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Torabi M, Sardari S, Rodríguez-Martínez A, Arabi N, Pérez-Sánchez H, Ghasemi F. Drug repurposing to identify potential FDA-approved drugs targeting three main angiogenesis receptors through a deep learning framework. Mol Divers 2025:10.1007/s11030-025-11214-6. [PMID: 40418485 DOI: 10.1007/s11030-025-11214-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/29/2025] [Indexed: 05/27/2025]
Abstract
Tumor cell survival depends on the presence of oxygen and nutrients provided by existing blood vessels, particularly when cancer is in its early stage. Along with tumor growth in the vicinity of blood vessels, malignant cells require more nutrients; hence, capillary sprouting occurs from parental vessels, a process known as angiogenesis. Although multiple cellular pathways have been identified, controlling them with one single biomolecule as a multi-target inhibitor could be an attractive strategy for reducing medication side effects. Three critical pathways in angiogenesis have been identified, which are activated by the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR). This study aimed to develop a methodology to discover multi-target inhibitors among over 2000 FDA-approved drugs. Hence, a novel ensemble approach was employed, comprising classification and regression models. First, three different deep autoencoder classifications were generated for each target individually. The top 100 trained models were selected for the high-throughput virtual screening step. After that, all identified molecules with a probability of more than 0.9 in more than 70% of the models were removed to ensure accurate consideration in the regression step. Since the ultimate aim of virtual screening is to discover molecules with the highest success rate in the pharmaceutical industry, various aspects of the molecules in different assays were considered by integrating ten different regression models. In conclusion, this paper contributes to pharmaceutical sciences by introducing eleven diverse scaffolds and eight approved drugs that can potentially be used as inhibitors of angiogenesis receptors, including VEGFR, FGFR, and EGFR. Considering three target receptors simultaneously is another central concept and contribution used. This concept could increase the chance of success, while reducing the possibility of resistance to these agents.
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Affiliation(s)
- Mohammadreza Torabi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soroush Sardari
- Medical Biotechnology Department, Drug Design and Bioinformatics Unit, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Alejandro Rodríguez-Martínez
- Computer Engineering Department, Bioinformatics and High-Performance Computing Research Group (BIO-HPC), Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
| | - Nooshin Arabi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Horacio Pérez-Sánchez
- Computer Engineering Department, Bioinformatics and High-Performance Computing Research Group (BIO-HPC), Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain.
| | - Fahimeh Ghasemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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2
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Wu Y, Chen Z, Shi M, Qiu S, Zhang Y. Nimotuzumab and bevacizumab combined with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme: a retrospective single-arm study. J Neurooncol 2025; 172:429-436. [PMID: 39760795 DOI: 10.1007/s11060-024-04932-8] [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: 11/17/2024] [Accepted: 12/26/2024] [Indexed: 01/07/2025]
Abstract
PURPOSE Glioblastoma (GBM), the most common malignant tumor of the central nervous system (CNS) in adults, continues to result in poor survival rates despite standard treatment. Advancements in understanding GBM's molecular complexity have increased interest in targeted therapeutic approaches. This retrospective, single-center, single-arm study combined nimotuzumab and bevacizumab with radiotherapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed GBM. The objectives were to determine the efficacy of this treatment combination and the associated toxicity. METHODS A retrospective analysis of clinical data of GBM patients treated at our institution from September 2021 to May 2023 with postoperative combination therapy of nimotuzumab, bevacizumab, and TMZ concurrent with RT, as well as maintenance therapy with bevacizumab and TMZ. Follow-ups were performed every 3 to 6 months via hospital visits and telephone interviews. The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoint was the incidence of adverse events (AEs). RESULTS A total of 18 patients were included. The median follow-up time was 23 months. The one-year PFS rate was 77.8%, and the one-year OS rate was 94.4%. The median PFS was 18 months (95%CI, 15.9-20.1), and the median OS was 28 months (95%CI, 18.9-37.1). All AEs were controllable. CONCLUSION The combination of nimotuzumab and bevacizumab with TMZ and RT appears to demonstrate efficacy and safety in newly diagnosed GBM patients, providing a reference for clinical treatment. Further prospective studies are needed to confirm our results.
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Affiliation(s)
- Yaping Wu
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Zhiying Chen
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Mingtao Shi
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Shuo Qiu
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Yongchun Zhang
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China.
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Buonsenso D, Cotugno N, Amodio D, Pascucci GR, Di Sante G, Pighi C, Morrocchi E, Pucci A, Olivieri G, Colantoni N, Romani L, Rotili A, Neri A, Morello R, Sali M, Tremoulet A, Raffaelli F, Zampino G, Rossi P, Valentini P, Palma P. Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls. Pediatr Res 2025:10.1038/s41390-025-03837-0. [PMID: 39849114 DOI: 10.1038/s41390-025-03837-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Recent proteomic studies have documented that Long COVID in adults is characterized by a pro-inflammatory signature with thromboinflammation. However, if similar events happen also in children with Long COVID has never been investigated. METHODS We performed an extensive protein analysis of blood plasma from pediatric patients younger than 19 years of age Long COVID and a control group of children with acute COVID-19, MIS-C, and healthy controls resulted similar for sex distribution and age. Children were classified as Long COVID if symptoms persisted for at least 8 weeks since the initial infection, negatively impacted daily life and could not be explained otherwise. RESULTS 112 children were included in the study, including 34 children fulfilling clinical criteria of Long COVID, 32 acute SARS-CoV-2 infection, 27 MIS-C and 19 healthy controls. Compared with controls, pediatric Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A Machine Learning model based on proteomic profile was able to identify LC with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97. CONCLUSIONS Pediatric Long COVID patients have a well distinct blood protein signature marked by increased ongoing general and endothelial inflammation, similarly as happens in adults. IMPACT Pediatric Long COVID has a distinct blood protein signature marked by increased ongoing general and endothelial inflammation. This is the first study studying and documenting proinflammatory profile in blood samples of children with long COVID. Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A proteomic profile was able to identify Long COVID with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97. These findings may inform development of future diagnostic tests.
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Affiliation(s)
- Danilo Buonsenso
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Nicola Cotugno
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Donato Amodio
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Rubens Pascucci
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
- Probiomics S.r.l., Via Montpellier 1, Rome, 00133, Italy
| | - Gabriele Di Sante
- Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, University of Perugia, Rome, Italy
| | - Chiara Pighi
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Elena Morrocchi
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Alessandro Pucci
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Giulio Olivieri
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Nicole Colantoni
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Lorenza Romani
- Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Arianna Rotili
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Alessia Neri
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Rosa Morello
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Michela Sali
- Department of Biotechnological, Basic, Intensivological and Perioperatory Sciences-Section of Microbiology, Università Cattolica del S Cuore, Rome, 00168, Italy
- Department of Laboratory and Infectivology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Italy
| | - Adriana Tremoulet
- Department of Pediatrics & Kawasaki Disease Research Center, University of California San Diego (UCSD), San Diego, CA, USA
- Rady Children's Hospital, San Diego, CA, USA
| | - Francesca Raffaelli
- Department of Laboratory and Infectivology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Italy
| | - Giuseppe Zampino
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Paolo Rossi
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
- Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Piero Valentini
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Paolo Palma
- Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
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Nandi A, Nigar T, Das A, Dey YN. Network pharmacology analysis of Plumbago zeylanica to identify the therapeutic targets and molecular mechanisms involved in ameliorating hemorrhoids. J Biomol Struct Dyn 2025; 43:161-175. [PMID: 37948311 DOI: 10.1080/07391102.2023.2280681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
Plumbago zeylanica is an important plant used in the Ayurvedic system of medicine for the treatment of hemorrhoids or piles. Despite its clinical uses, its molecular mechanism, for ameliorating hemorrhoids is not yet explored. Hence, the present study evaluated the plausible molecular mechanisms of P. zeylanica in the treatment of hemorrhoids using network pharmacology and other in silico analysis. Network pharmacology was carried out by protein, GO, and KEGG enrichment analysis. Further ADME/T, molecular docking and dynamics studies of the resultant bioactive compounds of P. zeylanica with the regulated proteins were evaluated. Results of the network pharmacology analysis revealed that the key pathways and plausible molecular mechanisms involved in the treatment effects of P. zeylanica on hemorrhoids are cell migration, proliferation, motility, and apoptosis which are synchronized by cancer, focal adhesion, and by signalling relaxin, Rap1, and calcium pathways which indicates the involvement of angiogenesis and vasodilation which are the characteristic features of hemorrhoids. Further, the molecular docking and dynamics studies revealed that the bio active ingredients of P. zeylanica strongly bind with the key target proteins in the ambiance of hemorrhoids. Hence, the study revealed the mechanism of P. zeylanica in ameliorating hemorrhoids.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Arijit Nandi
- Department of Pharmacology, Dr. B.C. Roy College of Pharmacy and Allied Health Sciences, West Bengal, India
| | - Tanzeem Nigar
- Department of Pharmacology, Dr. B.C. Roy College of Pharmacy and Allied Health Sciences, West Bengal, India
| | - Anwesha Das
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Palaj, Gandhinagar, Gujarat, India
| | - Yadu Nandan Dey
- Department of Pharmacology, Dr. B.C. Roy College of Pharmacy and Allied Health Sciences, West Bengal, India
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Wang Z, Xu H, Xue B, Liu L, Tang Y, Wang Z, Yao K. MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis. Commun Biol 2024; 7:1700. [PMID: 39725699 DOI: 10.1038/s42003-024-07367-z] [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: 03/16/2023] [Accepted: 04/17/2024] [Indexed: 12/28/2024] Open
Abstract
Diabetic foot ulcer (DFU) is a common but devastating complication of diabetes mellitus and might ultimately lead to amputation. Elucidating the regulatory mechanism of wound healing in DFU is quite important for developing DFU management strategies. Here, we show, mecenchymal stem cell (MSC)-derived exosomes promoted the proliferation, migration and angiogenesis of high glucose-treated endothelial cells and reduced cell apoptosis. These effects were further enhanced by MSC-derived exosomes carrying circMYO9B overexpression. Mechanistically, circMYO9B promoted the translocation of hnRNPU from nucleus to cytoplasm and consequently destabilized CBL, thereby reducing the ubiquitination and degradation of KDM1A to promote VEGFA expression in endothelial cells. MSC-derived exosomes carrying circMYO9B promotes angiogenesis and thus accelerates diabetic wound healing through regulating the hnRNPU/CBL/KDM1A/VEGFA axis, indicating potential therapeutic targets and strategies for DFU treatment.
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Affiliation(s)
- Zheng Wang
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Hongbo Xu
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Bichen Xue
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Lian Liu
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Yulin Tang
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Zhichao Wang
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China
| | - Kai Yao
- Department of Vascular surgery, The Third Xiangya Hospital Central South University, Changsha, 410000, Hunan Province, PR China.
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Jin LL, Lu HJ, Shao JK, Wang Y, Lu SP, Huang BF, Hu GN, Jin HC, Wang CQ. Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer. Mol Cell Biochem 2024; 479:3037-3047. [PMID: 38145448 DOI: 10.1007/s11010-023-04907-9] [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: 08/18/2023] [Accepted: 11/25/2023] [Indexed: 12/26/2023]
Abstract
The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.
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Affiliation(s)
- Lu-Lu Jin
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Hua-Jun Lu
- Department of Oncological Radiotherapy, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Jun-Kang Shao
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Yan Wang
- Department of Medical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Shi-Ping Lu
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Bi-Fei Huang
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Gui-Nv Hu
- Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Hong-Chuan Jin
- Laboratory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China
| | - Chao-Qun Wang
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China.
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Adegboyega FN, Anifowose LO, Hammad SF, Ghazy MA. Repurposing Antiviral Drugs as Potential Anti-EGFR Agents in NSCLC: A Structure-Based Screening and Molecular Dynamics Analysis. Chem Biodivers 2024; 21:e202400898. [PMID: 39078025 DOI: 10.1002/cbdv.202400898] [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: 04/09/2024] [Revised: 07/04/2024] [Accepted: 07/29/2024] [Indexed: 07/31/2024]
Abstract
One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expression of oncogenic proteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti-EGFR agents for NSCLC. We used structure-based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i. e. surpassing a threshold of -8.5 kcal mol-1) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (-9.8 kcal mol-1), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti-EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.
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Affiliation(s)
- Fikayo N Adegboyega
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Lateef O Anifowose
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Sherif F Hammad
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Mohamed A Ghazy
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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8
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Trivedi AH, Wang VZ, McClain EJ, Vyas PS, Swink IR, Snell ED, Cheng BC, DeMeo PJ. The Categorization of Perinatal Derivatives for Orthopedic Applications. Biomedicines 2024; 12:1544. [PMID: 39062117 PMCID: PMC11274709 DOI: 10.3390/biomedicines12071544] [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: 05/01/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Musculoskeletal (MSK) pathology encompasses an array of conditions that can cause anything from mild discomfort to permanent injury. Their prevalence and impact on disability have sparked interest in more effective treatments, particularly within orthopedics. As a result, the human placenta has come into focus within regenerative medicine as a perinatal derivative (PnD). These biologics are sourced from components of the placenta, each possessing a unique composition of collagens, proteins, and factors believed to aid in healing and regeneration. This review aims to explore the current literature on PnD biologics and their potential benefits for treating various MSK pathologies. We delve into different types of PnDs and their healing effects on muscles, tendons, bones, cartilage, ligaments, and nerves. Our discussions highlight the crucial role of immune modulation in the healing process for each condition. PnDs have been observed to influence the balance between anti- and pro-inflammatory factors and, in some cases, act as biologic scaffolds for tissue growth. Additionally, we assess the range of PnDs available, while also addressing gaps in our understanding, particularly regarding biologic processing methods. Although certain PnD biologics have varying levels of support in orthopedic literature, further clinical investigations are necessary to fully evaluate their impact on human patients.
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Affiliation(s)
- Amol H. Trivedi
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
- Drexel University College of Medicine, Drexel University, University City Campus, Philadelphia, PA 19104, USA
| | - Vicki Z. Wang
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Edward J. McClain
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Praveer S. Vyas
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Isaac R. Swink
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Edward D. Snell
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Boyle C. Cheng
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Patrick J. DeMeo
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
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9
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Lee HJ, Choi HJ, Jeong YJ, Na YH, Hong JT, Han JM, Hoe HS, Lim KH. Developing theragnostics for Alzheimer's disease: Insights from cancer treatment. Int J Biol Macromol 2024; 269:131925. [PMID: 38685540 DOI: 10.1016/j.ijbiomac.2024.131925] [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: 01/01/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
The prevalence of Alzheimer's disease (AD) and its associated economic and societal burdens are on the rise, but there are no curative treatments for AD. Interestingly, this neurodegenerative disease shares several biological and pathophysiological features with cancer, including cell-cycle dysregulation, angiogenesis, mitochondrial dysfunction, protein misfolding, and DNA damage. However, the genetic factors contributing to the overlap in biological processes between cancer and AD have not been actively studied. In this review, we discuss the shared biological features of cancer and AD, the molecular targets of anticancer drugs, and therapeutic approaches. First, we outline the common biological features of cancer and AD. Second, we describe several anticancer drugs, their molecular targets, and their effects on AD pathology. Finally, we discuss how protein-protein interactions (PPIs), receptor inhibition, immunotherapy, and gene therapy can be exploited for the cure and management of both cancer and AD. Collectively, this review provides insights for the development of AD theragnostics based on cancer drugs and molecular targets.
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Affiliation(s)
- Hyun-Ju Lee
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Hee-Jeong Choi
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Yoo Joo Jeong
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea
| | - Yoon-Hee Na
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Ji Min Han
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
| | - Hyang-Sook Hoe
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea.
| | - Key-Hwan Lim
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
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10
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Pesce NA, Plastino F, Reyes-Goya C, Bernd J, Pavone V, Dal Monte M, Kvanta A, Locri F, André H. Mitigation of human iris angiogenesis through uPAR/LRP-1 interaction antagonism in an organotypic ex vivo model. FASEB J 2024; 38:e23533. [PMID: 38451430 DOI: 10.1096/fj.202301892rr] [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: 09/15/2023] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/08/2024]
Abstract
Rubeosis Iridis (RI) is characterized by an increase in neovascularization and inflammation factors in the iris. During angiogenesis, the urokinase plasminogen activator (uPA) and its receptor (uPAR) play a pivotal role in extracellular matrix remodeling, where uPAR regulates endothelial cell migration and proliferation through assembly with transmembrane receptors. Here, in the context of hypoxia-induced angiogenesis, the uPA/uPAR system blockage was investigated by using UPARANT in a novel ex vivo human iris organotypic angiogenesis assay. The effects of uPA/uPAR system antagonism in the humanized model of ocular pathologic angiogenesis were analyzed by sprouting angiogenesis and protein assays (western, dot blots, and co-immunoprecipitation) and correlated to vascular endothelial growth factor (VEGF) inhibition. Phosphoprotein and co-immunoprecipitation assay illustrated an unidentified antagonism of UPARANT in the interaction of uPAR with the low-density lipoprotein receptor-related protein-1 (LRP-1), resulting in inhibition of β-catenin-mediated angiogenesis in this model. The effects of uPA/uPAR system inhibition were focal to endothelial cells ex vivo. Comparison between human iris endothelial cells and human retinal endothelial revealed an endothelial-specific mechanism of β-catenin-mediated angiogenesis inhibited by uPA/uPAR system blockage and not by VEGF inhibition. Collectively, these findings broaden the understanding of the effects of the uPA/uPAR system antagonism in the context of angiogenesis, revealing non-canonical β-catenin downstream effects mediated by LRP-1/uPAR interaction.
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Affiliation(s)
- Noemi Anna Pesce
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
- Department of Biology, University of Pisa, Pisa, Italy
| | - Flavia Plastino
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | | | - Jonathan Bernd
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Vincenzo Pavone
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | | | - Anders Kvanta
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Filippo Locri
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Helder André
- Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
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11
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Mannan A, Dhiamn S, Garg N, Singh TG. Pharmacological modulation of Sonic Hedgehog signaling pathways in Angiogenesis: A mechanistic perspective. Dev Biol 2023; 504:58-74. [PMID: 37739118 DOI: 10.1016/j.ydbio.2023.09.009] [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: 06/01/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
The Sonic hedgehog (SHh) signaling pathway is an imperative operating network that helps in regulates the critical events during the development processes like multicellular embryo growth and patterning. Disruptions in SHh pathway regulation can have severe consequences, including congenital disabilities, stem cell renewal, tissue regeneration, and cancer/tumor growth. Activation of the SHh signal occurs when SHh binds to the receptor complex of Patch (Ptc)-mediated Smoothened (Smo) (Ptc-smo), initiating downstream signaling. This review explores how pharmacological modulation of the SHh pathway affects angiogenesis through canonical and non-canonical pathways. The canonical pathway for angiogenesis involves the activation of angiogenic cytokines such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), stromal cell-derived factor 1α, transforming growth factor-β1 (TGF-β1), and angiopoietins (Ang-1 and Ang-2), which facilitate the process of angiogenesis. The Non-canonical pathway includes indirect activation of certain pathways like iNOS/Netrin-1/PKC, RhoA/Rock, ERK/MAPK, PI3K/Akt, Wnt/β-catenin, Notch signaling pathway, and so on. This review will provide a better grasp of the mechanistic approach of SHh in mediating angiogenesis, which can aid in the suppression of certain cancer and tumor growths.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiamn
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Nikhil Garg
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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12
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Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren-Bonnier M, Runold M, Bruchfeld J, Nickander J, Deng Q, Checa A, Desta L, Pernow J, Ståhlberg M. Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study. Sci Rep 2023; 13:20230. [PMID: 37981644 PMCID: PMC10658082 DOI: 10.1038/s41598-023-47539-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 11/14/2023] [Indexed: 11/21/2023] Open
Abstract
Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.
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Affiliation(s)
- Ali Mahdi
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden.
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
| | - Allan Zhao
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Emelie Fredengren
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
| | - Artur Fedorowski
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Frieder Braunschweig
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Malin Nygren-Bonnier
- Division of Physiotherapy, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Women's Health and Allied Health Professionals Theme, Medical Unit Occupational Therapy and Physiotherapy, Karolinska University Hospital, Stockholm, Sweden
| | - Michael Runold
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Judith Bruchfeld
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Jannike Nickander
- Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet, Stockholm, Sweden
| | - Qiaolin Deng
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Antonio Checa
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Liyew Desta
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - John Pernow
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Marcus Ståhlberg
- Department of Medicine; Solna, Karolinska Institute, 171 77, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
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13
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Bui TVA, Kim JJ, Huang X, Pu A, Li X, Hong SB, Choi YJ, Kim HW, Yao X, Park HJ, Ban K. Core-Shell Droplet-Based Angiogenic Patches for the Treatment of Ischemic Diseases: Ultrafast Processability, Physical Tunability, and Controlled Delivery of an Angiogenic Cocktail. ACS APPLIED MATERIALS & INTERFACES 2023; 15:50693-50707. [PMID: 37812574 DOI: 10.1021/acsami.3c09062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
The patch-based delivery system has been a promising therapeutic approach for treating various vascular diseases. However, conventional methods face several challenges, including labor-intensive and time-consuming processes associated with patch fabrication or factor incorporation, inadequate physical properties, and uncontrolled release of factors. These limitations restrict the potential applications in clinical settings. To overcome these issues, we propose a novel core-shell-shaped droplet patch system called an angiogenic patch (AP). Our system offers several distinct advantages over conventional patches. It enables a rapid and straightforward fabrication process utilizing only two biodegradable ingredients [alginate and ε-poly(l-lysine)], ensuring minimal toxicity. Moreover, the AP exhibits excellent physical integrity to match and withstand physiological mechanics and allows for customizable patch dimensions tailored to individual patients' pathological conditions. Notably, the AP enables facile loading of angiogenic cytokines during patch fabrication, allowing sustained release at a controlled rate through tunable network cross-linking. Subsequently, the AP, delivering a precisely formulated cocktail of angiogenic cytokines (VEGF, bFGF, EGF, and IGF), demonstrated significant effects on endothelial cell functions (migration and tubule formation) and survival under pathological conditions simulating ischemic injury. Likewise, in in vivo experiments using a mouse model of hindlimb ischemia, the AP encapsulating the angiogenic cocktail effectively restored blood flow following an ischemic insult, promoting muscle regeneration and preventing limb loss. With its simplicity and rapid processability, user-friendly applicability, physical tunability, and the ability to efficiently load and control the delivery of angiogenic factors, the AP holds great promise as a therapeutic means for treating patients with ischemic diseases.
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Affiliation(s)
- Thi Van Anh Bui
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
- Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
| | - Jin-Ju Kim
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Xin Huang
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
| | - Aoyang Pu
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
- Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
| | - Xin Li
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
| | - Seok Beom Hong
- Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Yeon-Jik Choi
- Division of Cardiology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, Catholic University College of Medicine, Seoul 06591, Republic of Korea
| | - Hae-Won Kim
- Institute of Tissue Regeneration Engineering, Dankook University, Cheonan 31116, Republic of Korea
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
- Mechanobiology Dental Medicine Research Center and College of Dentistry, Dankook University, Cheonan 31116, Republic of Korea
| | - Xi Yao
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
| | - Hun-Jun Park
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kiwon Ban
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
- Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon 999077, Hong Kong SAR
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14
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Horikami D, Sekihachi E, Omori K, Kobayashi Y, Kobayashi K, Nagata N, Kurata K, Uemura A, Murata T. Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis. J Lipid Res 2023; 64:100439. [PMID: 37666361 PMCID: PMC10571029 DOI: 10.1016/j.jlr.2023.100439] [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: 03/23/2023] [Revised: 08/19/2023] [Accepted: 08/22/2023] [Indexed: 09/06/2023] Open
Abstract
Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D2 is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D2 metabolite, 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-β antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis.
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Affiliation(s)
- Daiki Horikami
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Erika Sekihachi
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Keisuke Omori
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yui Kobayashi
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Koji Kobayashi
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Nanae Nagata
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kaori Kurata
- Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
| | - Akiyoshi Uemura
- Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
| | - Takahisa Murata
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
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15
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Guo Y, Hu Z, Chen J, Zhang J, Fan Z, Qu Q, Miao Y. Feasibility of adipose-derived therapies for hair regeneration: Insights based on signaling interplay and clinical overview. J Am Acad Dermatol 2023; 89:784-794. [PMID: 34883154 DOI: 10.1016/j.jaad.2021.11.058] [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: 02/17/2021] [Revised: 09/13/2021] [Accepted: 11/30/2021] [Indexed: 11/22/2022]
Abstract
Dermal white adipose tissue (dWAT) is a dynamic component of the skin and closely interacts with the hair follicle. Interestingly, dWAT envelops the hair follicle during anagen and undergoes fluctuations in volume throughout the hair cycle. dWAT-derived extracellular vesicles can significantly regulate the hair cycle, and this provides a theoretical basis for utilizing adipose tissue as a feasible clinical strategy to treat hair loss. However, the amount and depth of the available literature are far from enough to fully elucidate the prominent role of dWAT in modulating the hair growth cycle. This review starts by investigating the hair cycle-coupled dWAT remodeling and the reciprocal signaling interplay underneath. Then, it summarizes the current literature and assesses the advantages and limitations of clinical research utilizing adipose-derived therapies for hair regeneration.
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Affiliation(s)
- Yilong Guo
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jian Chen
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jiarui Zhang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhexiang Fan
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Qian Qu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
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16
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Ali M, Kwak SH, Byeon JY, Choi HJ. In Vitro and In Vivo Evaluation of Epidermal Growth Factor (EGF) Loaded Alginate-Hyaluronic Acid (AlgHA) Microbeads System for Wound Healing. J Funct Biomater 2023; 14:403. [PMID: 37623648 PMCID: PMC10455903 DOI: 10.3390/jfb14080403] [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: 06/21/2023] [Revised: 07/11/2023] [Accepted: 07/25/2023] [Indexed: 08/26/2023] Open
Abstract
The management of skin injuries is one of the most common concerns in medical facilities. Different types of biomaterials with effective wound-healing characteristics have been studied previously. In this study, we used alginate (Alg) and hyaluronic acid (HA) composite (80:20) beads for the sustained release of epidermal growth factor (EGF) delivery. Heparin crosslinked AlgHA beads showed significant loading and entrapment of EGF. Encapsulated beads demonstrated biocompatibility with rat L929 cells and significant migration at the concentration of AlgHAEGF100 and AlgHAEGF150 within 24 h. Both groups significantly improved the expression of Fetal Liver Kinase 1 (FLK-1) along with the Intercellular Adhesion Molecule-1 (ICAM-1) protein in rat bone Mesenchymal stem cells (rbMSCs). In vivo assessment exhibited significant epithelialization and wound closure gaps within 2 weeks. Immunohistochemistry shows markedly significant levels of ICAM-1, FLK-1, and fibronectin (FN) in the AlgHAEGF100 and AlgHAEGF150 groups. Hence, we conclude that the EGF-loaded alginate-hyaluronic acid (AlgHA) bead system can be used to promote wound healing.
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Affiliation(s)
- Maqsood Ali
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan 31538, Republic of Korea
| | - Si Hyun Kwak
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan 31538, Republic of Korea
| | - Je Yeon Byeon
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan 31538, Republic of Korea
| | - Hwan Jun Choi
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan 31538, Republic of Korea
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17
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Middelkoop MA, Don EE, Hehenkamp WJK, Polman NJ, Griffioen AW, Huirne JAF. Angiogenesis in abnormal uterine bleeding: a narrative review. Hum Reprod Update 2023; 29:457-485. [PMID: 36857162 PMCID: PMC10320491 DOI: 10.1093/humupd/dmad004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/12/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation. OBJECTIVE AND RATIONALE We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms. SEARCH METHODS A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale. OUTCOMES Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures. WIDER IMPLICATIONS AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.
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Affiliation(s)
- Mei-An Middelkoop
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
| | - Emma E Don
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
| | - Wouter J K Hehenkamp
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
| | - Nicole J Polman
- Department of Obstetrics and Gynaecology, Flevoziekenhuis, Almere, the Netherlands
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Judith A F Huirne
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
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18
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Sun N, Akay LA, Murdock MH, Park Y, Galiana-Melendez F, Bubnys A, Galani K, Mathys H, Jiang X, Ng AP, Bennett DA, Tsai LH, Kellis M. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease. Nat Neurosci 2023; 26:970-982. [PMID: 37264161 PMCID: PMC10464935 DOI: 10.1038/s41593-023-01334-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/17/2023] [Indexed: 06/03/2023]
Abstract
Cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascular cells, including 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast and ependymal cells. We identify 2,676 differentially expressed genes in AD, including downregulation of PDGFRB in pericytes, and of ABCB1 and ATP10A in endothelial cells, and validate the downregulation of SLC6A1 and upregulation of APOD, INSR and COL4A1 in postmortem AD brain tissues. We detect vasculature, glial and neuronal coexpressed gene modules, suggesting coordinated neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD differentially expressed genes directly linked to AD-associated genetic variants. Lastly, we show that APOE4 genotype-associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, as well as subsets of pericytes and fibroblasts.
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Affiliation(s)
- Na Sun
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Leyla Anne Akay
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Mitchell H Murdock
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Yongjin Park
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Pathology and Laboratory Medicine, Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Fabiola Galiana-Melendez
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Adele Bubnys
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Kyriaki Galani
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hansruedi Mathys
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xueqiao Jiang
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ayesha P Ng
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Li-Huei Tsai
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Manolis Kellis
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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19
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Lu CF, Liao CY, Chao HS, Chiu HY, Wang TW, Lee Y, Chen JR, Shiao TH, Chen YM, Wu YT. A radiomics-based deep learning approach to predict progression free-survival after tyrosine kinase inhibitor therapy in non-small cell lung cancer. Cancer Imaging 2023; 23:9. [PMID: 36670497 PMCID: PMC9854198 DOI: 10.1186/s40644-023-00522-5] [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: 09/21/2022] [Accepted: 01/05/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. Approximately half of the patients with EGFR-mutated NSCLC are treated with EGFR-TKIs and develop disease progression within 1 year. Therefore, the early prediction of tumor progression in patients who receive EGFR-TKIs can facilitate patient management and development of treatment strategies. We proposed a deep learning approach based on both quantitative computed tomography (CT) characteristics and clinical data to predict progression-free survival (PFS) in patients with advanced NSCLC after EGFR-TKI treatment. METHODS A total of 593 radiomic features were extracted from pretreatment chest CT images. The DeepSurv models for the progression risk stratification of EGFR-TKI treatment were proposed based on CT radiomic and clinical features from 270 stage IIIB-IV EGFR-mutant NSCLC patients. Time-dependent PFS predictions at 3, 12, 18, and 24 months and estimated personalized PFS curves were calculated using the DeepSurv models. RESULTS The model combining clinical and radiomic features demonstrated better prediction performance than the clinical model. The model achieving areas under the curve of 0.76, 0.77, 0.76, and 0.86 can predict PFS at 3, 12, 18, and 24 months, respectively. The personalized PFS curves showed significant differences (p < 0.003) between groups with good (PFS > median) and poor (PFS < median) tumor control. CONCLUSIONS The DeepSurv models provided reliable multi-time-point PFS predictions for EGFR-TKI treatment. The personalized PFS curves can help make accurate and individualized predictions of tumor progression. The proposed deep learning approach holds promise for improving the pre-TKI personalized management of patients with EGFR-mutated NSCLC.
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Affiliation(s)
- Chia-Feng Lu
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Yi Liao
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Heng-Sheng Chao
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Hwa-Yen Chiu
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-Wei Wang
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen Lee
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jyun-Ru Chen
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsu-Hui Shiao
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Yuh-Min Chen
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Te Wu
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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20
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Chakraborty A, Pacelli S, Alexander S, Huayamares S, Rosenkrans Z, Vergel FE, Wu Y, Chakravorty A, Paul A. Nanoparticle-Reinforced Tough Hydrogel as a Versatile Platform for Pharmaceutical Drug Delivery: Preparation and in Vitro Characterization. Mol Pharm 2023; 20:767-774. [PMID: 36322617 DOI: 10.1021/acs.molpharmaceut.2c00564] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Natural polymer-based hydrogels are excellent for encapsulating hydrophilic drugs, but they are mechanically weak and degrade easily. In this communication, we exploit the electrostatic interaction between nanosilicates (nSi) and gelatin methacrylate (GelMA) to form a mechanically tough nanocomposite hydrogel for pharmaceutical drug delivery. These hydrogels, prepared at subzero temperatures to form cryogels, displayed macroporous structures, which favors cell infiltration. The designed tough cryogel also showed a slower rate of degradation. Furthermore, we encapsulated the small molecule metformin and sustained the drug release under physiological conditions. Cryogel-loaded metformin reduced the effect of endothelial cell injury caused by nutrient deprivation in vitro. Finally, we hypothesize that this versatile nanocomposite material will find use in diverse biomedical applications.
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Affiliation(s)
- Aishik Chakraborty
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, ON N6A 5B9, Canada
| | - Settimio Pacelli
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
| | - Shana Alexander
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, ON N6A 5B9, Canada
| | - Sebastian Huayamares
- Department of Chemical & Petroleum Engineering, The University of Kansas, Lawrence, Kansas 66045, United States
| | - Zachary Rosenkrans
- Department of Chemical & Petroleum Engineering, The University of Kansas, Lawrence, Kansas 66045, United States
| | - Filippo Elmi Vergel
- Department of Chemical & Petroleum Engineering, The University of Kansas, Lawrence, Kansas 66045, United States
| | - Yuanyi Wu
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, ON N6A 5B9, Canada
| | - Adrija Chakravorty
- Department of Chemical Engineering, Birla Institute of Technology and Science Pilani, K K Birla Goa Campus, Zurinagar, Goa 403726, India
| | - Arghya Paul
- Department of Chemical and Biochemical Engineering, School of Biomedical Engineering, Department of Chemistry, The Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, London, ON N6A 5B9, Canada
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21
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Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne) 2023; 10:1140979. [PMID: 37020673 PMCID: PMC10067680 DOI: 10.3389/fmed.2023.1140979] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.
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Affiliation(s)
- Bailey D. Lyttle
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Bailey D. Lyttle,
| | - Alyssa E. Vaughn
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - James R. Bardill
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Anisha Apte
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Lauren T. Gallagher
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
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22
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Lyu T, Zhou S, Fang J, Wang L, Shi L, Dong Y, Zhang H. Convergent Genomic Signatures of High-Altitude Adaptation among Six Independently Evolved Mammals. Animals (Basel) 2022; 12:ani12243572. [PMID: 36552492 PMCID: PMC9774524 DOI: 10.3390/ani12243572] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/08/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
The species living in the Qinghai-Tibet Plateau provide an excellent model system for studying the relationship between molecular convergent evolution and adaptation. Distant species experiencing the same selection pressure (i.e., hypoxia, low temperature and strong ultraviolet radiation) are likely to evolve similar genetic adaptations independently. Here, we performed comparative genomics studies on six independently evolved high-altitude species. The results also showed that the convergent evolution of the six species was mainly reflected at the level of rapidly evolving genes, and the functions of these rapidly evolving genes were mainly related to hypoxia response and DNA damage repair. In addition, we found that high-altitude species had more gene family changes than their low-altitude relatives, except for the order Lagomorpha. The results also show that the convergence of the gene family contraction of high-altitude species is much greater than that of expansion, revealing a possible pattern of species in adapting to high-altitude. Furthermore, we detected a positive selection signature in four genes related to hypoxia response and ultraviolet radiation damage in these six species (FYCO1, ERBIN, SCAMP1 and CXCL10). Our study reveals that hypoxia response might play an important role in the adaptation of independently evolved species to a high-altitude environment, providing a basic perspective for further exploring the high-altitude adaptation mechanism of different related species in the future.
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Affiliation(s)
- Tianshu Lyu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150000, China
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Shengyang Zhou
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Jiaohui Fang
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Lidong Wang
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Lupeng Shi
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Yuehuan Dong
- College of Life Science, Qufu Normal University, Qufu 273165, China
| | - Honghai Zhang
- College of Life Science, Qufu Normal University, Qufu 273165, China
- Correspondence:
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23
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Liu C, Wang M, Zhang H, Li C, Zhang T, Liu H, Zhu S, Chen J. Tumor microenvironment and immunotherapy of oral cancer. Eur J Med Res 2022; 27:198. [PMID: 36209263 PMCID: PMC9547678 DOI: 10.1186/s40001-022-00835-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/22/2022] [Indexed: 11/10/2022] Open
Abstract
Oral cancer is one of the most common malignant tumors of the head and neck, not only affects the appearance, but also affects eating and even endangers life. The clinical treatments of oral cancer mainly include surgery, radiotherapy, and chemotherapy. However, unsatisfactory therapeutic effect and toxic side effects are still the main problems in clinical treatment. Tumor microenvironment (TME) is not only closely related to the occurrence, growth, and metastasis of tumor but also works in the diagnosis, prevention, and treatment of tumor and prognosis. Future studies should continue to investigate the relationship of TME and oral cancer therapy. This purpose of this review was to analyze the characteristics of oral cancer microenvironment, summarize the traditional oral cancer therapy and immunotherapy strategies, and finally prospect the development prospects of oral cancer immunotherapy. Immunotherapy targeting tumor microenvironment is expected to provide a new strategy for clinical treatment of oral cancer.
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Affiliation(s)
- Chang Liu
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Min Wang
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Haiyang Zhang
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Chunyan Li
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Tianshou Zhang
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Hong Liu
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China
| | - Song Zhu
- Hospital of Stomatology, Jilin University, Changchun, 130021, People's Republic of China.
| | - Jie Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China.
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24
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Schürmann M, Goon P, Sudhoff H. Review of potential medical treatments for middle ear cholesteatoma. Cell Commun Signal 2022; 20:148. [PMID: 36123729 PMCID: PMC9487140 DOI: 10.1186/s12964-022-00953-w] [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: 06/30/2022] [Accepted: 08/05/2022] [Indexed: 11/15/2022] Open
Abstract
Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn’s disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history.
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