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Vijayan S, Margesan T. The potential of Abrus precatorius leaves in arthritis alleviation computational approaches through lC-MS analysis. Future Sci OA 2025; 11:2483131. [PMID: 40131221 PMCID: PMC11938972 DOI: 10.1080/20565623.2025.2483131] [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: 03/02/2024] [Accepted: 02/20/2025] [Indexed: 03/26/2025] Open
Abstract
AIM This study explores the therapeutic potential of Abrus precatorius leaves in arthritis treatment using computational methods and LC-MS analysis. METHODS The plant material was taxonomically authenticated, and phytochemical analysis identified bioactive compounds such as alkaloids, flavonoids, and triterpenoids. RESULTS Swiss ADME analysis confirmed that multiple compounds complied with Lipinski's Rule of Five, while OSIRIS software indicated minimal toxicity. PASS analysis predicted anti-inflammatory and antioxidant activities. Molecular docking simulations of Abrine with key rheumatoid arthritis (RA) targets revealed strong binding affinities, suggesting potential mechanisms for RA treatment. CONCLUSION This research highlights the medicinal potential of Abrus precatorius leaves and emphasizes the importance of computational tools in understanding their pharmacological properties for arthritis management.
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Affiliation(s)
- Sukanya Vijayan
- Department of Pharmacognosy, SRM College of Pharmacy, SRMIST, Chengalpattu, Tamil Nadu, India
| | - Thirumal Margesan
- Department of Pharmacognosy, SRM College of Pharmacy, SRMIST, Chengalpattu, Tamil Nadu, India
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2
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Zulkifli NA, Nor Azmi NJ, Yusop N, Mohamad S. Unveiling the cytotoxicity of Trichomonas tenax: Pathogenic mechanisms and implications for oral health. Microb Pathog 2025; 204:107578. [PMID: 40228755 DOI: 10.1016/j.micpath.2025.107578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/25/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Affiliation(s)
- Nurin Aqilah Zulkifli
- School of Dental Sciences, Universiti Sains Malaysia, Health Campus, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Nurin Jazlina Nor Azmi
- School of Dental Sciences, Universiti Sains Malaysia, Health Campus, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Norhayati Yusop
- School of Dental Sciences, Universiti Sains Malaysia, Health Campus, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Suharni Mohamad
- School of Dental Sciences, Universiti Sains Malaysia, Health Campus, 16150, Kubang Kerian, Kelantan, Malaysia.
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3
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Xie H, Li W, Han X, Li M, Zhao Q, Xu Y, Su H, Meng W. Identification of RIPK3 as a target of flavonoids for anti-necroptosis in vitro. Bioorg Chem 2025; 161:108503. [PMID: 40328155 DOI: 10.1016/j.bioorg.2025.108503] [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: 02/15/2025] [Revised: 04/16/2025] [Accepted: 04/20/2025] [Indexed: 05/08/2025]
Abstract
Receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, has emerged as an important target for therapeutic intervention. Flavonoids are natural compounds known for their anti-inflammatory and antioxidant properties, with recent studies highlighting their potential to modulate necroptosis. In this study, we explored the potential of RIPK3 as a target for flavonoids to achieve anti-necroptosis and anti-inflammatory effects. A library of 63 flavonoids was tested for RIPK3 binding and kinase inhibition using fluorescence polarization (FP) competition assay and ADP-Glo kinase activity assay. Six flavonoids, including scutellarein, robinetin, baicalin, myricetin, baicalein, and tricetin, showed significant inhibition of RIPK3, with IC50 values ranging from 2.5 to 13.7 μM. Structural studies of tricetin and robinetin through co-crystallization and molecular docking revealed distinct binding modes of these flavonoids within the ATP-binding pocket of RIPK3. The anti-necroptosis effects of these flavonoids were further evaluated in human HT-29 cells and mouse embryonic fibroblasts (MEFs) using a TSZ-induced cell death assay, resulting in EC50 values in the tens of micromolar range. Western blot analysis demonstrated that these flavonoids inhibit the phosphorylation of RIPK3 and its downstream effector, mixed lineage kinase domain-like protein (MLKL), and disrupt the formation of RIPK1 and RIPK3 aggregates in the necroptosis pathway. These findings identify RIPK3 as a target of natural flavonoids for the first time and elucidate the molecular mechanism underlying the anti-necroptotic activity of these flavonoids.
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Affiliation(s)
- Hang Xie
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wanchen Li
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo 315100, China
| | - Xiaoyu Han
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Minjun Li
- Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Qiang Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yechun Xu
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Haixia Su
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Weihua Meng
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo 315100, China; Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD2 4BF, UK; Center for Public Health, Faculty of Medicine, Health and Life Sciences, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT12 6BA, UK.
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Gounder SK, Chuturgoon AA, Ghazi T. Exploring the cardiotoxic potential of fumonisin B1 through inflammatory pathways and epigenetic modifications: A mini review. Toxicon 2025; 261:108374. [PMID: 40286825 DOI: 10.1016/j.toxicon.2025.108374] [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: 02/10/2025] [Revised: 04/15/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
This review is centered around the cardiotoxic effects of fumonisin B1 (FB1), particularly its impact on sphingolipid metabolism, inflammation, and epigenetics. FB1 is a mycotoxin produced by Fusarium fungi, which mainly contaminates cereal grains and poses an adverse health risk to both humans and animals; however, its disease-causing capabilities remain to be uncovered, specifically its ability to exacerbate and cause cardiovascular disease. It disrupts sphingolipid metabolism by inhibiting ceramide synthase, leading to cellular dysfunction and contributes to conditions such as hypertension and eventual heart failure. FB1 is responsible for an altered inflammatory response, whereby it increases pro-inflammatory cytokines such as IL-6 and IL-1β, which contribute to cardiovascular diseases. Moreover, FB1 induces significant epigenetic changes, including DNA hypermethylation, histone modifications such as increased H3K9me2 and H3K9me3, inhibition of histone acetyltransferase activity, and changes in microRNA expression profiles. These epigenetic alterations can silence or activate inflammatory genes, exacerbating disease progression. This review thus highlights the need for further research to elucidate the connections between FB1, inflammation, epigenetic modifications, and cardiotoxicity, which could lead to better strategies for managing FB1-related adverse health risks.
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Affiliation(s)
- Selwyn Kyle Gounder
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa
| | - Anil Amichund Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa.
| | - Terisha Ghazi
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa.
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5
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Zhang Q, Zhou Q, Li H. Action and mechanisms of neferine in inflammatory diseases (Review). Mol Med Rep 2025; 32:174. [PMID: 40242976 PMCID: PMC12046375 DOI: 10.3892/mmr.2025.13539] [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: 09/28/2024] [Accepted: 02/17/2025] [Indexed: 04/18/2025] Open
Abstract
Neferine is a bisbenzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera, a traditional Chinese medicine. It has been extensively studied for its therapeutic potential in various disease models. Extensive research has highlighted its diverse pharmacological activities, including antitumor, anti‑inflammatory, anti‑fibrosis, anti‑oxidative stress, anti‑platelet aggregation and anti‑arrhythmic effects. The present review, however, focuses on the anti‑inflammatory properties of neferine, emphasizing its fundamental mechanisms as demonstrated in both in vivo and in vitro studies. By critically evaluating its effect on inflammation and the underlying pathways, this review aims to provide a comprehensive understanding of the potential of neferine in the management of inflammatory diseases. Furthermore, it seeks to establish a foundational framework for the future development of neferine as a novel therapeutic agent for inflammatory conditions.
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Affiliation(s)
- Qin Zhang
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
| | - Qiaoling Zhou
- Department of Nephropathy, Xiangya Hospital Central-South University, Changsha, Hunan 410028, P.R. China
| | - Huihui Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
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Jaouhari Y, Bordiga M, Travaglia F, Coisson JD, Costa-Barbosa A, Sampaio P, Botelho C, Gullón B, Ferreira-Santos P. Microwave-assisted extraction of raspberry pomace phenolic compounds, and their bioaccessibility and bioactivity. Food Chem 2025; 478:143641. [PMID: 40058250 DOI: 10.1016/j.foodchem.2025.143641] [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: 11/21/2024] [Revised: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 04/06/2025]
Abstract
Raspberry pomace (RBP) is rich in phenolic compounds. This study aims to optimize the extraction of phenolics from RBP and assess their bioaccessibility and bioactivity. The extraction process revealed that ethanol 50 % was the most effective solvent. Microwave-assisted hydroethanolic extraction (MAE) significantly outperformed conventional methods, with optimal conditions of 200 °C for 10 min yielding the highest concentrations of total phenolics (68 mg GAE/g RBP) and flavonoids (63 mg RE/g RBP). Eleven phenolic compounds were identified by HPLC-ESI-MS, with gallic acid and protocatechuic acid being the most prevalent. The gastrointestinal digestion revealed that although some phenolics suffered degradation (like ferulic acid and quercetin), phenolics are more bioaccessible and have relevant antioxidant activity. RBP extract exhibited anti-inflammatory activity by downregulating pro-inflammatory IL-1β and upregulating anti-inflammatory IL-10 cytokines in LPS-activated macrophages. These findings underscore the effectiveness of MAE in extracting bioactives from RBP, highlighting its potential in developing functional foods and nutraceuticals.
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Affiliation(s)
- Yassine Jaouhari
- Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100 Novara, Italy
| | - Matteo Bordiga
- Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100 Novara, Italy
| | - Fabiano Travaglia
- Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100 Novara, Italy
| | - Jean-Daniel Coisson
- Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100 Novara, Italy
| | - Augusto Costa-Barbosa
- Centre of Molecular and Environmental Biology (CBMA) / Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; Institute of Science and Innovation for Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Paula Sampaio
- Centre of Molecular and Environmental Biology (CBMA) / Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; Institute of Science and Innovation for Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Cláudia Botelho
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Beatriz Gullón
- Department of Chemical Engineering, Faculty of Science, University of Vigo (Campus Ourense), As Lagoas, 32004 Ourense, Spain; IAA - Instituto de Agroecoloxía e Alimentación, University of Vigo (Campus Auga), As Lagoas, 32004 Ourense, Spain
| | - Pedro Ferreira-Santos
- Department of Chemical Engineering, Faculty of Science, University of Vigo (Campus Ourense), As Lagoas, 32004 Ourense, Spain; IAA - Instituto de Agroecoloxía e Alimentación, University of Vigo (Campus Auga), As Lagoas, 32004 Ourense, Spain.
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Lulic I, Lulic D, Pavicic Saric J, Bacak Kocman I, Rogic D. Personalized translational medicine: Investigating YKL-40 as early biomarker for clinical risk stratification in hepatocellular carcinoma recurrence post-liver transplantation. World J Transplant 2025; 15:103036. [DOI: 10.5500/wjt.v15.i2.103036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 02/21/2025] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) presents a significant challenge, with recurrence rates ranging from 8% to 20% globally. Current biomarkers, such as alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), lack specificity, limiting their utility in risk stratification. YKL-40, a glycoprotein involved in extracellular matrix remodeling, hepatic stellate cell activation, and immune modulation, has emerged as a promising biomarker for post-LT surveillance. Elevated serum levels of YKL-40 are associated with advanced liver disease, tumor progression, and poorer post-LT outcomes, highlighting its potential to address gaps in early detection and personalized management of HCC recurrence. This manuscript synthesizes clinical and mechanistic evidence to evaluate YKL-40’s predictive utility in post-LT care. While preliminary findings demonstrate its specificity for liver-related pathologies, challenges remain, including assay standardization, lack of prospective validation, and the need to distinguish between malignant and non-malignant causes of elevated levels. Integrating YKL-40 into multi-biomarker panels with AFP and DCP could enhance predictive accuracy and enable tailored therapeutic strategies. Future research should focus on multicenter studies to validate YKL-40’s clinical utility, address confounding factors like graft rejection and systemic inflammation, and explore its role in predictive models driven by emerging technologies such as artificial intelligence. YKL-40 holds transformative potential in reshaping post-LT care through precision medicine, providing a pathway for better outcomes and improved management of high-risk LT recipients.
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Affiliation(s)
- Ileana Lulic
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Dinka Lulic
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
- Immediate Medical Care Unit, Saint James Hospital, Sliema SLM-1030, Malta
| | - Jadranka Pavicic Saric
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Iva Bacak Kocman
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Dunja Rogic
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, Zagreb 10000, Croatia
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Llach CD, Le GH, Shah H, Marcato LM, Brietzke E, Gill H, Tabassum A, Badulescu S, Rosenblat JD, McIntyre RS, Mansur RB. Peripheral and central inflammation in depression: How large is the gap and can we bridge it with PET neuroimaging and neural-derived extracellular vesicles? J Neuroimmunol 2025; 403:578587. [PMID: 40174479 DOI: 10.1016/j.jneuroim.2025.578587] [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: 07/24/2024] [Revised: 02/28/2025] [Accepted: 03/16/2025] [Indexed: 04/04/2025]
Abstract
Major depressive disorder (MDD) presents as a multifaceted syndrome with complex pathophysiology and variable treatment responses, posing significant challenges in clinical management. Neuroinflammation is known to play pivotal mechanism in depression, linking immune responses with central nervous system (CNS) dysfunction. This review explores the interplay between peripheral and central inflammatory processes in MDD, emphasizing discrepancies in biomarker validity and specificity. While peripheral markers like cytokines have historically been investigated as proxies for neuroinflammation, their reliability remains contentious due to inconsistent findings, lack of correlation with neuroinflammatory markers, the influence of confounding variables, and the role of regulatory mechanism within the CNS. Additionally, the human brain shows a pattern of regionalized inflammation. Current methodologies for investigating neuroinflammation in humans in vivo, including neural-derived extracellular vesicles (EVs) and positron emission tomography (PET) neuroimaging using translocator protein, offer promising avenues while facing substantial limitations. We propose that future research in MDD may benefit from combined microglia-derived EV-TSPO PET neuroimaging analyses to leverage the strengths and mitigate the limitations of both individual methods.
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Affiliation(s)
- Cristian-Daniel Llach
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Gia Han Le
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada
| | - Hiya Shah
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Liz M Marcato
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Elisa Brietzke
- Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada
| | - Hartej Gill
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Aniqa Tabassum
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Sebastian Badulescu
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada
| | - Joshua D Rosenblat
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Rodrigo B Mansur
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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He Y, Huang M, Wang Y, Cai X, Xiao F. Inhibition of CTSC contributes to psoriasis inflammation and keratinocyte hyperproliferation by NF-κB signaling pathway. Int Immunopharmacol 2025; 157:114808. [PMID: 40339488 DOI: 10.1016/j.intimp.2025.114808] [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: 12/28/2024] [Revised: 04/07/2025] [Accepted: 05/03/2025] [Indexed: 05/10/2025]
Abstract
It was found that mutations in the Cathepsin C (CTSC) gene are responsible for Papillon-Lefevre syndrome which has a characteristic clinical feature of palmoplantar hyperkeratosis and psoriasiform lesions. However, its function in psoriasis is unclear so far. This study aims to investigate the roles and mechanisms of CTSC in psoriasis. The expression of CTSC was investigated by the analysis of single cell RNA sequencing (scRNA-seq) data and skin lesions of psoriasis patients. The role of CTSC in psoriasis was analyzed in human immortalized keratinocytes (HaCaT) stimulated with different inflammatory factors and mice of imiquimod (IMQ)-induced psoriasiform dermatitis. We showed that the expression of CTSC was significantly increased in the analysis of scRNA-seq data, which was identified in skin lesions of psoriasis patients and IMQ-induced psoriasis-like mice, and primary human keratinocytes and HaCaT cells stimulated with a cocktail of cytokines. In the presence of inflammatory factors or IMQ, CTSC inhibitor and knockdown of CTSC using siRNA exhibited significantly increased keratinocytes proliferation and the levels of proinflammatory cytokines. In vitro and in vivo experiments further showed that inhibited CTSC in psoriasis could activate the pathway of nuclear factor-κB (NF-κB). This study firstly outlines that inhibition of CTSC can contribute to inflammation and keratinocyte hyperproliferation by NF-κB pathway in psoriasis. It may provide a new perspective on understanding of the pathogenesis of psoriasis.
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Affiliation(s)
- Yue He
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei 230032, Anhui, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei 230032, Anhui, China
| | - Maoxin Huang
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei 230032, Anhui, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei 230032, Anhui, China
| | - Yu Wang
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei 230032, Anhui, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei 230032, Anhui, China
| | - Xinying Cai
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei 230032, Anhui, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei 230032, Anhui, China; Collaborative Innovation Center of Complex and Severe Skin Disease, Anhui Medical University, Hefei 230032, Anhui, China
| | - Fengli Xiao
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei 230032, Anhui, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei 230032, Anhui, China; Collaborative Innovation Center of Complex and Severe Skin Disease, Anhui Medical University, Hefei 230032, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, Anhui, China; The Center for Scientific Research of Anhui Medical University, Hefei 230032, Anhui, China.
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Zoheir KMA, Ali NI, Ashour AE, Kishta MS, Othman SI, Rudayni HA, Rashad AA, Allam AA. Lipoic acid improves wound healing through its immunomodulatory and anti-inflammatory effects in a diabetic mouse model. J Diabetes Metab Disord 2025; 24:56. [PMID: 39868353 PMCID: PMC11759746 DOI: 10.1007/s40200-025-01559-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 10/28/2024] [Indexed: 01/28/2025]
Abstract
Objectives Diabetes mellitus is a chronic disease that has become more prevalent worldwide because of lifestyle changes. It leads to serious complications, including increased atherosclerosis, protein glycosylation, endothelial dysfunction, and vascular denervation. These complications impair neovascularization and wound healing, resulting in delayed recovery from injuries and an elevated risk of infections. The present study aimed to investigate the effect of lipoic acid (LA) on the key mediators involved in the wound healing process, specifically CD4 + CD25 + T cell subsets, CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, T-helper-17 (Th17) cells that generate IL-17 A, glucocorticoid-induced tumor necrosis factor receptor (GITR) expressing cells, as well as cytokines such as IL-2, IL-1β, IL-6, and TNF-α and IFN-γ. These mediators play crucial roles in epidermal and dermal proliferation, hypertrophy, and cell migration. Methods We divided mice into 5 groups: the non-diabetic (normal control; NC), wounded non-diabetic mice (N + W), wounded diabetic mice (D + W), wounded diabetic mice treated with 50 mg/kg lipoic acid (D + W + L50) for 14 days, and wounded diabetic mice treated with 100 mg/kg lipoic acid (D + W + L100) for 14 days. Results Flow cytometric analysis indicated that lipoic acid-treated mice exhibited a significant decrease in the frequency of intracellular cytokines (IL-17 A, TNF-α and IFN-γ) in CD4 + T cells, as well as a reduction in the number of GITR-expressing cells. Conversely, a significant upregulation in the number CD4+, CD25+, FOXp3 + and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells was observed in this group compared to both the normal + wounded (N + W) and diabetic + wounded (D + W) groups. Additionally, the mRNA Levels of inflammatory mediators (IL-2, IL-1β, IL-6, and TNF-α) were downregulated in lipoic acid-treated mice compared to other groups. T thereby he histological findings of diabetic skin wounds treated with lipoic acid showed well-healed surgical wounds. Conclusions These findings support the beneficial role of lipoic acid in fine-tuning the balance between anti-inflammatory and pro-inflammatory cytokines, influencing both their release and gene expression.
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Affiliation(s)
- Khairy M. A. Zoheir
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza 12622 Egypt
| | - Neama I. Ali
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza 12622 Egypt
| | - Abdelkader E. Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Salman International University, Ras Sudr, South Sinai Egypt
| | - Mohamed S. Kishta
- Hormones Department, Medical Research and Clinical Studies Institute, and Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, 12622 Egypt
| | - Sarah I. Othman
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, 11671 Riyadh, Saudi Arabia
| | - Hassan A. Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11623 Saudi Arabia
| | - Ahmed A. Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829 Egypt
| | - Ahmed A. Allam
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11623 Saudi Arabia
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Sahu M, Jain U. Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167764. [PMID: 40088576 DOI: 10.1016/j.bbadis.2025.167764] [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: 09/09/2024] [Revised: 02/15/2025] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1-7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.
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Affiliation(s)
- Mridul Sahu
- School of Health Sciences and Technology (SoHST), UPES, Bidholi, Dehradun - 248007, India
| | - Utkarsh Jain
- School of Health Sciences and Technology (SoHST), UPES, Bidholi, Dehradun - 248007, India.
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12
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Wang J, Miao Z, Gao Y, Xie Z, Liu M, Zou W. Formyl peptide receptor 2: a potential therapeutic target for inflammation-related diseases. Pharmacol Rep 2025; 77:593-609. [PMID: 40102363 DOI: 10.1007/s43440-025-00704-x] [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: 10/09/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 03/20/2025]
Abstract
Formyl peptide receptor 2 (FPR2) is a G protein-coupled receptor with seven transmembrane domains, widely distributed in human cells. It plays a crucial role in inflammation-related diseases. Known for its "double-edged sword" nature, FPR2 can bind a variety of exogenous and endogenous ligands, mediating both pro-inflammatory and anti-inflammatory responses in tissues such as eyes, liver, joints, lungs, nerves, and blood vessels. FPR2's bioactivities are regulated by a complex network of genes and signaling pathways. However, the precise regulatory mechanisms governing its functions in different inflammatory conditions are still not well understood. This review summarizes the FPR2's activities in various inflammation-related diseases and looks into its potential as a therapeutic target. This review highlights recent advances in developing exogenous agonists for FPR2 and discusses receptor expression across species to support nonclinical research. Overall, this review aims to clarify FPR2's role in inflammation and provide insights for the development of new drugs against inflammatory diseases.
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Affiliation(s)
- Jiaying Wang
- School of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Hengyang, 421001, China
| | - Zhishuo Miao
- Key Laboratory of Drug Metabolism Research and Evaluation of the State Drug Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yinhuang Gao
- Key Laboratory of Drug Metabolism Research and Evaluation of the State Drug Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - ZhiZhong Xie
- School of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Hengyang, 421001, China
| | - Menghua Liu
- Key Laboratory of Drug Metabolism Research and Evaluation of the State Drug Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Wei Zou
- School of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Hengyang, 421001, China.
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13
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Zheng Z, Gao J, Ma Y, Hou X. Cellular and Molecular Mechanisms of Phytochemicals Against Inflammation-Associated Diseases and Viral Infection. Cell Biol Int 2025; 49:606-633. [PMID: 40091269 DOI: 10.1002/cbin.70011] [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: 12/13/2024] [Revised: 02/14/2025] [Accepted: 02/18/2025] [Indexed: 03/19/2025]
Abstract
Inflammation-associated diseases have become widespread and pose a significant threat to human health, and the therapeutic methods for diverse diseases are inadequate due to the undesirable effects of synthetic ingredients. Recently, more and more evidence indicated that phytochemicals, plant secondary metabolites, have numerous therapeutic functions against human diseases via affecting a variety of mechanisms with their distinct advantages of high efficiency and low toxicity. Here, we highlight the mechanisms of phytochemicals to hinder inflammation-associated diseases (including Inflammatory diseases, cardiovascular diseases, metabolic syndrome, neurological disorders, skin diseases, respiratory diseases, kidney diseases, gastrointestinal diseases, retinal diseases, viral infections) by regulating the crosstalk among various signal cascades (including MicroRNAs, SIRT1, DNMTs, NF-κB, NLRP3, TGF-β, the Gasdermin-mediated pyroptosis pathway), which can be considered as a novel and potential therapeutic strategy. Furthermore, phytochemicals could prevent virus infection by disturbing different targets in the virus replication cycle. However, natural plants have shown limited bioavailability due to their low water solubility, the use of adjuvants such as liposomal phytochemicals, phytochemical nanoparticles and phytochemicals-phospholipid complex promote their bioavailability to exhibit beneficial effects against various diseases. The purpose of this review is to explore the molecular mechanisms and promising applications of phytochemicals in the fields of inflammation-associated diseases and virus infection to provide some direction.
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Affiliation(s)
- Zhaodi Zheng
- College of Medical Imaging and Laboratory, Jining Medical University, Jining, China
| | - Junying Gao
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, China
| | - Yubing Ma
- College of Medical Imaging and Laboratory, Jining Medical University, Jining, China
| | - Xitan Hou
- College of Medical Imaging and Laboratory, Jining Medical University, Jining, China
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14
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Song Y, Li C, Fang Y, Shen Z, Ge X, Wang R, Xia W, Huang R, Qiu H, Pan H, Hong J. Inflammatory cytokine profile in non-small cell lung Cancer (NSCLC) patients during early enhanced recovery after surgery (ERAS) period and its relation to hospital length of stay. Cytokine 2025; 190:156918. [PMID: 40120149 DOI: 10.1016/j.cyto.2025.156918] [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: 01/13/2025] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 03/25/2025]
Abstract
PURPOSE Immunoregulatory cytokines may play a fundamental role in tumor growth and the acute surgical stress response. Inflammatory cytokine profiles have the potential to serve as biomarkers. This study aimed to correlate tumor- or surgery-related inflammatory cytokine profile, derived from data mining, with clinical data and the hospital length of stay for non-small cell lung cancer (NSCLC) patients during the early enhanced recovery after surgery (ERAS) period. METHODS A multi-phase detection approach was used, involving pre- and post-operative NSCLC patients and matched healthy controls. In the screening phase, plasma levels of 48 cytokines were quantified using a Luminex multiplex bead array to identify tumor- or surgery-related cytokine profiles. In the confirmation phase, differentially expressed cytokines were validated using ELISA with a new set of samples. Tumor-related cytokines were identified by comparing preoperative NSCLC patients with controls, while tumor or surgery-related cytokines were determined by comparing with the same cohort before and after surgery, as well as postoperative patients with controls. We then searched cancer genomics databases and protein atlas resources to investigate cytokine-related RNA expression and RNA-protein interactions. Finally, we integrated and standardized our results, conducting correlation analysis to explore relationships between cytokines, hospital length of stay, and clinical data. RESULTS During the initial phase of the ERAS, a comprehensive array of differential cytokines associated with tumors or surgery, including Eotaxin, IL-1β, IL-1Ra, IL-6, IL-13, IL-16, IP-10, MCP-1, PDGF-BB, RANTES, SCF, and TRAIL, were identified. Preoperative levels of RANTES, urea nitrogen, prognostic-nutritional index, and age may serve as potential indicators for predicting hospital length of stay. CONCLUSION The multi-phase detection analysis has identified a plasma cytokine signature for NSCLC patients during the early ERAS period. Assessment of cytokine profiles and clinical data may reveal unique insights into short-term survival outcome under ERAS.
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Affiliation(s)
- Yongxia Song
- The First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China; School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Chengcheng Li
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Yan Fang
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Ziyi Shen
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Xiaoling Ge
- Department of General Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Rui Wang
- Department of Medical Service, the First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Wanli Xia
- Department of General Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Ruoyu Huang
- Clinical laboratory, the First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Huan Qiu
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China
| | - Huaguang Pan
- Department of General Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, No. 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, China..
| | - Jingfang Hong
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, China; Nursing International Collaboration Research Center of Anhui Province, Hefei, China..
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15
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Kini SU, My Thi Vy H, Subramanian M, Krishnamoorthy PM, Duong SQ, Rocheleau G, Narula J, Do R, Nadkarni GN. Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis. IJC HEART & VASCULATURE 2025; 58:101663. [PMID: 40276302 PMCID: PMC12019459 DOI: 10.1016/j.ijcha.2025.101663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/26/2025]
Abstract
Background The Val30Met (V30M) and Val122Ile (V122I) transthyretin (TTR) mutations often beget hereditary amyloid transthyretin amyloidosis (hATTR). Since symptoms are progressively debilitating and potentially fatal if untreated, low survival rates result from late diagnoses of hATTR patients. This retrospective analysis of microarray and biobank data helped establish clinical biomarkers for early hATTR detection. Methods In a Portuguese sample of V30M carriers (n = 183), gene profiling identified dysregulated immune markers. Among African Americans (AA) and Hispanic/Latinx Americans (HA) from the Mount Sinai BioMe Biobank (n = 28,718), a case-control style Phenome-Wide Association Study (PheWAS; odds ratio [95% confidence interval]) of V122I for phenotypic and echocardiogram traits (β coefficients [95 % CI]) determined gene pleiotropy. Results Among V30M profiles, 96 (52.4%) were symptomatic, expressing upregulated neutrophil activity (p < 10-16), IL-6/JAK/STAT3 signaling (p < 10-3), and downregulated CD4+T cell expression (p = 0.009), compared to their asymptomatic counterparts. In BioMe, 562 (2.0%) were V122I carriers, demonstrating associations with heart failure (1.71 [1.23-2.39]; p = 0.0014), amyloidosis (20.79 [8.42-51.31]; p = 4.67 × 10-11), secondary/extrinsic cardiomyopathies (17.73 [7.25-43.37]; p = 2.97 × 10-10), peripheral nerve disorders (4.14 [2.42-7.09]; p = 2.26 × 10-7), primary angle-closure glaucoma (8.03 [3.15-20.46]; p = 1.27 × 10-5), malignant neoplasm of the female breast (4.48 [2.23-9.00]; p = 2.48 × 10-5), fracture of tibia and fibula (8.42 [3.25-21.89]; p = 1.19 × 10-5), and Carpal tunnel syndrome (2.62 [1.68-4.11]; p = 2.44 × 10-5). Echocardiographic presentations included higher LVEDV (15.87 [9.63-22.10]; p = 6.04 × 10-7) and LA length (1.52 [0.69-2.35]; p = 3.31 × 10-4). Race-stratified associations identified that AA presented more severe cardiac abnormalities than HA. Conclusions This study identified inflammatory biomarkers upregulated in symptomatic V30M carriers and phenotypic/echocardiographic traits associated with V122I, representing comorbidities of hATTR pathology. Such markers can provide the basis for future improvements in diagnostic regimes to deliver early therapies.
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Affiliation(s)
- Sameer U. Kini
- Scarsdale High School, Scarsdale, NY, United States of America
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Ha My Thi Vy
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Madhav Subramanian
- Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, MO, United States of America
| | - Parasuram M. Krishnamoorthy
- Department of Medicine, Division of Cardiology, Mount Sinai Hospital, New York, NY, United States of America
| | - Son Q. Duong
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Division of Pediatric Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Ghislain Rocheleau
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Jagat Narula
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Girish N. Nadkarni
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Division of Data Driven and Digital Medicine (D3M), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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16
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Jayab NA, Abed A, Talaat IM, Hamoudi R. The molecular mechanism of NF-κB dysregulation across different subtypes of renal cell carcinoma. J Adv Res 2025; 72:501-514. [PMID: 39094893 DOI: 10.1016/j.jare.2024.07.030] [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: 04/17/2024] [Revised: 06/27/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND The nuclear factor kappa B (NF-κB) is a critical pathway that regulates various cellular functions, including immune response, proliferation, growth, and apoptosis. Furthermore, this pathway is tightly regulated to ensure stability in the presence of immunogenic triggers or genotoxic stimuli. The lack of control of the NF-κB pathway can lead to the initiation of different diseases, mainly autoimmune diseases and cancer, including Renal cell carcinoma (RCC). RCC is the most common type of kidney cancer and is characterized by complex genetic composition and elusive molecular mechanisms. AIM OF REVIEW The current review summarizes the mechanism of NF-κB dysregulation in different subtypes of RCC and its impact on pathogenesis. KEY SCIENTIFIC CONCEPT OF REVIEW This review highlights the prominent role of NF-κB in RCC development and progression by driving the expression of multiple genes and interplaying with different pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In silico analysis of RCC cohorts and molecular studies have revealed that multiple NF-κB members and target genes are dysregulated. The dysregulation includes receptors such as TLR2, signal-transmitting members including RelA, and target genes, for instance, HIF-1α. The lack of effective regulatory mechanisms results in a constitutively active NF-κB pathway, which promotes cancer growth, migration, and survival. In this review, we comprehensively summarize the role of dysregulated NF-κB-related genes in the most common subtypes of RCC, including clear cell RCC (ccRCC), chromophobe RCC (chRCC), and papillary RCC (PRCC).
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Affiliation(s)
- Nour Abu Jayab
- Research Institute for Medical and Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates
| | - Alaa Abed
- Research Institute for Medical and Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, 27272 Sharjah, United Arab Emirates
| | - Iman M Talaat
- Research Institute for Medical and Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates; Pathology Department, Faculty of Medicine, Alexandria University, 21131 Alexandria, Egypt.
| | - Rifat Hamoudi
- Research Institute for Medical and Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates; BIMAI-Lab, Biomedically Informed Artificial Intelligence Laboratory, University of Sharjah, 27272 Sharjah, United Arab Emirates; Division of Surgery and Interventional Science, University College London, London, United Kingdom; ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, 27272 Sharjah, United Arab Emirates.
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17
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Matos RCD, Bitencourt AFA, Santana PAL, de Oliveira ADM, Inoue TT, Machado BC, Caldeira ASP, Cunha Júnior ADS, Moreira CPDS, Scopel M, Machado RR. Phytochemical profile and biological activities of the hydroethanolic extract of Pouteria guianensis: A pharmacological investigation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119818. [PMID: 40245965 DOI: 10.1016/j.jep.2025.119818] [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: 01/23/2025] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The investigation of Brazil's vast plant biodiversity is crucial. The genus Pouteria, though minimally explored chemically and pharmacologically, has numerous ethnopharmacological reports. AIM OF THE STUDY This study aims to evaluate the antioxidant, anti-inflammatory, antinociceptive, angiogenic, and cytotoxic properties of hydroethanolic extract from the leaves of P. guianensis, as well as to characterize its chemical composition. MATERIAL AND METHODS Several extracts from P. guianensis leaves were evaluated for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) reduction model. Chromatographic analyses and chemometric correlations were also applied. The 80 % hydroethanolic extract was selected and dereplicated using spectrometric techniques, and its anti-inflammatory and antinociceptive activities were assessed through carrageenan-induced paw edema, pain models, and the hot plate test. Antiangiogenic properties were evaluated using the chorioallantoic membrane (CAM) technique and cytokines levels were also measured. RESULTS Chemometric analyses identified myricitrin as a potential active marker for antioxidant activity, with mass spectrometry revealing a high phenolic content, particularly flavonoids quantified at 2.47 % and tannins at 17.19 %. Previous oral administration (p.o.) of the 80 % hydroethanolic extract of P. guianensis demonstrated significant anti-inflammatory and antinociceptive effects without impairing the animals' motor function. The hydroethanolic extract reduced TNF-α and IL-1β levels and also exhibited antiangiogenic properties, suggesting potential mechanisms for its anti-inflammatory action. Furthermore, no toxicity was observed in the CAM model. CONCLUSION This study highlights the significant pharmacological activities of P. guianensis hydroethanolic extract, warranting further investigation into its mechanisms of action. Additionally, it provides the first chemical characterization of the species, revealing a high phenolic content.
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Affiliation(s)
- Rafael Christian de Matos
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil; Centro Especializado Em Plantas Aromáticas, Medicinais e Tóxicas - CEPLAMT-Museu de História Natural e Jardim Botânico da Universidade Federal de Minas Gerais, Rua Gustavo da Silveira 1035, Horto, 31.080-010, Belo Horizonte, MG, Brazil.
| | - Ana Flávia Alvarenga Bitencourt
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
| | - Pedro Augusto Lemos Santana
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
| | | | - Thomas Toshio Inoue
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
| | - Bárbara Charine Machado
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
| | - Alisson Samuel Portes Caldeira
- Grupo Química de Produtos Naturais Bioativos, Instituto René Rachou, Fundacão, Oswaldo Cruz, Avenida Augusto de Lima 1715, Barro Preto, 30190-002, Belo Horizonte, MG, Brazil.
| | - Armando Da Silva Cunha Júnior
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
| | - Carolina Paula de Souza Moreira
- Serviço de Desenvolvimento Tecnológico Farmacêutico, Fundação Ezequiel Dias, Rua Conde Pereira Carneiro 80, Gameleira, 30510-010, Belo Horizonte, MG, Brazil.
| | - Marina Scopel
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil; Centro Especializado Em Plantas Aromáticas, Medicinais e Tóxicas - CEPLAMT-Museu de História Natural e Jardim Botânico da Universidade Federal de Minas Gerais, Rua Gustavo da Silveira 1035, Horto, 31.080-010, Belo Horizonte, MG, Brazil.
| | - Renes Resende Machado
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Campus Pampulha, 31.270-901, Belo Horizonte, MG, Brazil.
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18
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Bernal-Millán MJ, Roa-Coria JE, Flores-Murrieta FJ, Huerta-Cruz JC, Gutiérrez-Grijalva EP, León-Félix J, Angulo-Escalante MA, Heredia JB, Carrasco-Portugal MC. Anti-inflammatory effect of free and microencapsulated extract of Lippia graveolens Kunth in a carrageenan-induced paw edema model and an ovalbumin-induced asthma model in mice. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119905. [PMID: 40306498 DOI: 10.1016/j.jep.2025.119905] [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: 12/18/2024] [Revised: 04/23/2025] [Accepted: 04/28/2025] [Indexed: 05/02/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lippia graveolens Kunth has been widely used in traditional Mexican medicine to relieve stomach pain, menstrual pain, and respiratory illnesses (flu and cough). However, its anti-inflammatory effect has not been studied in acute and chronic inflammation models. AIM OF THE STUDY to evaluate the effect of L. graveolens Kunth extract and microcapsules against paw and airway inflammation. MATERIALS AND METHODS Paw edema in mice was induced with carrageenan, while allergic asthma was sensitized and challenged with ovalbumin. L. graveolens Kunth samples were orally administered to mice in 30, 100, 300, 560, and 717 mg/kg doses to evaluate edema size, while for the following tests, the 560 mg/kg dose was administered. Inflammatory cell count, serum IgE level, and detection of proinflammatory cytokine levels in serum, plantar tissue, and lung tissue were analyzed. RESULTS Edema thickness measurement revealed that L. graveolens Kunth reduces paw inflammation and could potentially be anti-inflammatory in acute and chronic inflammation. Treatments with L. graveolens Kunth significantly decreased the number of inflammatory cells in the blood, the production of IgE in serum, and the cytokines IL-1β, IL-6, and TNF-α levels in serum, paw, and lungs. CONCLUSIONS These findings suggest that L. graveolens Kunth has an anti-inflammatory effect on carrageenan-induced paw edema and ovalbumin-induced allergic asthma in mice and might be a promising protective agent for inflammatory diseases.
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Affiliation(s)
- Manuel J Bernal-Millán
- Centro de Investigación en Alimentación y Desarrollo A.C., Col. Campo el Diez, Culiacán, CP 80110, Sinaloa, Mexico
| | - José E Roa-Coria
- Laboratorio de Farmacología Clínica y Experimental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Secretaría de Salud, Ciudad de México, 14080, Mexico
| | - Francisco J Flores-Murrieta
- Laboratorio de Farmacología Clínica y Experimental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Secretaría de Salud, Ciudad de México, 14080, Mexico; Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina Del Instituto Politécnico Nacional, Ciudad de México, 11340, Mexico
| | - Juan C Huerta-Cruz
- Laboratorio de Farmacología Clínica y Experimental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Secretaría de Salud, Ciudad de México, 14080, Mexico
| | - Erick P Gutiérrez-Grijalva
- Cátedras CONAHCYT-Centro de Investigación en Alimentación y Desarrollo A.C, Col. Campo el Diez, Culiacán, CP 80110, Sinaloa, Mexico
| | - Josefina León-Félix
- Centro de Investigación en Alimentación y Desarrollo A.C., Col. Campo el Diez, Culiacán, CP 80110, Sinaloa, Mexico
| | - Miguel A Angulo-Escalante
- Centro de Investigación en Alimentación y Desarrollo A.C., Col. Campo el Diez, Culiacán, CP 80110, Sinaloa, Mexico
| | - J Basilio Heredia
- Centro de Investigación en Alimentación y Desarrollo A.C., Col. Campo el Diez, Culiacán, CP 80110, Sinaloa, Mexico.
| | - Miriam C Carrasco-Portugal
- Laboratorio de Farmacología Clínica y Experimental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Secretaría de Salud, Ciudad de México, 14080, Mexico.
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19
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de Melo Bisneto AV, de Paiva FEA, Fernandes AS, Roma RR, Silva LS, Chiesi GV, Franchi LP, Cardoso CG, Teixeira CS, Chen-Chen L. Dioclea violacea lectin exerts pro-angiogenic effects by increasing VEGF and TNF-α levels via carbohydrate recognition domain. Cytokine 2025; 192:156966. [PMID: 40424746 DOI: 10.1016/j.cyto.2025.156966] [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: 02/06/2025] [Revised: 05/13/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025]
Abstract
Due to their interesting biological activities, a mannose-binding lectin isolated from Dioclea violacea seeds, known as DvL have attracted considerable attention. In this study, we performed macroscopic, histologic, and immunohistochemical analysis on chicken embryo chorioallantoic membranes (CAM) to investigate the effects of DvL on the angiogenic process. Data showed a potential angiogenic effect of DvL at the highest concentrations tested (50 and 100 μg/mL). This effect was confirmed through increased neovascularization, inflammatory cells, and fibroblasts in histological analysis of the CAM. In addition, the immunohistochemistry of CAM showed that DvL induced secretion of TNF-α and VEGF, important cytokines involved in angiogenesis. Therefore, increased neovascularization may result from a pro-inflammatory response through VEGF and TNF-α secretion. In contrast, the DvL effects on the angiogenic process and the TNF-α and VEGF secretion were significantly reduced by co-incubation with mannose. Thus, protein-carbohydrate interactions between DvL and cell membrane glycans are likely the main events involved in this effect. Therefore, our results demonstrated that DvL is a potent angiogenic agent, suggesting its potential application as a prototype molecule for developing new drugs with healing properties.
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Affiliation(s)
- Abel Vieira de Melo Bisneto
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil; Estacio de Goiás University Center, 74063-010, Goiânia, Brazil
| | - Felipe Eduardo Alves de Paiva
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Amanda Silva Fernandes
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Renato Rodrigues Roma
- Center for Agrarian Sciences and Biodiversity, Federal University of Cariri, 63130-025, Crato, Brazil
| | - Luana Santos Silva
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Giovana Valsani Chiesi
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Leonardo Pereira Franchi
- Department of Biochemistry and Molecular Biology of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Clever Gomes Cardoso
- Department of Morphology of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Claudener Souza Teixeira
- Center for Agrarian Sciences and Biodiversity, Federal University of Cariri, 63130-025, Crato, Brazil
| | - Lee Chen-Chen
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil.
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20
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Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chem Biol Interact 2025; 413:111489. [PMID: 40147618 DOI: 10.1016/j.cbi.2025.111489] [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: 06/02/2024] [Revised: 02/23/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Richard Valko
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Jan Liska
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University, 811 08, Bratislava, Slovakia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic
| | - Kamil Kuca
- Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 5005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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21
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Ortega-Vidal J, Reddy MM, Pérez-Fuentes N, Alvariño R, Burth S, Alfonso A, Vale C, Virués-Segovia JR, Mungkaje A, Botana LM, Thomas OP. Contignasterines, Anti-Inflammatory 2-Aminoimidazole Steroids from the Sponge Neopetrosia cf. rava Collected in the Bismarck Sea. JOURNAL OF NATURAL PRODUCTS 2025; 88:1244-1252. [PMID: 40055660 DOI: 10.1021/acs.jnatprod.5c00118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Sponges of the genus Neopetrosia are known for the production of a large diversity of bioactive metabolites. Contignasterines A (1) and B (2) were isolated as major metabolites of the sponge Neopetrosia cf. rava collected in the Bismarck Sea along with the known and highly bioactive steroid contignasterol (3) possessing a similar oxidized aglycone. Contignasterines are characterized by the presence of a 2-aminoimidazole branched on the side-chains of the oxidized steroid, and 1 also contains an unusual phosphate group at C-7. The anti-inflammatory activities of these compounds were investigated and revealed that all three compounds inhibited the production of pro-inflammatory mediators.
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Affiliation(s)
- Juan Ortega-Vidal
- School of Biological and Chemical Sciences, Ryan Institute, University of Galway, H91TK33 Galway, Ireland
| | - Maggie M Reddy
- School of Biological and Chemical Sciences, Ryan Institute, University of Galway, H91TK33 Galway, Ireland
| | - Nadia Pérez-Fuentes
- Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, Avenida Carballo Calero s/n, 27002 Lugo, Spain
| | - Rebeca Alvariño
- Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, Avenida Carballo Calero s/n, 27002 Lugo, Spain
| | - Svenja Burth
- School of Biological and Chemical Sciences, Ryan Institute, University of Galway, H91TK33 Galway, Ireland
| | - Amparo Alfonso
- Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, Avenida Carballo Calero s/n, 27002 Lugo, Spain
| | - Carmen Vale
- Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, Avenida Carballo Calero s/n, 27002 Lugo, Spain
| | - Jorge R Virués-Segovia
- Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Cádiz, 11001, Spain
- Instituto de Investigación en Biomoléculas (INBIO), Universidad de Cádiz, Cádiz, 11001, Spain
| | - Augustine Mungkaje
- Biological Sciences Discipline, University of Papua New Guinea, P.O. Box 320, University 134, National Capital District, Port Moresby, 9999, Papua New Guinea
| | - Luis M Botana
- Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, Avenida Carballo Calero s/n, 27002 Lugo, Spain
| | - Olivier P Thomas
- School of Biological and Chemical Sciences, Ryan Institute, University of Galway, H91TK33 Galway, Ireland
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22
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Fadaly WAA, Elshewy A, Abusabaa AHA, Amin DME, Abdelhady HK, Haredy HH, Mahmoud AM, Ibrahim NA, Nemr MTM. Novel pyrazole carboxylate derivatives as lonazolac bioisosteres with selective COX-2 inhibition: design, synthesis and anti-inflammatory activity. Mol Divers 2025:10.1007/s11030-025-11220-8. [PMID: 40405028 DOI: 10.1007/s11030-025-11220-8] [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: 03/02/2025] [Accepted: 05/07/2025] [Indexed: 05/24/2025]
Abstract
Two novel series of di-aryl/tri-aryl substituted pyrazole ester derivatives 15a-h and 19a-d were designed, synthesized as novel non-acidic lonazolac analogs and tested for its COX-2, 5-LOX, 15-LOX, iNOS, pro-inflammatory cytokines TNF-α and PGE2 inhibitory activities. All the tested compounds showed excellent COX-2 inhibitory activity (IC50 = 0.059-3.89 μM), compared to that of celecoxib (IC50 = 0.22 μM), where derivatives 15c, 15d, 15 h and 19d were found to be the most potent showing COX-2 selectivity index in range of (S.I. = 28.56-98.71) compared to celecoxib (S.I. = 13.65). Moreover, the most potent four derivatives 15c, 15d, 15 h and 19d showed outstanding 5-LOX and 15-LOX inhibitory activities (IC50 = 0.24-0.81, 0.20-2.2 respectively, compared to zileuton IC50 = 1.52 and 0.54, respectively). Further investigation of the anti-inflammatory mechanistic study of derivatives 15c, 15d, 15 h and 19d revealed that these four compounds exhibited comparable TNF-α and PGE2 (LPS-induced pro-inflammatory cytokines) inhibitory activities (IC50 = 0.77-1.20 μM and 0.28-0.52 μM respectively) when compared to celecoxib (IC50 = 0.87 μM and 0.38 μM respectively) as reference drug using lipopolysaccharide-activated RAW 264.7 macrophages. Based on the advanced inhibitory activity of compounds 15c, 15d, 15 h and 19d against LPS-induced pro-inflammatory mediators (TNF-α and PGE2), inducible nitric oxide synthase (iNOS) inhibition assay was carried out. Remarkably, compounds 15c, 15d, 15 h and 19d showed higher potency with lower IC50 (0.41-0.61 µM) when compared to the reference drug celecoxib (0.48 µM). Prior to in vivo anti-inflammatory activity screening, cytotoxicity testing was performed to ascertain safe and non-toxic concentrations of each compound. Safe doses of compounds were determined using lipopolysaccharide-activated RAW 264.7 macrophages, moreover results showed that compounds 15c, 15d, 15 h and 19d were more safer (less cytotoxic) with higher IC50 (178.95-301.40 µM) when compared to the reference drug celecoxib (148.90 µM). In vivo anti-inflammatory activity of the target compounds 15c, 15d, 15 h and 19d reinforced the results of in vitro screening as the derivatives 15c, 15d, 15 h and 19d showed (ED50 = 8.22-31.22 mg/kg, respectively) and were more potent than celecoxib (ED50 = 40.39 mg/kg). All screened derivatives 15c, 15d, 15 h and 19d were less ulcerogenic (ulcer indexes = 1.22-3.93) than lonazolac (ulcer index = 20.30) and comparable to celecoxib (ulcer index = 3.02). In silico docking and ADME studies were carried out in order to clarify the interactions of the most active derivatives 15c, 15d, 15 h and 19d with the target enzymes and their pharmacokinetic parameters.
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Affiliation(s)
- Wael A A Fadaly
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Ahmed Elshewy
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo, 11562, Egypt
- Department of Natural and Applied Sciences, College of Arts and Sciences, The American University of Iraq-Baghdad (AUIB), Baghdad, Iraq
| | - Ahmed H A Abusabaa
- Department of Pharmaceutical Organic and Medicinal Chemistry, Faculty of Pharmacy, Fayoum University, Fayoum, 63514, Egypt
| | - Dina M E Amin
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | | | - Haredy Hassan Haredy
- Pharmacology Department, Faculty of Medicine, Al-Azhar University, Assuit, Egypt
| | - Asmaa M Mahmoud
- Biochemistery Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Nashwa A Ibrahim
- Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Mohamed T M Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo, 11562, Egypt.
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23
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Choo MZY, Chua JAT, Lee SXY, Ang Y, Wong WSF, Chai CLL. Privileged natural product compound classes for anti-inflammatory drug development. Nat Prod Rep 2025; 42:856-875. [PMID: 40066695 DOI: 10.1039/d4np00066h] [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: 05/23/2025]
Abstract
Covering: up to early 2025Privileged compound classes of anti-inflammatory natural products are those where there are many reported members that possess anti-inflammatory properties. The identification of these classes is of particular relevance to drug discovery, as they could serve as valuable starting points in developing effective and safe anti-inflammatory agents. The privileged compound classes of natural products include the polyphenols, coumarins, labdane diterpenoids, sesquiterpene lactones, isoquinoline and indole alkaloids, each offering a variety of molecular scaffolds and functional groups that enable diverse interactions with biological targets. From a medicinal chemistry point of view, natural products are both a boon and a bane. The multi-targeting nature of natural products is a boon in the treatment of multi-factorial diseases such as inflammation, but promiscuity, poor potency and pharmacokinetic properties are significant hurdles that must be addressed to ensure these compounds can be effectively used as therapeutics. In addition, there are continued controversies regarding the efficacies of some of these natural products that will continue to polarise their use. In this review, examples of natural products of six privileged compound classes will be discussed for their potential use and possible further development as anti-inflammatory drugs.
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Affiliation(s)
- Malcolm Z Y Choo
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
| | - Julian A T Chua
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
| | - Sean X Y Lee
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
| | - Yuet Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.
- Drug Discovery and Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore
| | - Christina L L Chai
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
- Drug Discovery and Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore
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24
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Kim JH, Che DN, Park JH, Shin JY, Jang SI, Cho BO. Anti-inflammatory effects of Elsholtzia ciliata extract on Poly I:C-treated RAW264.7 cells. JOURNAL OF ETHNOPHARMACOLOGY 2025:120026. [PMID: 40412777 DOI: 10.1016/j.jep.2025.120026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/20/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammation is a vital biological response to noxious stimuli, including physical injury and pathogenic infection, and involves immune cells and various inflammatory mediators, limiting cell damage and eliminating pathogens. Although essential for healing, inflammation can cause symptoms, such as fever, swelling, pain, and itching, potentially reducing quality of life. Elsholtzia ciliata used in traditional medicine has numerous medicinal characteristics such as antiviral, antibacterial, antipyretic, diaphoretic, carminative, astringent, and diuretic effects. AIM OF THE STUDY This study aimed to evaluate the anti-inflammatory properties of E. ciliata extract (ECE) in RAW264.7 cells treated with polyinosinic polycytidylic acid (Poly I:C). MATERIALS AND METHODS PGE2, IL-1β, TNF-α, IFN-β, and IL-6 levels were quantified by ELISA and/or real-time PCR. COX-2 and iNOS expression was analyzed using western blotting and real-time PCR. Phosphorylation and expression levels of signaling proteins, including AKT, IRF3, TBK1, STAT1, MAPKs, IκB, and IκK were analyzed using western blotting. The active substance of ECE was determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS). RESULTS Our detections revealed that ECE inhibited the levels of nitric oxide and central inflammatory mediators, such as iNOS and COX-2. Furthermore, ECE downregulated the expression of pro-inflammatory cytokines, including PGE2, IL-1β, TNF-α, IFN-β, and IL-6. Additionally, ECE inhibited the phosphorylation of several cell signaling pathways, including AKT, TBK1/IRF3, MAPK, and NF-κB, in Poly I:C-treated RAW264.7 cells. CONCLUSIONS These results highlight E. ciliata as a candidate for mitigating virus-induced inflammation, providing valuable insights into its use in the development of new anti-inflammatory therapeutics.
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Affiliation(s)
- Jang Hoon Kim
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, 92, Bisan-ro, Soi-myeon, Eumseong-gun, Chungbuk 27709, Republic of Korea.
| | - Denis Nchang Che
- Immunology Laboratory, Seoul Songdo Colorectal Hospital, 78, Dasan-ro, Jung-gu, Seoul 04597, Republic of Korea.
| | - Ji Hyeon Park
- Institute of Health Science, Jeonju University, 303, Cheonjam-ro, Wansan-gu, Jeonju-si, Jeonbuk-do 55069, Republic of Korea.
| | - Jae Young Shin
- Institute of Health Science, Jeonju University, 303, Cheonjam-ro, Wansan-gu, Jeonju-si, Jeonbuk-do 55069, Republic of Korea.
| | - Seon Il Jang
- Institute of Health Science, Jeonju University, 303, Cheonjam-ro, Wansan-gu, Jeonju-si, Jeonbuk-do 55069, Republic of Korea; Department of Health Management, Jeonju University, 303, Cheonjam-ro, Wansan-gu, Jeonju-si, Jeonbuk-do 55069, Republic of Korea.
| | - Byoung Ok Cho
- Institute of Health Science, Jeonju University, 303, Cheonjam-ro, Wansan-gu, Jeonju-si, Jeonbuk-do 55069, Republic of Korea.
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25
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Shaernejad S, Nosrat A, Baeeri M, Hashemi Goradel N, SeyedSadeghi M, Akbariani M, Arabzadeh A, Rahimifard M, Haghi-Aminjan H. Role of hesperidin/hesperetin against chemotherapy-induced cardiotoxicity: a systematic review of non-clinical studies. Cancer Cell Int 2025; 25:186. [PMID: 40405281 PMCID: PMC12100833 DOI: 10.1186/s12935-025-03828-5] [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: 12/20/2024] [Accepted: 05/11/2025] [Indexed: 05/24/2025] Open
Abstract
Despite the undeniable role of chemotherapeutics in cancer treatment, their administration may be associated with various side effects. Cardiac injury is among the most crucial side effects related to the induction of chemotherapeutic agents. Since the heart is a vital organ, cardiotoxicity often prevents clinicians from continuing chemotherapy. Hesperidin and hesperetin, flavonoids derived from citrus fruits, possess several pharmaceutical properties. This study firstly explores the cardioprotective effects of hesperidin and hesperetin against chemotherapy-induced cardiotoxicity mechanisms, emphasizing their potential as adjunctive therapies. Key literature gaps are identified, and further mechanistic studies will be proposed. The findings underscore the translational potential of these flavonoids, advocating for rigorous preclinical optimization and clinical trials to validate their efficacy and safety. This review lays a foundation for integrating natural compounds into cardioprotective strategies in oncology. A systematic search was conducted in databases (PubMed, Scopus, ISI) until May 2025, according to PRISMA principles. The search terms were chosen according to our research objective and queried in the title and abstract. Following the screening of 82 papers, twelve articles were selected based on our inclusion and exclusion criteria. Based on the evaluated results, chemotherapy adversely affects cardiac tissue, leading to elevated risks of morbidity and mortality. Co-administration of hesperidin and hesperetin with chemotherapy prevents heart injury and preserves cardiac function, maintaining it almost like a normal heart. The protective role of hesperidin and hesperetin is based on their ability to fight free radicals, reduce inflammation, and stop cell death. Nonclinical investigations indicate that hesperidin and hesperetin ameliorate chemotherapy-induced cardiotoxicity. Nonetheless, they may influence the efficacy of anticancer medications, which primarily function by elevating oxidants, inflammation, and apoptosis. This indicates that meticulously designed trials are necessary to evaluate the efficacy and safety of this combination along with the synergistic potential of them in preventing chemotherapy-induced cardiotoxicity while maintaining anticancer effectiveness.
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Affiliation(s)
- Sina Shaernejad
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ali Nosrat
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Maryam Baeeri
- Toxicology and Diseases Specialty Group, Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Mirsalim SeyedSadeghi
- Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mostafa Akbariani
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - AmirAhmad Arabzadeh
- Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mahban Rahimifard
- Toxicology and Diseases Specialty Group, Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran.
| | - Hamed Haghi-Aminjan
- Toxicology and Diseases Specialty Group, Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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26
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Law COK, Leung HM, Wang M, Nie Q, Pham QH, Han KC, Wong TS, Chow KT, Lo PK, Lau TCK. Harnessing intracellular bacteria in bladder by intravesical delivery of antibiotics-loaded nanodiamonds to reduce the recurrence of urinary tract infection. J Nanobiotechnology 2025; 23:367. [PMID: 40394627 PMCID: PMC12093853 DOI: 10.1186/s12951-025-03459-y] [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: 02/06/2025] [Accepted: 05/11/2025] [Indexed: 05/22/2025] Open
Abstract
Treating urinary tract infections (UTIs) effectively is a difficult task due to the emergence of antibiotic-resistant bacteria and limited antibiotic access to intracellular bacteria within the bladder lining. Numerous studies of the antibiotics-nanodiamonds (NDs) synthesis and their inhibitory effect on bacteria have been performed previously. However, their effectiveness and toxicity in cell-based and animal infection models remain unclear. In this study, we presented the utilization of biopolymer-coated nanodiamonds for the delivery of tetracycline (TET) to the intracellular bacterial communities within the bladder cells using an intravesical delivery approach, aiming to effectively treat UTIs. Compared with antibiotics alone, the TET-loaded ND-based carrier system significantly improved the clearance of intracellular bacteria in the infected cell and animal models. Moreover, the intravesical delivery avoids the potential toxic effects from NDs accumulation in the organs, and minimizes the loss of the drugs during delivery. These results offer a promising strategy to treat chronic infections and prevent the recurrence of urinary tract infections (rUTIs).
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Affiliation(s)
- Carmen Oi Kwan Law
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China
| | - Hoi Man Leung
- Department of Chemistry and State Key Laboratory of Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
- Biotech and Health Care, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Meijun Wang
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China
| | - Qichang Nie
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China
| | - Quynh Hoa Pham
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China
| | - Kam Chu Han
- Department of Pathology, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Kowloon, Hong Kong SAR, 999077, China
| | - Tak Siu Wong
- Department of Pathology, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Kowloon, Hong Kong SAR, 999077, China
| | - Kwan Ting Chow
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China.
| | - Pik Kwan Lo
- Department of Chemistry and State Key Laboratory of Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China.
- Biotech and Health Care, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China.
| | - Terrence Chi Kong Lau
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong, SAR, 999077, China.
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Klimova EM, Lavinska OV, Drozdova LA. The role of DAMP cytotoxic fractions in the immune markers' disruption in patients with urgent surgical pathology and against the background of post-COVID-19 syndrome. Immunol Lett 2025:107033. [PMID: 40409597 DOI: 10.1016/j.imlet.2025.107033] [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: 12/20/2024] [Revised: 05/08/2025] [Accepted: 05/15/2025] [Indexed: 05/25/2025]
Abstract
BACKGROUND As a result of the SARS-CoV-2 pandemic, various population groups were formed that had acute and asymptomatic COVID-19. A survey in these groups revealed with equal frequency an asthenic symptom complex, the so-called post-COVID-19 syndrome (PCS). The frequency of urgent surgical pathology against the background of PCS and structural and functional disorders of various organs was increased. The aim - to study the dynamics of immunoresistance factors changes in patients with urgent surgical pathology that developed against the background of PCS and to identify pathogenic markers of the severe course and the risk of mortality. MATERIALS AND METHODS To examine patients with PCS and urgent cardiovascular (n = 103) and abdominal (n = 106) pathology we used the following methods: fluorescence microscopy, confocal microscopy, flow cytometry, spectrophotometry, ELISA. RESULTS We revealed a temporal dependence of immune dysfunction in patients with a comorbid course of urgent surgical pathology and PCS. The nature of the DAMP (damage-associated molecular patterns) cytotoxic fractions ratio was associated with certain changes in innate and adaptive immunity factors, severity of the condition and risk of mortality. At the first stage (2020-2021), patients with PCS has disorders of the humoral and cellular components of innate immunity against the background of an increase in the oligopeptide and peptide DAMP fractions. At the second stage (2022-2024) of PCS development, changes in innate as well as adaptive immunity were observed against the background of an increase in the cytotoxic oligonucleotide DAMP fraction (mortality was 17.3%). CONCLUSIONS The identified markers of impaired immunoresistance in cardiovascular and abdominal urgent pathology can be used to select targeted therapy tactics.
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Affiliation(s)
- Elena M Klimova
- Department of Molecular Biology and Biotechnology, V.N. Karazin Kharkiv National University, 4 Pl. Svobody, 61022 Kharkiv, Ukraine; Diagnostic Laboratory with Enzyme Immunoassay and Immunofluorescence Analysis, State Institution "Zaycev V.T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine", vyizd Likarskyi, 1, 61103, Kharkiv, Ukraine.
| | - Olena V Lavinska
- Department of Molecular Biology and Biotechnology, V.N. Karazin Kharkiv National University, 4 Pl. Svobody, 61022 Kharkiv, Ukraine; Diagnostic Laboratory with Enzyme Immunoassay and Immunofluorescence Analysis, State Institution "Zaycev V.T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine", vyizd Likarskyi, 1, 61103, Kharkiv, Ukraine
| | - Larisa A Drozdova
- Diagnostic Laboratory with Enzyme Immunoassay and Immunofluorescence Analysis, State Institution "Zaycev V.T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine", vyizd Likarskyi, 1, 61103, Kharkiv, Ukraine
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Sofidiya MO, Olaosilo J, Alarape D, Owolabi O, Ajayi AM. The leaves of Flabellaria paniculata Cav. (Malphigiaceae) exhibit anti-inflammatory, antioxidant and antinociceptive activities invivo. JOURNAL OF ETHNOPHARMACOLOGY 2025; 350:120004. [PMID: 40403896 DOI: 10.1016/j.jep.2025.120004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 05/15/2025] [Accepted: 05/19/2025] [Indexed: 05/24/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The leaves of Flabellaria paniculata Cav. (Malpighiaceae) are used in the treatment of conditions associated with inflammation and pain. AIM OF THE STUDY The study aimed at evaluating the anti-inflammatory and antinociceptive effects of ethanol extract from the leaves of F. paniculata. MATERIALS AND METHODS The extract was obtained by maceration with ethanol (95 %) and characterized by GC-MS. The anti-inflammatory effect was assessed in carrageenan, serotonin, histamine-induced paw oedema and xylene-induced ear oedema models at the dose of 50, 100 and 200 mg/kg. Antioxidant parameters and cytokine production (IL-6, and TNF-α) levels were determined in carrageenan air pouch model. The antinociceptive property was also evaluated. RESULTS The extract at 200 mg/kg showed significant anti-inflammatory activity at 2 h (39.66 %, inhibition) which lasted for 5 h (70.37 %, inhibition) in carrageenan paw oedema. In the air pouch model, the extract decreased neutrophils and monocytes counts in the exudate but not lymphocytes count. At the dose of 200 mg/kg, the release of TNF-α and IL-6 was inhibited by 56.6 % and 35.9 %, respectively. The extract boosted catalase and SOD activities in addition to GSH level. Xylene-induced ear oedema was inhibited by 52.25, 62.62 and 64.97 %, at the dose of 50, 100 and 200 mg/kg, respectively. Antinociceptive activity of the extract (100 and 200 mg/kg) was significant in acetic acid-induced writhing test (53.33 and 54.57 %, inhibition) and the late phase of formalin test (88.04 % and 92.13 %, inhibition). No significant effect was found on motor performance in the open field. The GC-MS profile revealed the presence of 15 compounds, with cyclododecyne, hexadecanoic acid, ethyl ester, n-Hexadecanoic acid, (E)-9-Octadecenoic acid ethyl ester, 1,4,2,5 Cyclo-hexanetetrol and phytol, acetate as the main compounds. CONCLUSION F. paniculata demonstrated anti-inflammatory and antinociceptive effect and the anti-inflammatory mechanism could be through inhibition of the inflammatory markers and oxidative parameters.
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Affiliation(s)
- Margaret O Sofidiya
- Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria.
| | - Janet Olaosilo
- Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria.
| | - Dolapo Alarape
- Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria.
| | - Oluwatobi Owolabi
- Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria.
| | - Abayomi M Ajayi
- Department of Pharmacology & Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Nigeria.
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Singh A, Singh S, Singh N, Singh J. Electrochemical Immunosensor for C-Reactive Protein Detection Using an Optimized Bioinspired Ni-Doped Copper Ferrite Nanocomposite Interface for Cardiovascular Disease Management. ACS APPLIED BIO MATERIALS 2025. [PMID: 40388346 DOI: 10.1021/acsabm.5c00406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
Currently, cardiovascular diseases (CVDs) are the leading cause of death globally. According to the WHO, the number of CVDs-related deaths increases by 20% annually. C-reactive protein (CRP), a biomarker for CVDs that sharply rises during cardiac events, was used to monitor these critical conditions at an early stage. To address the need for highly sensitive, selective, and portable CRP detection, a nickel-doped copper ferrite nanoparticle-based electrochemical biosensor was developed. In this work, optimized nickel-doped copper ferrite (Ni(0.10)CuFe2O4) nanoparticles (NPs) were synthesized by doping copper ferrite NPs with varying nickel concentrations (0.05, 0.10, 0.15, and 0.20 M) via a hydrothermal method using aqueous leaf extract of Magnolia grandiflora. The NPs were characterized by using XRD, FT-IR, UV, SEM, EDX, and HR-TEM/TEM. The synthesized NPs were deposited on a functionalized indium tin oxide (ITO) surface via the electrophoretic deposition (EPD) method. Electrochemical sensing was performed by using electrochemical impedance spectroscopy (EIS). The biosensor demonstrated linear detection of CRP biomarkers across a range of 0.5 to 500 ng/mL, with a sensitivity of 5.426 Ω/ng cm2 at 0.5 ng/mL and 0.68244 Ω/ng cm2 at 500 ng/mL. The limit of detection (LOD) values were 0.038 ng/mL (lower concentration range) and 0.033 ng/mL (higher concentration of the analyte range).
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Affiliation(s)
- Astha Singh
- Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj211007, Uttar Pradesh, India
| | - Siddhima Singh
- Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj211007, Uttar Pradesh, India
| | - Neelottma Singh
- Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj211007, Uttar Pradesh, India
| | - Jay Singh
- Department of Chemistry, Institute of Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
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Bartra C, Vuraić K, Yuan Y, Codony S, Valdés-Quiroz H, Casal C, Slevin M, Máquez-Kisinousky L, Planas AM, Griñán-Ferré C, Pallàs M, Morisseau C, Hammock BD, Vázquez S, Suñol C, Sanfeliu C. Microglial pro-inflammatory mechanisms induced by monomeric C-reactive protein are counteracted by soluble epoxide hydrolase inhibitors. Int Immunopharmacol 2025; 155:114644. [PMID: 40215773 DOI: 10.1016/j.intimp.2025.114644] [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: 09/20/2024] [Revised: 04/01/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025]
Abstract
Monomeric C-reactive protein (mCRP) is a pro-inflammatory molecule generated by the dissociation of native CRP. Clinical and experimental studies suggest that mCRP deposition in the brain induces Alzheimer's disease (AD) pathology and cognitive loss. Pathological neuroinflammation is increasingly suggested as relevant in AD. Innovative therapies against neuroinflammation are desperately needed, and inhibitors of the enzyme soluble epoxide hydrolase (sEH) are a promising new generation of anti-inflammatory drugs. Mouse primary microglia and BV2 cell line cultures were exposed to mCRP to analyze its pro-inflammatory mechanisms. sEH inhibitors, both newly synthesized UB-SCG-55 and UB-SCG-65, and the reference agent TPPU, were tested for their anti-inflammatory action against mCRP. Phenotypic changes were analyzed through cell imaging techniques, as well as molecular analysis of inflammatory mediators and gene activation pathways. Results show that mCRP triggers a pro-inflammatory response through three main inflammatory pathways: iNOS, NLRP3, and COX-2, followed by increased cytokine generation. Polarization of microglia toward a M1-like phenotype was confirmed by morphological analysis. Also, mCRP can bind to and cross the cell membrane, providing further insight into its mechanisms of action. sEH inhibitors were effective against mCRP induction of a reactive microglial phenotype. The first-line compound UB-SCG-55 emerged as the most potent anti-inflammatory against mCRP injury. Therefore, the direct activation of microglia by mCRP provides evidence of its role in triggering and exacerbating neurodegenerative diseases with a neuroinflammatory component, such as AD. Furthermore, the protection given by inhibitors of sEH confirms its potential as innovative drugs against deleterious effects of neuroinflammation.
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Affiliation(s)
- Clara Bartra
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain; PhD Program in Biotechnology, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 08034 Barcelona, Spain.
| | - Kristijan Vuraić
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Yi Yuan
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Sandra Codony
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Haydeé Valdés-Quiroz
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Carme Casal
- Microscopy Service, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
| | - Mark Slevin
- CCAMF, George Emil Palade Universitatea de Medicina, Farmacie, Stiinte se Technologie, "George Emil Palade" din Targu-Mures, 540142, Tirgu Mures, Romania
| | - Leonardo Máquez-Kisinousky
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Anna M Planas
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Christophe Morisseau
- Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, United States
| | - Bruce D Hammock
- Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, United States
| | - Santiago Vázquez
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Cristina Suñol
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
| | - Coral Sanfeliu
- Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain.
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Liu T, Wu H, Wei J. Beyond the Brain: Exploring the multi-organ axes in Parkinson's disease pathogenesis. J Adv Res 2025:S2090-1232(25)00352-2. [PMID: 40383292 DOI: 10.1016/j.jare.2025.05.034] [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: 02/26/2025] [Revised: 04/20/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Parkinson's Disease (PD), a complex neurodegenerative disorder, is increasingly recognized as a systemic condition involving multi-organ interactions. Emerging evidence highlights roles of organ-brain axes (lung-, liver-, heart-, muscle-, bone-, and gut-brain) in PD pathogenesis. These axes communicate via neural, circulatory, endocrine, and inflammatory pathways, collectively driving neurodegeneration. For example, lung dysfunction in PD involves respiratory impairment and inflammatory signaling, while gut dysbiosis triggers α-synuclein aggregation via the vagus nerve. Such cross-organ interactions underscore PD's systemic nature, challenging traditional brain-centric models. AIM OF REVIEW 1. Decipher mechanisms linking peripheral organs (e.g., lung, gut) to PD via shared pathways. 2. Explore bidirectional organ-brain interactions (e.g., liver metabolism affecting neurotoxin clearance). 3. Propose multi-organ therapeutic strategies targeting integrated signaling networks. Key Scientific Concepts of Review. 1. Lung-Brain Axis: Respiratory dysfunction (motor impairment, inflammation) exacerbates neurodegeneration. 2. Liver-Brain Axis: Metabolic dysregulation alters neurotoxin clearance; drugs (e.g., levodopa) impact liver function. 3. Heart-Brain Axis: Autonomic dysfunction reduces cerebral blood flow; neuroendocrine changes promote α-synuclein pathology. 4. Muscle-Brain Axis: Neuromuscular/metabolic disruptions worsen motor symptoms. 5. Bone-Brain Axis: Bone-derived hormones (osteocalcin, OCN) and inflammation influence cognition. 6. Gut-Brain Axis: Dysbiosis drives α-synuclein misfolding; gut metabolites modulate neuroinflammation. Integrated Mechanisms: Shared pathways (neuroinflammation, oxidative stress) create a regulatory network, suggesting therapies targeting multi-organ crosstalk (e.g., probiotics, anti-inflammatory agents).
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Affiliation(s)
- Tingting Liu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Haojie Wu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jianshe Wei
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China.
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Choo MZY, Lim ET, Wong WSF, Chai CLL. Discovery of an NF-κB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate. J Med Chem 2025. [PMID: 40378174 DOI: 10.1021/acs.jmedchem.5c00055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
In this study, the coumarin natural product minutuminolate (MNT) was used as a starting point for the development of anti-inflammatory agents. Through structure-activity relationship studies, a lead compound MD-1 was designed and synthesized, exhibiting significantly improved anti-inflammatory activities. Mechanistic studies revealed that MD-1 is a degrader of the p105 subunit of NF-κB. Gene knockdown experiments further showed that the Cullin-ring ligase (CRL) SCFβTrCP is involved in MD-1-induced p105 degradation. This leads to suppressed NF-κB transcriptional activity, which is consistent with its potent anti-inflammatory effects. Taken together, our work challenges the longstanding notion that NF-κB is undruggable, as we demonstrate that the p105 subunit of NF-κB is indeed tractable with small molecules. More importantly, our study highlights that natural products are valuable starting points for the discovery and development of anti-inflammatory agents with novel mechanisms of action.
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Affiliation(s)
- Malcolm Z Y Choo
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543 Singapore
| | - En Tong Lim
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543 Singapore
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600 Singapore
- Drug Discovery and Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, 117600 Singapore
| | - Christina L L Chai
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, 117543 Singapore
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Al-Ansari AA, Nejad FAB, Al-Nasr RJ, Prithula J, Rahman T, Hasan A, Chowdhury MEH, Alam MF. Predicting ICU Mortality Among Septic Patients Using Machine Learning Technique. J Clin Med 2025; 14:3495. [PMID: 40429489 DOI: 10.3390/jcm14103495] [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: 03/15/2025] [Revised: 04/26/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction: Sepsis leads to substantial global health burdens in terms of morbidity and mortality and is associated with numerous risk factors. It is crucial to identify sepsis at an early stage in order to limit its escalation and sequelae associated with the condition. The purpose of this research is to predict ICU mortality early and evaluate the predictive accuracy of machine learning algorithms for ICU mortality among septic patients. Methods: The study used a retrospective cohort from computerized ICU records accumulated from 280 hospitals between 2014 and 2015. Initially the sample size was 23.47K. Several machine learning models were trained, validated, and tested using five-fold cross-validation, and three sampling strategies (Under-Sampling, Over-Sampling, and Combination). Results: The under-sampled approach combined with augmentation for the Extra Trees model produced the best performance with Accuracy, Precision, Sensitivity, Specificity, F1-Score, and AUC of 90.99%, 84.16%, 94.89%, 88.48%, 89.20%, and 91.69%, respectively, with Top 30 features. For Over-Sampling, the Top 29 combined features showed the best performance with Accuracy, Precision, Sensitivity, Specificity, F1-Score, and AUC of 82.99%, 51.38%, 71.72%, 85.41%, 59.87%, and 78.56%, respectively. For Down-Sampling, the Top 31 combined features produced Accuracy, Precision, Sensitivity, Specificity, F1-Score, and AUC of 81.78%, 49.08%, 79.76%, 82.21%, 60.76%, and 80.98%, respectively. Conclusions: Machine learning models can reliably predict ICU mortality when suitable clinical predictors are utilized. The study showed that the proposed Extra Trees model can predict ICU mortality with an accuracy of 90.99% accuracy using only single-entry data. Incorporating longitudinal data could further enhance model performance.
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Affiliation(s)
- Aisha A Al-Ansari
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Fatima A Bahman Nejad
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Roudha J Al-Nasr
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Johayra Prithula
- Department of Electrical and Electronics Engineering, University of Dhaka, Dhaka 1000, Bangladesh
| | - Tawsifur Rahman
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha 2713, Qatar
| | - Muhammad E H Chowdhury
- Department of Electrical Engineering, College of Engineering, Qatar University, Doha 2713, Qatar
| | - Mohammed Fasihul Alam
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
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Perez-Moreno E, de la Peña A, Toledo T, Saez J, Pérez-Molina F, Espinoza S, Metz C, Díaz-Valdivia N, Azócar L, Prado C, Pacheco R, Segovia-Miranda F, Godoy AS, Amador CA, Feuerhake T, González A, Soza A. Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury. Mol Med 2025; 31:192. [PMID: 40375122 DOI: 10.1186/s10020-025-01245-y] [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: 02/05/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin-8 (Gal-8), a tandem-repeat β-galactoside-binding lectin, plays a role in epithelial cell proliferation, epithelial-mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal-8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear. METHODS To investigate the endogenous role of Gal-8 in AKI, we compared the responses of Gal-8 knockout (Gal-8-KO; Lgals8-/- bearing a β-gal cassette under the Lgals8 gene promoter) and wild-type (Lgals8+/+) mice in a nephrotoxic folic acid (FA)-induced AKI model. Renal Gal-8 expression was assessed by β-galactosidase staining, lectin-marker colocalization, and RT-qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro-inflammatory T cells. RESULTS Galectin-8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8+/+ and Lgals8-/- mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8+/+ mice showed slightly worse damage. By the fibrotic phase, Lgals8-/- mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8+/+ mice. CONCLUSIONS Endogenous Gal-8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating extracellular matrix homeostasis and mitigating fibrosis. Additionally, Gal-8 contributes to inflammation resolution by limiting persistent immune cell infiltration, particularly IL-17-secreting cells.
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Affiliation(s)
- Elisa Perez-Moreno
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Adely de la Peña
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
| | - Tomás Toledo
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Javiera Saez
- Laboratorio de Fisiopatología Renal, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Francisca Pérez-Molina
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Sofía Espinoza
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Claudia Metz
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Nicole Díaz-Valdivia
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Lorena Azócar
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Carolina Prado
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Laboratorio de Neuroinmunología, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Rodrigo Pacheco
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Laboratorio de Neuroinmunología, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Fabian Segovia-Miranda
- Department of Cell Biology, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile
| | - Alejandro S Godoy
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Cristian A Amador
- Laboratorio de Fisiopatología Renal, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Teo Feuerhake
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alfonso González
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
- Facultad de Medicina, Universidad San Sebastián, Santiago, Chile.
| | - Andrea Soza
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
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Wang H, Wu J, Wang P, Wang W, Gao L, Liu D, Ding X, Su T. The relationship between "microbiota-gut-brain" axis and depression: Chronic stress-induced inflammation. Physiol Behav 2025; 294:114881. [PMID: 40090436 DOI: 10.1016/j.physbeh.2025.114881] [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: 01/18/2025] [Revised: 03/03/2025] [Accepted: 03/14/2025] [Indexed: 03/18/2025]
Abstract
This study aims to investigate the pathogenesis of depression in mice using the chronic unpredictable mild stress (CUMS) model, with a particular focus on the changes in inflammatory gene networks and inflammatory factor levels under the condition of gut microbiota dysbiosis. The results indicate that CUMS-induced mice exhibited significant depressive-like behaviors. Specifically, they displayed reduced sucrose intake in the sucrose preference test, decreased central area distance and time in the open field test, and reduced percentage of entries and time spent in the open arm in the elevated plus maze test. Molecular biological analysis indicated that CUMS treatment significantly upregulated the levels of inflammatory factors TNF-α, IL-1β, IL-6, and IFN-γ in the serum and hippocampus of mice. Through high-throughput sequencing and Pearson correlation analysis, it was found that the levels of inflammatory factors were significantly positively correlated with the expression of multiple inflammatory pathway genes, as well as the abundance of beneficial and harmful bacteria. Furthermore, the persistent changes in inflammatory factors ultimately led to neuronal cell death. This study provides strong evidence for the role of disrupted "microbiota-gut-brain" axis homeostasis in the pathogenesis of CUMS-induced depression in mice. This finding offers a new perspective for understanding the pathological mechanisms of depression and provides strategies for future depression treatment.
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Affiliation(s)
- Haohao Wang
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China; Anhui Traditional Chinese Medicine Ecological Agricultural Engineering Research Center, Lu'an, 237012, China
| | - Jinxiang Wu
- College of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, 230012, China
| | - Pan Wang
- College of Materials and Chemical Engineering, West Anhui University, Lu'an, 237012, China
| | - Wei Wang
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China; Anhui Traditional Chinese Medicine Ecological Agricultural Engineering Research Center, Lu'an, 237012, China
| | - Leilei Gao
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China; Anhui Traditional Chinese Medicine Ecological Agricultural Engineering Research Center, Lu'an, 237012, China
| | - Dong Liu
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China; Anhui Traditional Chinese Medicine Ecological Agricultural Engineering Research Center, Lu'an, 237012, China; Anhui Modern Traditional Chinese Medicine Industry Commonality Technology Research Center, Lu'an, 237012, China.
| | - Xiaoyuan Ding
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China.
| | - Ting Su
- College of biological and pharmaceutical engineering, West Anhui University, Lu'an, 237012, China; Anhui Traditional Chinese Medicine Ecological Agricultural Engineering Research Center, Lu'an, 237012, China
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Alagarsamy KN, Saleth LR, Diedkova K, Zahorodna V, Gogotsi O, Pogorielov M, Dhingra S. MXenes in healthcare: transformative applications and challenges in medical diagnostics and therapeutics. NANOSCALE 2025; 17:11785-11811. [PMID: 40261131 DOI: 10.1039/d4nr04853a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
MXenes, a novel class of two-dimensional transition metal carbides, exhibit exceptional physicochemical properties that make them highly promising for biomedical applications. Their application has been explored in bioinstrumentation, tissue engineering, and infectious disease management. In bioinstrumentation, MXenes enhance the sensitivity and response time of wearable sensors, including piezoresistive, electrochemical, and electrophysiological sensors. They also function effectively as contrast agents in MRI and CT imaging for cancer diagnostics and therapy. In tissue engineering, MXenes contribute to both hard and soft tissue regeneration, playing a key role in neural, cardiac, skin and bone repair. Additionally, they offer innovative solutions in combating infectious and inflammatory diseases by facilitating antimicrobial surfaces and immune modulation. Despite their potential, several challenges hinder the clinical translation of MXene-based technologies. Issues related to synthesis, scalability, biocompatibility, and long-term safety must be addressed to ensure their practical implementation in medical applications. This review provides a comprehensive overview of MXenes in next-generation medical diagnostics, including the role they play in wearable sensors and imaging contrast agents. It further explores their applications in tissue engineering and infectious disease management, highlighting their antimicrobial and immunomodulatory properties. Finally, we discuss the key barriers to clinical translation and propose strategies for overcoming these limitations. This review aims to bridge current advancements with future opportunities for integration of MXenes in healthcare.
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Affiliation(s)
- Keshav Narayan Alagarsamy
- Institute of Cardiovascular Sciences, St Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada.
| | - Leena Regi Saleth
- Institute of Cardiovascular Sciences, St Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada.
| | - Kateryna Diedkova
- Institute of Atomic Physics and Spectroscopy, University of Latvia, Jelgavas iela 3, Riga, Latvia, LV-1004
- Biomedical Research Center, Sumy State University, Kharkivska street 116, Sumy, Ukraine, 40007
| | - Veronika Zahorodna
- Materials Research Center, 19/33A Yaroslaviv Val/O.Honchara str, Kyiv, 01034, Ukraine
| | - Oleksiy Gogotsi
- Biomedical Research Center, Sumy State University, Kharkivska street 116, Sumy, Ukraine, 40007
- Materials Research Center, 19/33A Yaroslaviv Val/O.Honchara str, Kyiv, 01034, Ukraine
| | - Maksym Pogorielov
- Institute of Atomic Physics and Spectroscopy, University of Latvia, Jelgavas iela 3, Riga, Latvia, LV-1004
- Biomedical Research Center, Sumy State University, Kharkivska street 116, Sumy, Ukraine, 40007
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada.
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37
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Song D, Khan A, Dong MH, Lei CW, Feng TT, Zhou Y, Wei X. Anti-Inflammatory Mechanism Prediction of Sinomenine Based on Network Pharmacology and Its Biological Activity Verification. BIOLOGY 2025; 14:543. [PMID: 40427732 DOI: 10.3390/biology14050543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025]
Abstract
Inflammation is a widespread physiological response that occurs when the body is stimulated by pathogens or endogenous signals [...].
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Affiliation(s)
- Da Song
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
- Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China
| | - Afsar Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan
| | - Ming-Hong Dong
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - Chuan-Wen Lei
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
- Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China
| | - Ting-Ting Feng
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
- Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China
| | - Ying Zhou
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
- Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China
| | - Xin Wei
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
- Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China
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38
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Singh DD. NLRP3 inflammasome: structure, mechanism, drug-induced organ toxicity, therapeutic strategies, and future perspectives. RSC Med Chem 2025:d5md00167f. [PMID: 40370650 PMCID: PMC12070810 DOI: 10.1039/d5md00167f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/22/2025] [Indexed: 05/16/2025] Open
Abstract
Drug-induced toxicity is an important issue in clinical medicine, which typically results in organ dysfunction and adverse health consequences. The family of NOD-like receptors (NLRs) includes intracellular proteins involved in recognizing pathogens and triggering innate immune responses, including the activation of the NLRP3 inflammasome. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a critical component for both innate and adaptive immune responses and has been implicated in various drug-induced toxicities, including hepatic, renal, and cardiovascular diseases. The unusual activation of the NLRP3 inflammasome causes the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which can lead to more damage to tissues. Targeting NLRP3 inflammasome is a potential therapeutic endeavour for suppressing drug-induced toxicity. This review provides insights into the mechanism, drug-induced organ toxicity, therapeutic strategies, and prospective therapeutic approaches of the NLRP3 inflammasome and summarizes the developing therapies that target the inflammasome unit. This review has taken up one of the foremost endeavours in understanding and inhibiting the NLRP3 inflammasome as a means of generating safer pharmacological therapies.
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Affiliation(s)
- Desh Deepak Singh
- Amity Institute of Biotechnology, Amity University Rajasthan Jaipur 303002 India +91 9450078260
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Fusco A, Guarnieri A, Scieuzo C, Triunfo M, Salvia R, Donnarumma G, Falabella P. Hermetia illucens-Derived Chitosan: A Promising Immunomodulatory Agent for Applications in Biomedical Fields. Biomacromolecules 2025; 26:3224-3233. [PMID: 40300853 PMCID: PMC12076490 DOI: 10.1021/acs.biomac.5c00362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 05/01/2025]
Abstract
Chitosan, renowned for its important biological properties, is a valuable pharmaceutical excipient for different therapeutic approaches. Currently, the demand for the biopolymer on the market is growing, and, for this reason, it is important to biologically characterize the biopolymer produced from an alternative source to crustaceans, specifically the bioconverter insect Hermetia illucens. In this work, insect chitosan, yielded via heterogeneous and homogeneous deacetylation from larvae, pupal exuviae, and adults, was studied as an immunomodulatory agent. The inflammatory response of immortalized human keratinocyte cells was induced by Salmonella enterica subsp. enterica serovar Typhimurium lipopolysaccharide. After that, the ability of the biopolymer to reduce the expression of the pro-inflammatory cytokines IL-6, IL-8, IL-1α, and TNF-α was tested after 6 and 24 h of treatment. Insect chitosan samples effectively downregulated cytokine expression, with improved activity obtained from heterogeneous chitosan treatments.
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Affiliation(s)
- Alessandra Fusco
- Department
of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy
- Department
of Experimental Medicine, University of
Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Anna Guarnieri
- Department
of Basic and Applied Sciences, University
of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Carmen Scieuzo
- Department
of Basic and Applied Sciences, University
of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
- Spinoff
XFlies s.r.l, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Micaela Triunfo
- Department
of Basic and Applied Sciences, University
of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Rosanna Salvia
- Department
of Basic and Applied Sciences, University
of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
- Spinoff
XFlies s.r.l, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Giovanna Donnarumma
- Department
of Experimental Medicine, University of
Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Patrizia Falabella
- Department
of Basic and Applied Sciences, University
of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
- Spinoff
XFlies s.r.l, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
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Vasarri M, De Marchi L, Pretti C, Barletta E, Degl'Innocenti D. Antioxidant and Anti-Inflammatory Properties of Four Native Mediterranean Seagrasses: A Review of Bioactive Potential and Ecological Context. Mar Drugs 2025; 23:206. [PMID: 40422796 DOI: 10.3390/md23050206] [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: 04/09/2025] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025] Open
Abstract
This review provides current knowledge of the potential benefits of native Mediterranean seagrasses for human health, specifically focusing on their anti-inflammatory and antioxidant properties. The four main species examined-Posidonia oceanica, Cymodocea nodosa, Zostera marina, and Zostera noltii-are integral components of marine ecosystems, providing essential habitats and supporting biodiversity. Recent studies highlight their rich bioactive compounds that show significant therapeutic potential against oxidative stress and chronic inflammation, which are prevalent in various health disorders. This overview synthesizes the current literature, emphasizing the mechanisms through which these seagrasses exert their beneficial effects. Furthermore, it addresses the environmental implications of the excessive use and abuse of conventional anti-inflammatory drugs, advocating for a shift towards natural alternatives derived from marine resources. By exploring the bioactivity of these Mediterranean seagrasses, research here collected underscores the importance of integrating marine plants into health and wellness strategies, thereby promoting both human health and ecosystem sustainability. This exploration not only enriches the understanding of their applications on human health but also stimulates further research in this promising field, paving the way for innovative approaches to combat chronic diseases and support environmental conservation.
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Affiliation(s)
- Marzia Vasarri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Lucia De Marchi
- Department of Veterinary Sciences, University of Pisa, Viale delle Piagge 2, 56124 Pisa, Italy
| | - Carlo Pretti
- Department of Veterinary Sciences, University of Pisa, Viale delle Piagge 2, 56124 Pisa, Italy
- Interuniversity Center of Marine Biology and Applied Ecology "G. Bacci" (CIBM), Viale N. Sauro 4, 57128 Leghorn, Italy
| | - Emanuela Barletta
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Donatella Degl'Innocenti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
- Interuniversity Center of Marine Biology and Applied Ecology "G. Bacci" (CIBM), Viale N. Sauro 4, 57128 Leghorn, Italy
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41
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Hou X, Chen R, Wu J, Huang Y, Zhang X, Xu S, He L. Selective COX-2 inhibitors from natural sources: Insights from the analysis of components absorbed into blood from Isatidis Radix Lignans. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119930. [PMID: 40354841 DOI: 10.1016/j.jep.2025.119930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 05/02/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Isatis tinctoria L. (Isatidis Radix) is a type of Chinese medicine used to treat various inflammations. Lignans are the main active ingredients of Isatidis Radix, which exhibit potent anti-inflammatory properties. However, the targets underlying the anti-inflammatory effects of Isatidis Radix remain unclear. AIM OF THE STUDY The objective of this research was to investigate the active constituents of Isatidis Radix and the molecular mechanisms behind its anti-inflammatory properties. MATERIALS AND METHODS Firstly, Liquid Chromatography-Mass Spectrometry (LC-MS), network pharmacology, and molecular docking were employed to identify the active ingredients and key targets of Isatidis Radix lignans and predict their underlying anti-inflammatory mechanisms. Secondly, the enzyme-linked immunosorbent assay (ELISA) and the LPS-induced cell model were employed to verify the selective inhibitory effect of the active ingredients on the key target COX-2. Finally, the analgesic and anti-inflammatory effects were evaluated using the hot-plate test, acetic acid-induced writhing, complete Freund's adjuvant-induced paw edema, and xylene-induced ear edema assays. RESULTS A total of 24 compounds were found to be absorbed into the bloodstream, including 15 prototype components and 9 metabolites, as determined by LC-MS analysis. Furthermore, Network pharmacology analysis revealed that COX-2 served as the central target in the anti-inflammatory mechanism of Isatidis Radix lignans. Lariciresinol, a class of lignans derived from Isatidis Radix, selectively inhibited COX-2 and reduced inflammatory marker production in vitro and in vivo. It significantly increased the incubation period of heat pain, reduced writhing frequency, and decreased the severity of ear and foot swelling. Moreover, lariciresinol had no obvious gastrointestinal side effects and was not toxic to cardiomyocytes. CONCLUSION Our study indicates that Isatidis Radix lignans exert their anti-inflammatory effect by selectively inhibiting the COX-2 enzyme and confirms lariciresinol as a natural selective COX-2 inhibitor.
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Affiliation(s)
- Xianbang Hou
- School of Pharmacy, Nanjing University of Chinese Medicine Hanlin College, Taizhou, 225300, China; Nanjing University of Chinese Medicine Hanlin College, Taizhou Key Laboratory of Traditional Chinese Medicine and Comprehensive Health Products Development, TaiZhou Engineering Research Center for Quality and Industrialization of Traditional Chinese Medicine, Taizhou, 225300, China
| | - Ran Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Juan Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujie Huang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xueyuan Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine Hanlin College, Taizhou, 225300, China
| | - Shaobao Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Liwei He
- School of Pharmacy, Nanjing University of Chinese Medicine Hanlin College, Taizhou, 225300, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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42
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Potdar MB, Bhamare RP, Agrawal YO, Belgamwar AV. Crosstalk Between Signaling Stroke Cascade and Therapeutic Receptors PPAR-γ, ROCK, CB1R, and CB2R: From Mechanism to Therapies. Transl Stroke Res 2025:10.1007/s12975-025-01352-2. [PMID: 40338418 DOI: 10.1007/s12975-025-01352-2] [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: 12/14/2024] [Revised: 02/07/2025] [Accepted: 04/15/2025] [Indexed: 05/09/2025]
Abstract
Stroke remains a leading cause of disability and mortality worldwide, primarily due to the complex and multifaceted nature of its pathophysiology. This review aims to provide a comprehensive and mechanistic understanding of the crosstalk between key signaling pathways activated during stroke and the therapeutic potential of specific receptors: PPAR-γ, ROCK, CB1R, and CB2R. We delve into the intricate signaling cascades that occur post-stroke, including excitotoxicity, oxidative stress, and inflammation, highlighting the pivotal molecular players involved. PPAR-γ, known for its neuroprotective and anti-inflammatory properties, emerges as a critical modulator in stroke therapy. ROCK, a central component in the Rho/ROCK pathway, is implicated in vascular and neuronal damage, making its inhibition a promising therapeutic strategy. The roles of CB1R and CB2R within the endocannabinoid system are explored, with a focus on their dualistic nature in neuroprotection and neurotoxicity. The review further examines the interconnectivity of these receptors within the stroke signaling network, proposing that their synergistic modulation could enhance therapeutic outcomes. Current therapeutic approaches, including pharmacological and multi-target strategies, are critically evaluated, addressing the challenges in translating mechanistic insights into clinical practice. Additionally, the identification and utilization of biomarkers for stroke diagnosis and therapy monitoring are discussed, offering a glimpse into future prospects. Emerging therapies, novel drug developments, and personalized medicine approaches are presented as potential game-changers in stroke treatment.
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Affiliation(s)
- Mrugendra B Potdar
- Department of Pharmaceutics, Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Rohit P Bhamare
- Department of Pharmaceutics, Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Yogeeta O Agrawal
- Department of Pharmaceutics, Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Aarti V Belgamwar
- Department of Pharmaceutics, Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India.
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43
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Bolger-Chen M, Lopera Higuita M, Pendexter CA, Mojoudi M, Uygun K, Tessier SN. Enhancing outcomes in Langendorff-perfused rodent hearts through perfusion parameter optimization. Sci Rep 2025; 15:15935. [PMID: 40335499 PMCID: PMC12059170 DOI: 10.1038/s41598-025-00159-3] [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: 10/07/2024] [Accepted: 04/25/2025] [Indexed: 05/09/2025] Open
Abstract
Despite important advancements in addressing cardiovascular diseases (CVDs), there has been an overall lack of progress in the field, leading to a slower decline in the rate of CVDs related deaths, and even an increase for some risk groups (e.g. increase in stroke mortality) exacerbated by an aging and obese population. While a multi-faceted problem, this deceleration may be influenced by the preferred model systems utilized in translation research. Cardiac cell lines, although easier to handle, lack biological accuracy due to the unnatural modifications required for successful culture and may not recapitulate complex 3-dimensional structural and environmental factors. At the same time, whole animal experimentation provides unwanted complexity during initial scientific development. Alternatively, ex vivo perfusion of isolated rodent hearts provides the needed biological accuracy with decreased organismal complexity. This platform facilitates the evaluation of the isolated heart, without neuro-reflexes and/or humoral contributions, unveiling the direct effects of stimuli in heart function/homeostasis. This manuscript leverages the wide array of perfusion parameters (i.e. perfusate, flow rate, coronary pressures), to demonstrate the capability of ex vivo heart perfusion protocols to accommodate a large range of experimental needs. Through this work, it was determined that the use of physiological perfusion pressures leads to increased left ventricular (LV) pressures but results in a loss of function over time, making it ideal conditions for organ assessment. Conversely, lower-than-physiological perfusion pressures lead to decreased LV pressures but prevent loss of function over time, which is preferable when longer perfusion times are relevant to experimental needs. Similarly, the use of adenosine as a pharmacological intervention was found to decrease both edema formation and inflammatory responses. In contrast, the use of packed red blood cells as oxygen carriers appears to induce a pro-inflammatory response and cause greater cardiac damage, particularly when combined with low perfusion pressures.
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Affiliation(s)
- Maya Bolger-Chen
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA
| | - Manuela Lopera Higuita
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA
| | - Casie A Pendexter
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA
| | - Mohammadreza Mojoudi
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA
| | - Shannon N Tessier
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children's Boston, Boston, MA, USA.
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44
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Lee SH, Hwang D, Lee JW, Goo TW, Yun EY. The Identification of a Glucuronyltransferase-Related Gene, GlcAT-S, with Putative Mucus Protection and Anti-Inflammatory Effects from Gut-Damaged Drosophila by Dextran Sulfate Sodium (DSS). BIOLOGY 2025; 14:513. [PMID: 40427702 DOI: 10.3390/biology14050513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/28/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025]
Abstract
The intestinal epithelium, which is protected by mucosal surfaces composed of mucins and other glycoproteins, functions as a selective barrier that absorbs nutrients while preventing the translocation of harmful substances. To understand the mechanisms between mucosal disruption and tissue inflammation, we orally administrated a mucus-disrupting agent, dextran sodium sulfate, to Drosophila melanogaster and screened 63 differentially expressed genes (DEGs). Through a database search using bioinformatics tools (CHEA3 and WebGestalt), we identified ELK1 as a potential key transcription factor for the selected DEGs, and among the 63 DEGs, ELK1-related genes, B3GAT3, FIBP, and TENT2 (GlcAT-S, Fibp, and Wisp in Drosophila), were selected as the relevant genes that respond to mucus disruption. We confirmed that enterocyte (EC)-specific GlcAT-S knockdown by RNAi significantly reduced gut length and increased intestinal stem cell proliferation in Drosophila. Additionally, in EC-specific GlcAT-S-knockdown flies, it was observed that the mucus-production-related genes, Muc68D and Mur29B, were specifically reduced, whereas the inflammatory cytokines egr and upd3 were overexpressed. This study provides evidence that GlcAT-S is involved in the regulation of intestinal inflammation in Drosophila and plays a protective role against mucus disruption. Our findings suggest that GlcAT-S may be a potential therapeutic target for the treatment of intestinal inflammatory diseases such as IBD.
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Affiliation(s)
- Seung Hun Lee
- Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea
| | - Dooseon Hwang
- Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea
- Department of Future Food and Resources Technology, Donga University of Health, Yeongam 58439, Republic of Korea
| | - Jang-Won Lee
- Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea
| | - Tae-Won Goo
- Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju 38766, Republic of Korea
| | - Eun-Young Yun
- Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea
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45
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Huang J, Xiong M, Ou X, Li H, Shang S, Huo Z, Hu L, Chen Q, Zhang R. Development of a light-initiated chemiluminescent assay platform for rapid detection of multiple inflammatory biomarkers. Talanta 2025; 295:128297. [PMID: 40349662 DOI: 10.1016/j.talanta.2025.128297] [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: 02/15/2025] [Revised: 05/02/2025] [Accepted: 05/06/2025] [Indexed: 05/14/2025]
Abstract
The accurate and timely detection of inflammatory biomarkers, including C-reactive protein (CRP), interferon-γ (IFN-γ), and procalcitonin (PCT), is critical for the diagnosis and monitoring of various diseases. Traditional immunoassays often suffer from complex workflows, long incubation times, and limited multiplexing capabilities, which restrict their utility in high-throughput or point-of-care applications. To overcome these challenges, we developed a light-initiated chemiluminescent assay (LICA) platform, leveraging the synthesis and functionalization of photosensitive microspheres and luminescent microspheres encapsulated with β-diketonate-Eu(III) complexes for the rapid detection of CRP, IFN-γ, and PCT. The LICA platform exhibited excellent analytical performances, achieving detection limits of 6.2 ng mL-1 for CRP, 0.32 pg mL-1 for IFN-γ, and 0.012 ng mL-1 for PCT, alongside remarkable specificity and reproducibility. We further validated the LICA platform by analyzing clinical blood samples, and the results were in excellent agreement with those obtained using well-established clinical methods, with a correlation coefficient exceeding 0.9940. Mechanistic investigations revealed that singlet oxygen is the key reactive species driving luminescence, while efficient intramolecular energy transfer from the ligands to the Eu(III) metal center plays a critical role in the emission of luminescence. Our findings underscore the potential of the LICA platform as a transformative tool for the detection of multiple inflammatory biomarkers, particularly in scenarios requiring rapid, multiplexed detection of inflammatory biomarkers.
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Affiliation(s)
- Jinlian Huang
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China
| | - Mengtian Xiong
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China
| | - Xiaoqi Ou
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China
| | - Haiqin Li
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China
| | - Shibo Shang
- Department of Laboratory Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, PR China
| | - Zhiming Huo
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China
| | - Liangshan Hu
- Department of Laboratory Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, PR China.
| | - Qingsong Chen
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China.
| | - Runkun Zhang
- Guangdong Provincial Engineering Technology Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, PR China.
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46
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Majdalawieh AF, Khatib BK, Terro TM. α-Mangostin Is a Xanthone Derivative from Mangosteen with Potent Immunomodulatory and Anti-Inflammatory Properties. Biomolecules 2025; 15:681. [PMID: 40427574 DOI: 10.3390/biom15050681] [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: 03/25/2025] [Revised: 04/28/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
α-Mangostin, a bioactive xanthone derived from the Garcinia mangostana L. Clusiaceae (G. mangostana) fruit, has demonstrated significant anti-inflammatory and immunomodulatory properties. Chronic inflammation plays a critical role in the pathogenesis of various diseases, including metabolic disorders, autoimmune conditions, and cancer. Conventional anti-inflammatory therapies, such as non-steroidal anti-inflammatory drugs (NSAIDs), often carry undesirable side effects, prompting the need for safer, natural alternatives. This review consolidates the existing literature on the mechanisms by which α-mangostin exerts its anti-inflammatory effects, including the suppression of pro-inflammatory cytokines, modulation of immune cell activity, and inhibition of key signaling pathways such as nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). Additionally, α-mangostin exhibits immunomodulatory properties by influencing both innate and adaptive immune responses, affecting macrophage polarization, T cell differentiation, and cytokine production. Its efficacy has been observed in numerous disease models, including joint disorders, digestive and metabolic conditions, hepatic diseases, neurological disorders, and respiratory ailments. The potential therapeutic applications of α-mangostin as an anti-inflammatory agent warrant further investigation through preclinical and clinical studies to validate its efficacy and safety.
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Affiliation(s)
- Amin F Majdalawieh
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
- Advanced Biosciences and Bioengineering Research Center, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
| | - Bayan K Khatib
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
| | - Tala M Terro
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
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47
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Lyu Z, Wu Y, Hu F, Zheng X, Ma D, Xu Z, Ding Y, Liu X, Huo S. Controlled release of ionic carrier hydrogels for sequential immunomodulation to facilitate stage-specific treatment of infectious wound. Biomaterials 2025; 322:123376. [PMID: 40349534 DOI: 10.1016/j.biomaterials.2025.123376] [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: 03/28/2025] [Accepted: 04/24/2025] [Indexed: 05/14/2025]
Abstract
Infected wounds present a significant clinical challenge, exacerbated by antibiotic resistance, which complicates effective treatment. This study introduces a hydrogel (CC/AP@CM) embedded with core-shell bioactive glass nanoparticles designed for the controlled, sequential release of copper (Cu2+) and magnesium (Mg2+) ions. The hydrogel is crosslinked via a Schiff base reaction, endowing it with injectable, self-healing, and adhesive properties. Notably, the bilayer structure of the bioactive glass within the hydrogel allows an initial release of Cu2+ ions to trigger an early-stage pro-inflammatory and antimicrobial response, followed by Mg2+ ions that support tissue repair and an anti-inflammatory environment. This design aligns with natural wound healing stages, promoting a shift in macrophage polarization from the M1 to M2 phenotype, effectively balancing antibacterial defense with tissue regeneration. The hydrogel demonstrated robust antibacterial efficacy against MRSA, increased angiogenesis, and enhanced fibroblast proliferation and migration in vitro. In a murine wound model, it significantly accelerated wound closure and immune activation, including responses from dendritic cells and T cells. These findings suggest that this hydrogel, through its stage-specific immunomodulatory properties and temporally controlled ion release, offers a promising strategy for treating complex wound infections, supporting both immune defense and tissue healing.
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Affiliation(s)
- Zhuocheng Lyu
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yuezhou Wu
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Fei Hu
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xu Zheng
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Dajun Ma
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhenjiang Xu
- Department of Orthopedic Surgery Spine Center Changzheng Hospital Navy Medical University, Shanghai, China
| | - Yurun Ding
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Xuesong Liu
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiaotong University, China.
| | - Shicheng Huo
- Department of Orthopedic Surgery Spine Center Changzheng Hospital Navy Medical University, Shanghai, China.
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48
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Ziadeh H, Calaway A, Gupta S, Bodner D, Brown JR, Schumacher FR, Wu CHW. Increased risk of upper tract urothelial carcinoma in patients with kidney stones: a large-scale analysis of the UK biobank. Urolithiasis 2025; 53:87. [PMID: 40335677 DOI: 10.1007/s00240-025-01758-5] [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: 03/22/2025] [Accepted: 04/22/2025] [Indexed: 05/09/2025]
Abstract
Kidney stone disease is a common and increasingly prevalent condition, with its incidence rising by 70% over the past two decades in the U.S. Lodgment of stones within the ureteral wall can cause urothelial injury, triggering inflammation, edema, and obstruction. Chronic inflammation has been linked to cancer development, contributing to tumorigenesis through cellular transformation, proliferation, invasion, angiogenesis, and metastasis. Studies suggest that recurrent nephrolithiasis can lead to a range of complications, including an increased risk of urinary tract cancer. This study investigates the association between kidney and ureteral stones and upper tract urothelial carcinoma (UTUC) risk using data from 502,144 individuals in the UK Biobank. We bidirectionally examined the presence of kidney stones and UTUC, applying a chi-square test to compute the odds ratio and assess statistical significance. A history of kidney stones was noted in 13,016 individuals, while 489,128 were stone-free. Among 511 UTUC cases, 50 had a history of kidney stones, whereas 461 were isolated UTUC. In contrast, 12,966 individuals had kidney stones without UTUC, and 488,667 were free of both conditions. Statistical analysis revealed an increased risk of UTUC in individuals with kidney stones [OR = 4.09 (95% CI 3.05-5.48), p < 0.001], indicating strong statistical significance. Our study demonstrates a fourfold increased risk of UTUC in individuals with a history of kidney stones. These findings highlight a significant association between kidney stones and UTUC, underscoring the need for further research on clinical management and cancer surveillance.
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Affiliation(s)
- Hachem Ziadeh
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
| | - Adam Calaway
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Donald Bodner
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
| | - Jason R Brown
- Department of Medical Oncology, University Hospitals, Seidman Cancer Center, Cleveland, OH, USA
| | - Fredrick R Schumacher
- Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Chen-Han Wilfred Wu
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA.
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA.
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49
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Inami N. Safety assessment of multiple systemic administration of human mesenchymal stem cell-conditioned medium for various chronic diseases. PLoS One 2025; 20:e0322497. [PMID: 40327651 PMCID: PMC12054860 DOI: 10.1371/journal.pone.0322497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 03/21/2025] [Indexed: 05/08/2025] Open
Abstract
Conditioned medium (CM) derived from human mesenchymal stem cells (MSCs) has shown potential as a therapeutic agent. However, the safety of its administration in human remains largely unexplored. This study evaluated the safety of multiple systemic administrations of MSC-CM, specifically adipose-derived and umbilical cord-derived MSC-CM, in 55 patients with various chronic diseases. Symptom assessments and blood tests were conducted before and after administration to monitor adverse events and measure the inflammatory marker C-reactive protein (CRP), respectively. The results demonstrated no serious adverse events attributed to MSC-CM administration. Although minor adverse events were observed, their causal relationship with MSC-CM remained unclear. Additionally, MSC-CM administration slightly reduced CRP levels, regardless of the administration route (intraarterial, intravenous, or inhalation). Additionally, a significant reduction in CRP levels was observed in patients with elevated CRP levels (CRP > 0.3) following MSC-CM administration. These findings suggest that repeated systemic administration of MSC-CM is likely safe and may have anti-inflammatory effects.
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Affiliation(s)
- Norihito Inami
- Seihoku Clinic, 775 Takawa, Oshibedani, Nishi-ku, Kobe, Hyogo, Japan
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50
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Saputra F, Pramata AD, Soegianto A, Hu SY. Polystyrene nanoplastics cause developmental abnormalities, oxidative damage and immune toxicity in early zebrafish development. Comp Biochem Physiol C Toxicol Pharmacol 2025; 295:110216. [PMID: 40339675 DOI: 10.1016/j.cbpc.2025.110216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Aquatic organisms are increasingly affected by polystyrene nanoplastics (PSNPs), which have the potential to disrupt development, induce oxidative stress, and impair immune function. This study examined the effects of PSNPs on zebrafish (Danio rerio) embryos exposed to 0.01, 0.1, 1, and 10 μg/mL from 2 to 120 h post-fertilization (hpf). The findings indicated that developmental abnormalities occurred in a dose-dependent manner, including delayed hatching, decreased survival rates, reduced body length, smaller eye diameter, and enlarged yolk sac area. PSNPs accumulated in the chorion and yolk sac as early as 6 hpf and were detected in vital tissues, such as the eyes, heart, yolk sac, liver, pancreas, intestine, neuromasts, and tail, immediately after hatching. By 120 hpf, PSNPs significantly reduced swimming distance and velocity. Exposure to PSNPs induced oxidative damage evidenced by altered expression of antioxidant-related genes (CAT1, GPX1A, SOD1, NRF2, KEAP1, HSP70, MT), disrupting cellular homeostasis and causing structural and organ defects. Immune toxicity was marked by dysregulated expression of immune-related genes (IL-1β, IL-6, NF-κB, TNF-α, C3B, TLR-1, TLR-3, TLR-4), indicating inflammation and innate immune activation triggered by oxidative damage. This study highlights the interconnected impacts of developmental abnormalities, oxidative damage, and immune toxicity caused by PSNPs exposure, highlighting the systemic impacts of nanoplastics contamination in aquatic environments.
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Affiliation(s)
- Febriyansyah Saputra
- Department of Biology, Faculty Sciences and Technology, Universitas Airlangga, Campus C, Surabaya 60115, Indonesia; Mathematics and Natural Sciences Doctoral Program, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Azzah Dyah Pramata
- Department of Materials and Metallurgical Engineering, Faculty of Industrial Technology and Systems Engineering, Institut Teknologi Sepuluh Nopember, Surabaya 60116, Indonesia.
| | - Agoes Soegianto
- Department of Biology, Faculty Sciences and Technology, Universitas Airlangga, Campus C, Surabaya 60115, Indonesia.
| | - Shao-Yang Hu
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912301, Taiwan.
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