, IL-6, IL-1β, and MPO. Furthermore, it resulted in histological improvements in ankle tissues, all without adverse effects on weight or immune organs. Mechanistically, geranyl acetone was found to impede the progression of RA by modulating the TLR4/MyD88/NF-κB signaling pathway. In conclusion, C. paniculatum demonstrates substantial therapeutic potential for RA due to its multi-target and multi-pathway activities. Moreover, geranyl acetone, when used as a standalone agent, exhibits significant promise in alleviating RA symptoms, offering a compelling avenue for further research and potential clinical applications.
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Affiliation(s)
- Chen Wang
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Wangxiang Huang
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Qianzi Chen
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Chenying Yang
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Haiting Zhu
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Xiya Chen
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Qiyi He
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
| | - Xiaodong Yu
- Engineering Research Center of Active Substance and Biotechnology, Ministry of Education, College of Life Science, Chongqing Normal University, Chongqing, China
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Shen YZ, Luo B, Zhang Q, Hu L, Hu YC, Chen MH. Exploration potential sepsis-ferroptosis mechanisms through the use of CETSA technology and network pharmacology. Sci Rep 2025; 15:13527. [PMID: 40253433 PMCID: PMC12009306 DOI: 10.1038/s41598-025-95451-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/20/2025] [Indexed: 04/21/2025] Open
Abstract
As an important self-protection response mechanism of the body, inflammation can not only remove the necrotic or even malignant cells in the body, but also take a series of targeted measures to eliminate the pathogen of foreign invasion and block the foreign substances that may affect the life and health of the body. Flavonoids have known anti-inflammatory, anti-oxidation, anti-cancer and other effects, including glycyrrhizin molecules is one of the representatives. Licochalcone D has known anti-inflammatory and antioxidant properties and is effective in the treatment of a variety of inflammatory diseases. However, the underlying mechanism for the treatment of sepsis remains unclear. In this study, the therapeutic potential of Licochalcone D for sepsis was studied by analyzing network pharmacology and molecular dynamics simulation methods. Sepsis-related genes were collected from the database to construct PPI network maps and drug-targeting network profiles. The potential mechanism of Licochalcone D in sepsis was predicted by gene ontology, KEGG and molecular dynamics simulation. Sixty drug-disease genes were subsequently validated. Go analysis showed that monomeric small molecule Licochalcone D could regulate the process of intracellular enzyme system. The KEGG pathway analysis showed that the signal pathway of the main effect was related to the calcium pathway. The results of intersections with iron death-related target genes showed that ALOX5, ALOX15B and other nine targets all had the effect of possibly improving sepsis, while GSE 54,514, GSE 95,233 and GSE 69,528 were used to analyze the survival rate and ROC curve. Five genes were screened, including ALOX5, ALOX15B, NFE2L2 and NR4A1, HIF1A. The results of molecular docking showed that ALOX5 and Licochalcone D had strong binding activity. Finally, the results of molecular dynamics simulation showed that there was good binding power between drug and target. In the present study, we utilized molecular dynamics simulation techniques to assess the binding affinity between the small-molecule ligand and the protein receptor. The simulation outcomes demonstrate that the binding interface between the ligand and receptor remains stable, with a calculated binding free energy (ΔG) of -32.47 kJ/mol. This signifies a high-affinity interaction between the ligand and receptor, suggesting the long-term stability of the small molecule under physiological conditions. These findings provide critical insights for drug development efforts. This study elucidates the therapeutic potential of Licochalcone D, a traditional Chinese medicine monomer, in improving sepsis through the regulation of ferroptosis, thereby providing a new direction and option for subsequent clinical drug development in the treatment of sepsis.
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Affiliation(s)
- Yu Zhou Shen
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China
| | - Bin Luo
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China
| | - Qian Zhang
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China
| | - Li Hu
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China.
| | - Ying Chun Hu
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China.
| | - Mu Hu Chen
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Sichuan, People's Republic of China.
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Li H, Hu H, Huang X, Zhang J, Che L, Li X, Bagen H, Qiqige W, Guleng W, Tong H. Investigating the mechanism of action of the Mongolian Medicine Areca Thirteen Pill (GY-13) in treating major depressive disorder based on integrated pharmacology. Medicine (Baltimore) 2025; 104:e42217. [PMID: 40258735 PMCID: PMC12014044 DOI: 10.1097/md.0000000000042217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 04/04/2025] [Indexed: 04/23/2025] Open
Abstract
Mongolian Medicine Areca Thirteen Pill (GY-13), a traditional Mongolian medicine, is esteemed for its efficacy in treating Heyi disease. Studies indicate its antidepressant effects on depression model rats induced by chronic stress, but the specific plant extracts (PEs) and their targets remain undetermined. Network pharmacology was applied to identify the key target SLC6A4 and crucial PEs in GY-13 for treating major depressive disorder (MDD). Molecular docking techniques were used to validate the binding capabilities between GY-13 components and SLC6A4. Mendelian randomization was employed to confirm SLC6A4 as a genetically predisposed gene to depression. Molecular dynamics simulations supported the binding affinity between SLC6A4 and PEs Kaempferol and Quercetin. Immunohistochemical techniques were used to confirm the down-regulatory effect of GY-13 on SLC6A4 in an animal model. The key target SLC6A4 and critical PEs Kaempferol and Quercetin in GY-13 were identified for MDD treatment. Strong binding affinity between these PEs and SLC6A4 was demonstrated, and the genetic predisposition of SLC6A4 to depression was confirmed. This study elucidates the molecular mechanisms of GY-13 in treating MDD, highlighting the importance of SLC6A4 and specific PEs Kaempferol and Quercetin in its therapeutic effects.
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Affiliation(s)
- Haotian Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hanqiong Hu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xuejie Huang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiachen Zhang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Limuge Che
- Medicine Innovation Center for Nationalities, Inner Mongolia Medical University, Hohhot, China
| | - Xiaoxuan Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hurile Bagen
- Mongolian Medical College, Inner Mongolia Medical University, Hohhot, China
| | - Wulan Qiqige
- Mongolian Medical College, Inner Mongolia Medical University, Hohhot, China
| | - Wuyunsiri Guleng
- Psychosomatic Medicine Department, Inner Mongolia International Mongolian Hospital, Hohhot, China
| | - Haiying Tong
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Institute of Ethnic Medicine, Beijing University of Chinese Medicine, Beijing, China
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Lei S, Wu Q, Zhang B, Lu M, Xia Y, Li N. Liver-Targeting Nanoparticles GA-MSe@AR Treat NAFLD Through Dual Lipid-Lowering and Antioxidant Efficacy. Int J Nanomedicine 2025; 20:5017-5037. [PMID: 40271147 PMCID: PMC12015739 DOI: 10.2147/ijn.s510577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/04/2025] [Indexed: 04/25/2025] Open
Abstract
Background and Purpose Non-alcoholic fatty liver disease (NAFLD) is prevalent worldwide and lacks effective treatments. Arctiin (AR), a natural product, has shown promise for NAFLD therapy, due to its antioxidant, anti-inflammatory, and inhibition adipogenesis properties. However, its therapeutic efficacy is hindered by low water solubility, poor bioavailability, and inadequate liver targeting. In this study, selenium-based antioxidant nanoparticles were developed to load and deliver AR to the liver for synergistic AR and selenium effective treatment of NAFLD. Methods The therapeutic potential of AR was analyzed by network pharmacology. GA-MSe@AR was synthesized by encapsulating AR within galactose-modified mesoporous selenium nanoparticles (GA-MSe) for liver-specific targeting. The nanoparticle size, chemical structure, and elemental composition were explored. The toxicity, cellular uptake, lysosomal escape, and AR release efficiency of GA-MSe@AR were investigated by in vitro experiments. The liver targeting ability of GA-MSe@AR was evaluated through live imaging. The lipid-lowering and antioxidant activities of GA-MSe@AR were assessed in both in vitro and in vivo NAFLD models. Additionally, its effects on inflammation and pancreatic function were analyzed in vivo. Results Network pharmacology analysis revealed AR may against NAFLD through regulating metabolism, inflammation, and oxidative stress. GA-MSe@AR exhibited low toxicity, efficient cellular uptake, remarkable lysosomal escape ability, and high AR release efficiency in vitro. In both in vitro and in vivo NAFLD models, GA-MSe@AR demonstrated more pronounced lipid-lowering and antioxidant properties than AR and GA-MSe. Additionally, GA-MSe@AR effectively targeted the liver, resulting in a greater decrease in blood glucose, lipids, ALT, AST levels, and reduction liver inflammation, as well as improved pancreatic function in high-fat diet (HFD)-fed mice compared to AR alone. Conclusion The GA-specific modification enhanced liver-targeted accumulation of the selenium-based nanoparticles, enabling precise targeted delivery of AR. GA-MSe@AR demonstrated superior lipid-lowering efficacy and antioxidant activity in a NAFLD mice model. These findings collectively establish GA-MSe@AR as a promising therapeutic candidate for NAFLD treatment.
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Affiliation(s)
- Sheng Lei
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
| | - Qiang Wu
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
| | - Bin Zhang
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
| | - Minqiang Lu
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
| | - Yu Xia
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
| | - Ning Li
- Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China
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Zhao Q, Dong G, Zhang X, Gao X, Li H, Guo Z, Gong L, Yang H. Unraveling the mechanism of core prescription in primary liver cancer: integrative analysis through data mining, network pharmacology, and molecular simulation. In Silico Pharmacol 2025; 13:63. [PMID: 40255256 PMCID: PMC12003234 DOI: 10.1007/s40203-025-00352-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 03/31/2025] [Indexed: 04/22/2025] Open
Abstract
This study aims to identify core Traditional Chinese Medicine compound prescriptions (TCM CPs) for Primary Liver Cancer (PLC) and their underlying mechanisms. A comprehensive search was conducted using China National Knowledge Infrastructure (CNKI) and the Chinese Medical Code V5.0, identifying 151 TCM CPs. Medication frequency and association rules were analyzed with TCMICS V3.0, while active compounds were identified via TCMSP and TCMIP V2.0. Targets were predicted using Swiss Target Prediction, and disease targets from DisGeNET, OMIM, and GeneCards were cross-referenced. A protein-protein interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using DAVID. In the process of studying active compounds, an orthogonal experiment was carried out on the extraction process of relevant herbs. The results of the orthogonal experiment and range analysis showed that for the extraction rate of the extract and the content of paeoniflorin, the decoction cycles had the most significant impact, followed by soaking time and water volume. The optimal extraction conditions were determined as soaking time of 30 min, water volume of tenfold, and 3 decoction cycles. Under these conditions, the extract yield reached 42.49%, and the paeoniflorin content was 73.60 mg/25.02 g crude herb (equivalent to 2.94 mg/g). ANOVA analysis further confirmed the significance of these factors. The results revealed 109 common targets between TCM component targets and disease targets, with key targets including STAT3, SRC, AKT1, HRAS, and PIK3CA. Molecular docking showed strong binding affinities of paeoniflorin and 3,5,6,7-tetramethoxy-2-(3,4,5-trimethoxyphenyl) chromone to PLC targets, with ADME predictions favoring paeoniflorin. Furthermore, Molecular Dynamics (MD) simulations revealed that paeoniflorin maintains stable binding to the target proteins, demonstrating promising conformational stability. The CCK-8 assay demonstrated that the core TCM CP exerted a dose-dependent inhibitory effect on HepG2 cells. After 24 h of intervention, the IC50 values of paeoniflorin and the TCM CP on HepG2 cells were 17.58 μg/mL and 120.5 μg/mL, respectively, which confirmed their anti-proliferative activity against PLC. This study identifies key active compounds and investigates their roles in modulating the Ras/Raf/MEK/ERK, AKT/NF-κB, and JAK-STAT signaling pathways, offering valuable insights into the therapeutic potential of TCM for PLC treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-025-00352-2.
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Affiliation(s)
- Qingsi Zhao
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Gaoyue Dong
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Xinyue Zhang
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Xing Gao
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Hongyu Li
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Zhongyuan Guo
- College of Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046 Henan China
- Institue of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700 China
| | - Leilei Gong
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 China
| | - Hong Yang
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
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Chakraborty A, Devarajan A, Kumar K, C S R, Madhusudhan MS, Ratnaparkhi GS, Kamat SS. Bioinformatics Analysis Identifies Sequence Determinants of Enzymatic Activity for the PHARC-Associated Lipase ABHD12. Biochemistry 2025; 64:1852-1863. [PMID: 40138185 DOI: 10.1021/acs.biochem.4c00865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
In humans, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) is an early onset autosomal recessive neurological disorder caused by deleterious mutations to ABHD12 (α/β-hydrolase domain protein # 12). Biochemically, ABHD12 functions as a lipase and catalyzes the hydrolysis of lysophosphatidylserine (lyso-PS) (lyso-PS lipase). By doing so, it controls the concentrations and signaling pathways regulated by this potent signaling lysophospholipid in the mammalian brain. While genetic mapping efforts have identified over 30 mutations in ABHD12 from human PHARC subjects, the biochemical activity of these pathogenic mutants remains unknown. To understand this, here, we performed an exhaustive bioinformatics survey and collated ABHD12 protein sequences from various organisms across evolution. Next, based on sequence alignments and structural modeling, we identified functionally relevant conserved residues in the ABHD12 protein sequence that are potentially important for its enzymatic activity. To validate these in silico findings, we generated numerous mutants of murine ABHD12, including those associated with human PHARC subjects, and assayed them for their enzymatic activity. Taken together, these complementary in silico and biochemical studies provide the first thorough sequence-function relationship for mammalian ABHD12, especially relevant in the context of PHARC. Finally, our evolutionary analysis identified CG15111 as an ABHD12 ortholog in the fruit fly (Drosophila melanogaster), and enzymatic assays indeed confirmed that recombinant CG15111 has robust lyso-PS lipase activity. Flies serve as an excellent animal system to model various human neurological diseases, and the identification of CG15111 as a Drosophila melanogaster ABHD12 ortholog opens new avenues to study PHARC in fly models.
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Affiliation(s)
- Arnab Chakraborty
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Archit Devarajan
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Kundan Kumar
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Rohith C S
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - M S Madhusudhan
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
- Department of Data Science, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Girish S Ratnaparkhi
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
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Oh KK, Yoon SJ, Eom JA, Lee KJ, Kwon GH, Kim DJ, Suk KT. The assembled decoders to prepare for "bioactive X″ against progressive deterioration of liver disease: From NAFLD to HCC. Eur J Med Chem 2025; 288:117385. [PMID: 39970728 DOI: 10.1016/j.ejmech.2025.117385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 01/07/2025] [Accepted: 01/30/2025] [Indexed: 02/21/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (-12.1 kcal/mol), and IL6- Forsythoside B (-11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.
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Affiliation(s)
- Ki-Kwang Oh
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Sang-Jun Yoon
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Jung-A Eom
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Kyeong Jin Lee
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Goo-Hyun Kwon
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Ki-Tae Suk
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, 24252, South Korea.
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Chen T, Lv D, Rong B, Shi Z, Li X, Jia Z, Gao Z, Zhong C. Phytochemical characterization and therapeutic mechanism of Xialiqi capsule on benign prostatic hyperplasia. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04108-9. [PMID: 40223034 DOI: 10.1007/s00210-025-04108-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/25/2025] [Indexed: 04/15/2025]
Abstract
Benign prostatic hyperplasia (BPH) is a common urological condition prevalent in elderly men. Xialiqi capsule (XLQC), a traditional Chinese patent medicine, is widely used to manage BPH. However, the precise mechanisms underlying XLQC's effectiveness in treating BPH are not well-understood. We aimed to investigate the phytochemical composition and therapeutic mechanisms of XLQC in the treatment of BPH. We conducted a comprehensive investigation that integrated high-performance liquid chromatography-mass spectrometry (LC-MS/MS), network pharmacological analysis, and animal experimental validation to explore potential pharmacodynamic compounds and mechanisms of action for XLQC in BPH treatment. In this study, a total of 12 components targeting eight molecular targets were identified; the major components included Danshensu, salidroside, 6-Acetylcodeine, azelaic acid, and berberine. The targets were CASP3, MMP9, PTGS2, IL6, ESR1, ERBB2, HIF1 A, and epidermal growth factor receptor (EGFR). Enrichment analysis revealed that the molecular targets are mainly through calcium signaling pathway, endocrine resistance, steroid hormone biosynthesis, HIF- 1 signaling pathway, and estrogen signaling pathway regulates cell proliferation and apoptosis as well as oxidative stress response. In vivo animal experiments demonstrated that XLQC effectively inhibited oxidative stress (OS) and cell proliferation by reducing malondialdehyde (MDA), increasing superoxide dismutase (SOD), and inhibiting the expression of Ki- 67 in prostate tissue, thereby improving prostate tissue morphology and reducing prostate index. XLQC can inhibit oxidative stress and cell proliferation, improve the morphology of prostate tissue, reduce the prostate index, and have therapeutic effects on BPH through multi-component, multi-target, and multi-pathway effects.
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Affiliation(s)
- Tengfei Chen
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong Province, China
| | - Dongfang Lv
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Baohai Rong
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong Province, China
| | - Zhuozhuo Shi
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong Province, China
| | - Xiaolin Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhichao Jia
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhaowang Gao
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong Province, China
| | - Chongfu Zhong
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong Province, China.
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Chen Q, Hu Q, Zhang F, Lu W, Yuan Z, Qiao F. Mechanistic evaluation of Jiu Wei Qing Zhi Gao in non-alcoholic fatty liver disease: insights from network Pharmacology and experimental validation. Hereditas 2025; 162:59. [PMID: 40221773 PMCID: PMC11992867 DOI: 10.1186/s41065-025-00427-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
CONTEXT Jiu Wei Qing Zhi Gao (JWQZG), a traditional Chinese medicine (TCM) formulation, is widely utilized in China for managing non-alcoholic fatty liver disease (NAFLD). OBJECTIVE This study aimed to elucidate the therapeutic mechanisms of JWQZG in the management of NAFLD. MATERIALS AND METHODS Network pharmacology was employed to predict the potential mechanisms of JWQZG in NAFLD management. In vivo experiments were conducted using C57BL/6J mice fed a high-fat diet (HFD) for 16 weeks, followed by treatment with JWQZG at three dosages (1.85, 3.7, and 7.4 g/kg/day) or metformin (150 mg/kg/day) for 8 weeks. In vitro studies utilized HepG2 cells exposed to 0.5 mM palmitic acid (PA) for 24 h to establish an NAFLD model, followed by exposure to JWQZG-containing serum at three concentrations for an additional 24 h. Western blot analysis was used to analyze the expression levels of key signaling pathway components. RESULTS Results of network pharmacology analysis identified the insulin signaling pathway as a potential mediator of the protective effects of JWQZG in NAFLD. Treatment with JWQZG markedly reduced hepatic steatosis and improved insulin resistance. This was accompanied by enhanced expression of key components in the insulin signaling pathway, including insulin receptor substrate 1 (IRS1), phosphorylated PI3K (p-PI3K), phosphorylated AKT (p-AKT), and phosphorylated GSK3β (p-GSK3β), compared to the NAFLD model group. CONCLUSIONS These findings provide robust evidence supporting the therapeutic potential of JWQZG in NAFLD and its modulation of the insulin signaling pathway. Furthermore, the study offers valuable insights for the discovery of anti-NAFLD compounds derived from TCM formulations.
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Affiliation(s)
- Qinlei Chen
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China
| | - Qianfeng Hu
- Nanjing University of Chinese Medicine, Nanjing, China, 210046
| | - Fan Zhang
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China
| | - Weiting Lu
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China
| | - Zheng Yuan
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China.
| | - Fei Qiao
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China.
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Ma J, Wei P, Xu X, Dong R, Deng X, Zhang F, Sun M, Li M, Liu W, Yao J, Cao Y, Ying L, Yang Y, Yang Y, Wu X, She G. Machine learning-assisted analysis of serum metabolomics and network pharmacology reveals the effective compound from herbal formula against alcoholic liver injury. Chin Med 2025; 20:48. [PMID: 40217538 PMCID: PMC11992827 DOI: 10.1186/s13020-025-01094-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 03/09/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND The popularity of herbal formulas is increasing worldwide. Nevertheless, the effective compound is challenging to identify due to its intricate composition and multiple targets. METHODS An integration machine learning-assisted approach was established, whereby the particular action mechanism and direct target were obtained through the correlation of compounds, targets, and metabolites. The association between a compound and an action pathway was selected from the shortest path of the "compound-target-pathway-disease" network, which was analyzed using the Floyd-Warshall algorithm. Subsequently, an investigation was conducted into the relationship between metabolites and action pathways, as well as targets, through the analysis of serum metabolomic profiling and the selection of metabolite biomarkers by random forest. In order to accurately identify the direct acting target as well as the most effective compound, the relationship between the compounds and their targets was investigated using a feature-based prediction model conducted by AdaBoost. The binding mode of the effective compound and the direct-acting target was verified by molecular docking, dynamics simulations, and western blotting. In this study, Baiji Wuweizi Granule (BWG) was employed to elucidate the effective compound against alcoholic liver injury (ALD). RESULTS BWG exerted an influence on the serum metabolomic, resulting in the identification of seven potential biomarkers. Furthermore, six effective compounds and the PI3K-AKT signalling pathway were identified through a co-analysis with the shortest path from compound to ALD in the "compound-target-pathway-disease" network. It was postulated that the effective compounds would bind with key targets from the PI3K-AKT signaling pathway, as indicated by the prediction model of compound-target interaction (R2 > 0.95). The dominant bonding type for the effective compounds and key targets was hydrogen bond. These results indicated that AKT1 was the notable target for BWG, and that 2,3,4,7-tetramethoxyphenanthrene was the marker compound for BWG against ALD. The present study provides evidence that the protective effect of BWG on ALD can be mediated by the PI3K-AKT signaling pathway. CONCLUSIONS Our findings demonstrate the value of a machine learning-assisted approach in identifying the key compound, target and pathway that underpin the efficacy of an herbal formula. This provides a foundation for future clinical and fundamental research.
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Affiliation(s)
- Jiamu Ma
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Peng Wei
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Xiao Xu
- Analysis and Test Center, Chinese Academy of Tropical Agricultural Sciences, Haikou, 571101, China
| | - Ruijuan Dong
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Xixi Deng
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Feng Zhang
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Mengyu Sun
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Mingxia Li
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Wei Liu
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Jianling Yao
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Yu Cao
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Letian Ying
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Yuqing Yang
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Yongqi Yang
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China
| | - Xiaopeng Wu
- Analysis and Test Center, Chinese Academy of Tropical Agricultural Sciences, Haikou, 571101, China.
| | - Gaimei She
- Beijing University of Chinese Medicine, Fangshan District, Beijing, 100029, China.
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Zhang J, Deng L, Deng L. Protein structural domain-disease association prediction based on heterogeneous networks. BMC Genomics 2025; 23:869. [PMID: 40211147 PMCID: PMC11987217 DOI: 10.1186/s12864-024-11117-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 12/02/2024] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Domains can be viewed as portable units of protein structure, folding, function, evolution, and design. Small proteins are often found to be composed of only a single domain, while most large proteins consist of multiple domains for achieving various composite cellular functions. A dysfunction in domains may affect the function of proteins in some disease. Inferring the disease-related domains will help our understanding of the mechanism of human complex diseases. RESULTS In this study, we firstly build a global heterogeneous information network based on structural-based domains, proteins, and diseases. Then the topological features of the network are extracted according to the meta-paths between domain and disease nodes. Finally, we train a binary classifier based on the XGBOOST (eXtreme Gradient Boosting) algorithm to predict the potential associations between domains and diseases. The results show that the binary classification model using the XGBOOST algorithm performs significantly better than models using other machine learning algorithms, achieving an AUC (Area Under Curve) score of 0.94 in the leave-one-out cross-validation experiment. CONCLUSIONS We develop a method to build a binary classifier using the topological features based on meta-paths and predict the potential associations between domains and diseases. Based on its predictive performance in independent test sets, the method is proved to be powerful. Moreover, representing domains and diseases through integrating more multi-omic data will further optimize predictive performance.
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Affiliation(s)
- Jingpu Zhang
- School of Computer and Data Science, Henan University of Urban Construction, 467000, Pingdingshan, China
| | - Lianping Deng
- School of Computer Science and Engineering, Central South University, 410075, Changsha, China
| | - Lei Deng
- School of Computer Science and Engineering, Central South University, 410075, Changsha, China.
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Ogloblinsky MSC, Conrad DF, Baudot A, Tournier-Lasserve E, Génin E, Marenne G. Benchmark of computational methods to detect digenism in sequencing data. Eur J Hum Genet 2025:10.1038/s41431-025-01834-9. [PMID: 40204980 DOI: 10.1038/s41431-025-01834-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 03/06/2025] [Accepted: 03/11/2025] [Indexed: 04/11/2025] Open
Abstract
Digenic inheritance is characterized by the combined alteration of two different genes leading to a disease. It could explain the etiology of many currently undiagnosed rare diseases. With the advent of next-generation sequencing technologies, the identification of digenic inheritance patterns has become more technically feasible, yet still poses significant challenges without any gold standard method. Here, we present a comprehensive overview of the existing methods developed to detect digenic inheritance in sequencing data and provide a classification in cohort-based and individual-based methods. The latter category of methods appeared the most applicable to rare diseases, especially the ones not needing patient phenotypic description as input. We discuss the availability of the different methods, their output and scalability to inform potential users. Focusing on methods to detect digenic inheritance in the case of very rare or heterogeneous diseases, we propose a benchmark using different real-life scenarios involving known digenic and putative neutral pairs of genes. Among these different methods, DiGePred stood out as the one giving the least number of false positives, ARBOCK as giving the greatest number of true positives, and DIEP as having the best balance between both. By synthesizing the state-of-the-art techniques and providing insights into their practical utility, this benchmark serves as a valuable resource for researchers and clinicians in selecting suitable methodologies for detecting digenic inheritance in a wide range of disorders using sequencing data.
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Affiliation(s)
| | - Donald F Conrad
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
| | - Anaïs Baudot
- Aix Marseille Univ, INSERM, Marseille Medical Genetics (MMG), Marseille, France
| | - Elisabeth Tournier-Lasserve
- Université Paris Cité, Inserm, NeuroDiderot, Unité Mixte de Recherche 1141, F-75019, Paris, France
- Assistance publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, F-75010, Paris, France
| | - Emmanuelle Génin
- Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France
- Assistance publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, F-75010, Paris, France
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Hu SJ, Chen GC, Wang FY, Fang YQ, Wang SQ, Song ZL, Zhao ZH, Zhang QL, Meng XY, Zhang QY, Qin LP. Network pharmacology analysis uncovers the mechanism of Shudihuang-Shanzhuyu herb pair in prevention and treatment of diabetic osteoporosis via PI3K/AKT pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119581. [PMID: 40054640 DOI: 10.1016/j.jep.2025.119581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/15/2025] [Accepted: 03/02/2025] [Indexed: 03/29/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic osteoporosis (DOP) is a complication of diabetes characterized by reduced bone mass and increased fracture risk. Shudihuang (Rehmanniae Radix Praeparata, RR) and Shanzhuyu (Corni Fructus, CF) form a classical herb pair known as RR-CF in traditional Chinese medicine (TCM) for nourishing Yin and tonifying the kidney, and have long been used for the treatment of diabetes and OP in TCM clinical practise. However, the potential mechanism underlying the preventive and therapeutic effects of RR-CF on DOP has not been clarified. AIM OF THE STUDY This study aimed to explore the protective effects of RR-CF on bone loss caused by diabetes and elucidate the underlying action mechanism. METHODS The chemical constituents in RR-CF were detected using UPLC-Q-Exactive-MS. Type 1 diabetes mellitus (T1DM) was induced in rats by injecting streptozotocin, followed by administration of RR-CF extracts for 10 weeks. Bone mineral density, morphometric bone parameters, and serum and urine biochemical markers were analyzed using Micro-CT and ELISA kits. An in vitro osteoblastic injury model was constructed by subjecting MC3T3-E1 cells to high glucose and used to evaluate the effects of the RR-CF on osteoblastic bone formation. The anti-DOP mechanism of RR-CF was explored by network pharmacologic analysis and then verified in osteoblasts damaged by high glucose. RESULTS A total of 56 compounds were identified in RR-CF. Treatment with RR-CF extracts improved the bone microstructure and mineral density in the T1DM rats, and decreased the level of urine deoxypyridinoline and serum carboxyl terminal peptide of type I procollagen. The network pharmacology analysis identified cornuside, hydroxygenkwanin, acteoside, catalpol and echinacoside as the potential active components of RR-CF against DOP by interacting with the key node genes such as AKT1, EGFR, TNF, MMP9 and HSP90α. Further GO and KEGG enrichment analysis suggested that the therapeutic effects of RR, CF and RR-CF seemed to be related to the regulation of hormones, inflammation and metabolism, as well as signaling transductions of PI3K-AKT, IL-17, TNF, MAPK and estrogen signaling pathways. RR-CF promoted osteoblast differentiation and bone formation in the MC3T3-E1 cells by regulating PI3K-AKT signaling pathway. CONCLUSION RR-CF herb pair inhibits bone loss caused by high glucose by regulating the PI3K-AKT signaling pathways.
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Affiliation(s)
- Si-Jing Hu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Gao-Ce Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Fang-Yuan Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Ying-Qi Fang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Si-Qi Wang
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210000, China
| | - Zi-le Song
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Zi-Hui Zhao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Quan-Long Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiong-Yu Meng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Qiao-Yan Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Lu-Ping Qin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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Özkaya Gül S, Şimşek B, Yıldız F, Aydemir E. Cytotoxic Effect of Escitalopram/Etoposide Combination on Etoposide-Resistant Lung Cancer. Pharmaceuticals (Basel) 2025; 18:531. [PMID: 40283966 PMCID: PMC12030030 DOI: 10.3390/ph18040531] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/26/2025] [Accepted: 03/30/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Antidepressants are a class of pharmaceuticals utilized for the management of many psychiatric disorders, including depression. A considerable number of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), have been documented to demonstrate significant anticancer properties in various cancer cell lines. Objectives: The aim of this study was to evaluate the selective cytotoxic and apoptotic effects of escitalopram oxalate (ES) alone and in combination with etoposide (ET) on ET-resistant A549 (A549/90E) lung cancer cells. Methods: The cytotoxic effects of the drugs were determined by CCK-8, trypan blue, and neutral red assays. Apoptosis was observed by Annexin V fluorescein isothiocyanate (FITC)/PI and mitochondrial membrane potential (ΔΨm) assays. Moreover, the effects of the drugs, alone and in combination, on apoptosis-related proteins, caspase-3, PTEN, and resistance-related P-gP were determined by ELISA. The relationship between drugs and lung cancer was determined with protein-protein interaction (PPI) network analysis. Results: Our results revealed that ES significantly exerted cytotoxic effects on both wild-type and A549/90E cells compared with BEAS-2B cells. The IC50 values of 48.67 and 51.6 μg/mL obtained for ET and ES, respectively, at the end of 24 h of incubation for A549 cells were applied reciprocally for each cell by including BEAS-2B together with the 2xIC50 and ½ IC50 values. The results of each combination were statistically evaluated with combination indices (CIs) obtained using the Compusyn synergistic effect analysis program. Combination doses with a synergistic effect in A549 and A549/90E cells and an antagonistic effect in BEAS-2B cells have been determined as ½ IC50 for ET and ½ IC50 for ES. ET ½ IC50, ES ½ IC50, and an ET ½ IC50 + ES ½ IC50 combination caused 18.37%, 55.19%, and 57.55% death in A549 cells, whereas they caused 44.9%, 22.4%, and 51.94% death in A549/90E cells, respectively. In A549 cells, the combination of ES ½ IC50 and ET ½ IC50 caused increased levels of caspase-3 (p < 0.01) and P-gP (p < 0.001), while PTEN levels remained unchanged. The combination resulted in an increase in caspase-3 (p < 0.001) and PTEN (p < 0.001) amounts, alongside a decrease in P-gP (p < 0.01) levels in A549/90E cells. The death mechanism induced by the combination was found to be apoptotic by Annexin V-FITC and ΔΨm assays. Conclusions: Based on our findings, ES was observed to induce cytotoxic and apoptotic activities in A549/90E cells in vitro. ES in combination therapy is considered to be effective to overcome ET resistance by reducing the amount of P-gP in A549/90E cells.
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Affiliation(s)
| | | | | | - Esra Aydemir
- Department of Biology, Faculty of Science, Akdeniz University, Antalya TR-07058, Turkey; (S.Ö.G.); (B.Ş.); (F.Y.)
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Chowdhury MR, Reddy RVS, Nampoothiri NK, Erva RR, Vijaykumar SD. Exploring bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson's disease. Metab Brain Dis 2025; 40:169. [PMID: 40184012 DOI: 10.1007/s11011-025-01585-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 03/17/2025] [Indexed: 04/05/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share overlapping molecular mechanisms, including estrogen signaling dysregulation, oxidative stress, and neuroinflammation. Standard treatments often lead to adverse effects due to unintended cross-talk with the estrogen signaling pathway. Identifying key regulatory genes and bioactive plant-derived compounds that modulate estrogen signaling without interfering with standard therapies offers a promising neuroprotective strategy. A network medicine and systems biology approach was used, beginning with the screening of 29 medicinal plants for ALS and 49 for PD, identifying 12 shared plants with neuroprotective potential. Bioactive compounds were screened for gene, protein, and pathway interactions, leading to target prediction (846 ALS-related and 690 PD-related targets) and disease association mining, which identified 93 overlapping genes (OGs). Protein-protein interaction (PPI) network analysis and MCODE clustering revealed ESR1, EGFR, and SRC as key hub-bottleneck (HB) genes, further validated via differential gene expression analysis. Gene ontology (GO) and pathway enrichment analyses revealed significant enrichment in estrogen signaling confirming the involvement of HB genes in neurodegenerative disease progression. Differential expression analysis confirmed ESR1 upregulation in ALS but downregulation in PD, suggesting a converse disease-specific regulatory pattern. Gene regulatory network (GRN) analysis identified hsa-miR-145-5p (ALS) and hsa-miR-181a-5p (PD) as key regulators, while FOXC1, GATA2, and TP53 emerged as crucial transcription factors (TFs) influencing disease progression. Molecular docking and MD simulations validated strong and stable interactions of Eupalitin (CYP19A1, -9.0 kcal/mol), Hesperetin (ESR1, -8.1 kcal/mol), and Sumatrol (PIK3CA, -8.9 kcal/mol). These phytochemicals, derived from Rosmarinus officinalis, Artemisia scoparia, Ocimum tenuiflorum, and Indigofera tinctoria, maintained stable hydrogen bonding and hydrophobic interactions for over 30% of a 25 ns simulation, supporting their therapeutic potential. The identification of ESR1, EGFR, and SRC as key targets, alongside estrogen signaling involvement, highlights the need for targeted nutraceutical interventions. These findings pave the way for safer, plant-based therapies that mitigate neurodegeneration while preserving estrogen signaling integrity, offering a promising adjuvant strategy alongside existing treatments.
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Affiliation(s)
- Mayank Roy Chowdhury
- Department of Biotechnology, National Institute of Technology, Tadepalligudem, Andhra Pradesh, 534101, India
| | - Ramireddy Venkata Sai Reddy
- Department of Biotechnology, National Institute of Technology, Tadepalligudem, Andhra Pradesh, 534101, India
| | - Navaneeth K Nampoothiri
- Department of Biotechnology, National Institute of Technology, Tadepalligudem, Andhra Pradesh, 534101, India
| | - Rajeswara Reddy Erva
- Department of Biotechnology, National Institute of Technology, Tadepalligudem, Andhra Pradesh, 534101, India
| | - Sudarshana Deepa Vijaykumar
- Department of Biotechnology, National Institute of Technology, Tadepalligudem, Andhra Pradesh, 534101, India.
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Li K, Zhang Y, Diao Y, Fan S. Paeonol regulates the DDIT4-mTOR signaling pathway in macrophages to promote diabetic wound healing. Int Immunopharmacol 2025; 151:114347. [PMID: 39987633 DOI: 10.1016/j.intimp.2025.114347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Diabetic foot ulcers are a common complication in people with diabetes, and patients with severe disease are at risk of amputation. Current studies have found that one of the reasons for the difficulty in healing diabetic foot ulcers is the Abnormal polarization of the M1/M2 phenotype of macrophages, which leads to a prolonged inflammatory period of the wound. The aim of this study was to investigate whether paeonol can promote the polarization of macrophages towards the M2 type and whether M2 type macrophages can regulate the DDIT4-mTOR signaling pathway and slow down the inflammatory response of diabetic foot ulcers. METHODS C57BL/6 mice were used to establish an animal model of diabetic foot ulcers and the effect of paeonol on wound healing was investigated. The effects of paeonol on wound healing of foot ulcer in diabetic mice were evaluated using histological staining and immunohistochemistry. The molecular mechanism of refractory healing of foot ulcers was speculated through network pharmacology. The effects of Paeonol on phenotypic polarization of macrophages and the mechanism of inhibiting inflammation were studied by q-PCR, ELISA, immunofluorescence and Western. RESULTS Paeonol can effectively promote wound healing in diabetic mice. HE staining showed that paeonol could improve the inflammatory infiltration in the ulcer wound of diabetic mice; Masson trichromatic staining showed that paeonol could increase the increase of muscle fibers and collagen in the wound tissue of diabetic mice; immunofluorescence results showed that paeonol could increase the angiogenesis in the wound tissue of diabetic mice. Network pharmacological analysis showed that the molecular mechanism of paeonol in treating diabetic wound healing may be through DDIT4-mTOR signaling pathway. q-PCR, ELISA, immunofluorescence and Western blot showed that paeonol could reduce the expression of the signature protein CD86 and inflammatory factors in M1 macrophages, and promote the phenotypic polarization of M2 macrophages, which is the mechanism of inhibiting inflammation by activating DDIT4-mTOR signaling pathway. CONCLUSION Paeonol can promote the polarization of macrophages towards M2 type, reduce inflammatory response and accelerate wound surface healing through DDIT4-mTOR signaling pathway, providing a new therapeutic strategy for the treatment of diabetic foot ulcers.
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Affiliation(s)
- Kun Li
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China.
| | - Yingying Zhang
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China
| | - Yunpeng Diao
- College of Pharmacy, Dalian Medical University, Dalian 116044, China; Dalian anti-infective traditional Chinese Medicine Development Engineering Technology Research Center, China
| | - Shuyuan Fan
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China.
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Chen J, Wen F, Zhou J, Tan M. Evaluating the Mechanism Underlying Multi-Compound Synergy of Banxia Decoction in the Treatment of Hashimoto's Thyroiditis Based on Network Pharmacology and Molecular Docking. Int J Gen Med 2025; 18:1887-1902. [PMID: 40196382 PMCID: PMC11972970 DOI: 10.2147/ijgm.s502321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/09/2025] [Indexed: 04/09/2025] Open
Abstract
Objective We aimed to utilize network pharmacological analysis and molecular docking to elucidate the potential mechanisms of Banxia Decoction (BD) action in the treatment of Hashimoto's thyroiditis (HT). Materials and Methods Active compounds and HT-related targets were predicted using databases and the intersection of the results was taken. STRING and DAVID 6.8 tools were used to obtain the protein-protein interaction (PPI) network and perform GO and KEGG evaluations, respectively. Discovery Studio 2017 R2 was utilized to perform molecular docking and RT-qPCR was conducted to confirm hub gene expressions in clinical samples. Results A total of 136 active compounds in BD were screened, and 74 potential targets related to HT were identified in BD. Further, 17 key targets in the PPI network were identified and HIF1A, EP300, PRKCA, and TERT were included for subnet analysis. Next, a network of "Chinese medicine-active compound-potential target-signal pathway" was obtained and the HIF-1 signaling pathway was identified as the key pathway. Finally, 8 active compounds and their stable binding to target proteins were confirmed by molecular docking; MAPK3, SRC, TERT, and HIF1A were upregulated in HT relative to the goiter samples. Conclusion The integration of network pharmacology and molecular docking provides a systematic framework for exploring the multi-component and multi-target characteristics of BD in HT, underscores the therapeutic potential of BD in HT by targeting genes and pathways involved in immune regulation and oxidative stress. These findings not only enhance our understanding of BD's pharmacological mechanisms but also lay the groundwork for the development of novel therapeutic strategies for HT.
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Affiliation(s)
- Jian Chen
- Department of Gastroenterology Medical Center and Thyroid Gastrointestinal Hernia Surgery, Digestive Disease Medical Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 412000, People’s Republic of China
| | - Fang Wen
- Department of Intensive Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 412000, People’s Republic of China
| | - Juan Zhou
- Department of Respiratory and Critical Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University, Zhuzhou, Hunan, 412000, People’s Republic of China
| | - Miduo Tan
- Department of Breast Surgery, Digestive Disease Medical Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 412000, People’s Republic of China
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Hu W, Wang H, Gan L, Lin Y, Fu Y, Tan W, Dou X, Ye L. Sulfonation of Capsaicin by sulfotransferases produces an anti-inflammatory metabolite with NF-κB pathway modulatory activity. Fitoterapia 2025; 182:106463. [PMID: 40090597 DOI: 10.1016/j.fitote.2025.106463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/18/2025]
Abstract
Capsaicin (CAP), the principal bioactive component of chili peppers (Capsicum annuum L.), is widely recognized for its anti-inflammatory properties. However, its oral bioavailability is low, likely due to extensive sulfonation metabolism. Despite the well-known pharmacological benefits of CAP, the role of sulfotransferase (SULT)-mediated sulfonation in modulating its therapeutic effects remains poorly understood. This study aims to elucidate the sulfonate metabolic profile of CAP, investigate the anti-inflammatory role of its sulfonate metabolite (CAP-S), and uncover the mechanisms underlying CAP-S's anti-inflammatory effects. In our study, the mono-sulfonate metabolite of CAP, designated as CAP-S ((E)-N-[(4-sulfo-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), is identified using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and proton nuclear magnetic resonance (1H-NMR). The metabolic profile of CAP was investigated in liver S9 fractions from human, rat, and mouse samples, with sulfonation of CAP examined using seven major recombinant SULT isoforms. The results demonstrate that CAP is primarily catalyzed by SULT1A subfamily and SULT1E1. The anti-inflammatory effects of CAP-S are evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and an acute liver injury (ALI) mouse model. CAP-S significantly reduces inflammatory mediators and nitric oxide (NO) production in LPS-induced RAW264.7 cells. In vivo, CAP-S treatment alleviates hepatocyte necrosis, inflammatory cell infiltration, and reduces aspartate aminotransferase, alanine aminotransferase, and malondialdehyde levels, while enhancing superoxide dismutase activity and decreasing NO production. Additionally, CAP-S exerts comparable anti-inflammatory effects to CAP by suppressing NF-κB p65 phosphorylation and reducing pro-inflammatory cytokines, as evidenced by network pharmacology and western blot assays. These findings underscore the role of sulfonation in modulating CAP's therapeutic potential.
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Affiliation(s)
- Wanyu Hu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hongyu Wang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Lili Gan
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yating Lin
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yufang Fu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Weiling Tan
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xianrui Dou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan 528300, China.
| | - Ling Ye
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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