{"title":"Recent Development in Celiac Disease: Pathophysiology, Animal Models and Treatments","authors":"Vishal Patel, Amit Joharapurkar, Mukul Jain","doi":"10.1002/ddr.70149","DOIUrl":"10.1002/ddr.70149","url":null,"abstract":"<div>\u0000 \u0000 <p>Celiac disease (CD) is an autoimmune disorder which is triggered by gluten in genetically susceptible individuals. There is no successful therapy for CD. A strict gluten-free diet (GFD) is the only remedy used in clinical practice, which highlights the need to develop pharmacotherapeutic approaches to treat CD. This review discussed the data from genetic, biochemical, and immunological research, which has identified the mechanisms that causes activation of gluten which cause sequential immunological cascade through antigen presenting cell (APC) and human leukocyte antigen (HLA) dependent pathway. Recent studies aim to develop medications that stimulate repair of intestinal barrier, modify gluten peptides to make less immunogenic, regulate immune responses, and reduce CD associated symptoms. These approaches are mostly investigated in addition to GFD. In addition to these approaches, therapies that may work without gluten restriction need to be prioritized for patients who continue to experience symptoms despite strict adherence to GFD.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tong Liu, Jiajie Kong, Zhaobin Li, Shuqiang Xi, Lei Liu
{"title":"Sestrin2 Regulates Mitochondrial Function and Autophagy via Nrf2/SIRT3 Signaling to Ameliorate Hypoxia/Reoxygenation-Induced Rat's Cardiomyocyte Injury","authors":"Tong Liu, Jiajie Kong, Zhaobin Li, Shuqiang Xi, Lei Liu","doi":"10.1002/ddr.70150","DOIUrl":"10.1002/ddr.70150","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitigating myocardial ischemia-reperfusion (I/R) injury poses a significant challenge, necessitating the exploration of novel therapeutic targets. Sestrin2 (Sesn2), a stress-induced protein, has emerged as a potential candidate for attenuating I/R injury, yet its precise mechanisms remain elusive. The role of Sesn2 was investigated using an in vitro model of H9C2 cardiomyocytes subjected to hypoxia-reoxygenation (H/R). Sesn2 expression was modulated through overexpression techniques, and cellular responses, including cell viability, inflammatory factor production, mitochondrial function, oxidative stress, autophagy, and apoptosis, were assessed. Furthermore, the role of the Nrf2/SIRT3 signaling pathway in the mechanism was explored via treating cells with Nrf2 inhibitor ML385. Sesn2 overexpression significantly improved cell viability, attenuated inflammatory factor production, preserved mitochondrial function, and mitigated oxidative stress in H/R-exposed cardiomyocytes. Additionally, Sesn2 enhanced autophagy and modulated the Nrf2/SIRT3 signaling pathway. Moreover, Sesn2-mediated protection was reversed upon inhibition of Nrf2 signaling, underscoring the importance of this pathway in Sesn2-induced protection. Our findings may elucidate the mechanism of Sesn2-mediated protection and highlight its potential as a therapeutic target to ameliorate H/R-induced cardiomyocyte injury.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting the Enzymatic Site of Botulinum Neurotoxin Type E With 8-Hydroxyquinolinol–Based Inhibitors: In Silico, In Vitro, and In Vivo Evaluation","authors":"Priyanka Sonkar, Vinita Chauhan Kushwah, Surabhi Agnihotri, Deeksha Disoriya, Manorama Vimal, Ram Kumar Dhaked","doi":"10.1002/ddr.70148","DOIUrl":"10.1002/ddr.70148","url":null,"abstract":"<div>\u0000 \u0000 <p>Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and effective active/passive prophylaxis available for the treatment. Therefore, it is highly desirable to develop a potential antidote to counter botulinum neurotoxicity. In this study, ~800 molecules were mined by a structure similarity search from open databases and docked into the pocket of the catalytic domain of botulinum toxin type E using AutoDock 4.2. Twenty-four small molecules with the best scoring function were selected and evaluated using in vitro and in vivo assays. Among these, two molecules, NSC1011 and NSC1012, were identified as inhibiting the catalytic activity of BoNT/E, with IC<sub>50</sub> values of 31.25 ± 1.0 μM and 55.45 ± 5.2 μM and <i>K</i><sub>D</sub> of 5.54E−07 and 6.51E−06 M, respectively. To find inhibitors that can reverse the neurotoxicity more effectively, we have derived and synthesized 12 analogs of NSC1011. These compounds showed higher inhibition than the parent molecules, with IC<sub>50</sub> and <i>K</i><sub>D</sub> values of 4.375 ± 2.3 µM and 1.61E−08 M (C25.12) and 10.25 ± 3.0 µM and 4.70E-08 M (C25.9). Compounds C25.9 and C25.12 completely protected mice in premixed doses and led to significant extension in survival of up to 60 h with therapeutic treatment. This study showed that these 8-HQ derivatives had the potency to inhibit BoNT/E by interacting with the active site. Further studies could lead to the development of undiscovered postexposure therapeutics against this deadly neurotoxin.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cationic Lipid Stearylamine Displays Fast-Acting Antimalarial Action Against In Vitro Blood Stages of Chloroquine Susceptible and Resistant Plasmodium falciparum Strains","authors":"Vinoth Rajendran, Keerthana Gurukkalot, Nimitha Cherthedath Naveen","doi":"10.1002/ddr.70147","DOIUrl":"10.1002/ddr.70147","url":null,"abstract":"<div>\u0000 \u0000 <p>The growing resistance of malarial parasites to antiplasmodial drugs has necessitated the development of a new class of potent molecules to reduce the global malaria burden. This study evaluated the antimalarial efficacy of the cationic lipid stearylamine (SA) on blood-stage <i>Plasmodium falciparum</i> using SYBR-Green I assay. We conducted in vitro studies to assess the timing of SA action in drug-sensitive (<i>Pf</i>3D7) and chloroquine-resistant (<i>Pf</i>INDO) strains of <i>P. falciparum</i>. Notably, SA demonstrated fast-acting cytostatic potential with 50% inhibitory concentration (IC<sub>50</sub>s) values of 2.17, 1.97, and 1.33 µg/mL for <i>Pf</i>3D7 and 3.50, 2.76, and 1.94 µg/mL for <i>Pf</i>INDO during the first generation cycle (12, 24, and 48 h), and the activity was maintained during the second generation cycle with IC<sub>50</sub> values at 72 h (1.15 µg/mL on <i>Pf</i>3D7 and 1.65 µg/mL on <i>Pf</i>INDO) and 96 h (1.43 µg/mL on <i>Pf</i>3D7 and 1.10 µg/mL on <i>Pf</i>INDO). Additionally, we explored the cytocidal potential of SA by exposing the parasites for 1, 2, 4, and 6 h and subsequent incubation for 48 h in SA-free conditions, which revealed an average IC<sub>50</sub> value of 1.68 µg/mL, demonstrating its irreversible parasite growth arrest. Moreover, SA induced reactive oxygen species (ROS) production at IC<sub>50</sub> concentrations, with minimal hemolytic effects. Our findings indicated that incorporating SA into lipid vehicles or other delivery systems loaded with antimalarial drugs can significantly reduce drug toxicity, enhance efficacy, and slow clinical resistance. Nevertheless, further preclinical studies are warranted to advance the antimalarial drug discovery pipeline.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Berberine as a Multi-Targeted Therapeutic Agent in Melanoma: Mechanisms, Efficacy, and Combination Therapies","authors":"Rong-rong Wang, Hui Wu, Meng-ling Feng, Jia-li Zhong, Rui-xi Li, Bo-xuan Zhou","doi":"10.1002/ddr.70144","DOIUrl":"10.1002/ddr.70144","url":null,"abstract":"<div>\u0000 \u0000 <p>Melanoma is a type of aggressive cancer distinguished by its high propensity for recurrence, the development of metastases, and an unfavorable outlook for recovery. Treatment modalities for melanoma encompass surgery, immunotherapy, and targeted therapies. In recent decades, berberine has garnered attention for its significant anticancer properties across various cancer types. This review systematically examines the molecular mechanisms of berberine in melanoma, particularly its modulation of critical signaling pathways, including B-RAF/MEK/ERK, PI3K/AKT, and NF-κB, which are essential for regulating melanoma cell proliferation and promoting apoptosis. Furthermore, berberine activates AMP-activated protein kinase, leading to the inhibition of cyclooxygenase-2, thereby reducing melanoma cell migration and invasion through decreased inflammation and enhanced cellular energy regulation. It also induces mitochondrial dysfunction and oxidative stress, promoting apoptosis while simultaneously inhibiting epithelial-to-mesenchymal transition, a key process in metastasis. Additionally, berberine modulates the immune microenvironment through Toll-like receptors, cytokine networks, and the regulation of various immune cells, thereby enhancing its antitumor effects. Recent studies have shown that the therapeutic effect of berberine is enhanced when used in combination with other therapies, especially immune checkpoint inhibitors, to improve antitumor immune responses. These findings highlight the potential of berberine as a multi-targeted agent for the treatment of melanoma, providing an avenue for further clinical exploration and integration into therapeutic strategies.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Space Pharmaceutical Manufacturing: Emergence of a New Era for Pharmaceutical Industry","authors":"Manali Patel, Anvi Naphade, Priti Mehta","doi":"10.1002/ddr.70145","DOIUrl":"10.1002/ddr.70145","url":null,"abstract":"<div>\u0000 \u0000 <p>The space environment, characterized by microgravity and elevated radiation, offers a unique platform for scientific research with transformative potential for biomedical and pharmaceutical industries. As launch costs have decreased and commercial innovation has advanced, utilization of space for research has surged, with both space stations and nano/microsatellites (CubeSats) serving as essential platforms for ground breaking experiments. This systematic review summarizing findings from 86 peer-reviewed articles and major space research initiatives, focusing on the biological and medical insights gained from space-based investigations. Studies conducted in microgravity have revealed significant alterations in bacterial physiology, including increased virulence and antibiotic resistance, as well as enhanced secondary metabolite production with potential pharmaceutical applications. Human physiological changes, such as muscle atrophy, bone demineralization, and cardiovascular deconditioning, mirror accelerated aging and disease states, providing valuable models for understanding and developing treatments for similar conditions on Earth. Space research has also highlighted the risk of kidney stone formation due to altered calcium metabolism and gut microbiome shifts, along with ophthalmological abnormalities such as Spaceflight-Associated Neuro-Ocular Syndrome (SANS), which offer insights into terrestrial eye diseases. Advanced technologies, including 3D bioprinting, lab-on-a-chip, and tissue chips, have enabled sophisticated experiments in regenerative medicine and disease modeling. Microgravity facilitates the growth of high-quality drug crystals, improving drug stability, efficacy, and delivery methods, as exemplified by innovations in monoclonal antibody formulations and cancer therapeutics. Despite these advances, challenges such as limited data availability, high operational costs, and the complexity of translating space findings to Earth-based applications remain. In conclusion, space-based research is driving significant advancements in pharmaceutical science and medicine, uncovering novel disease mechanisms, therapeutic targets, and drug development strategies. Continued investment and interdisciplinary collaboration are essential to realize the full potential of space research for global healthcare innovation.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Farid M. Sroor, Ahmed A. F. Soliman, Wagdy K. B. Khalil, Khaled Mahmoud
{"title":"Comparative Study of Pyridine and Pyrimidine Derivatives as Promising Anti-Inflammatory Agents: Design, Synthesis, and LPS-Induced RAW 264.7 Macrophages","authors":"Farid M. Sroor, Ahmed A. F. Soliman, Wagdy K. B. Khalil, Khaled Mahmoud","doi":"10.1002/ddr.70146","DOIUrl":"10.1002/ddr.70146","url":null,"abstract":"<div>\u0000 \u0000 <p>In this study, we aimed to design and synthesize a novel series of pyridine and pyrimidine derivatives and evaluate their anti-inflammatory activity against RAW 264.7 macrophages. Using chalcones (<b>5a−f</b>) as suitable precursors, we disclosed a novel series of pyridine (<b>7a−f</b>) and pyrimidine (<b>9a−e</b>) derivatives via the reaction of <b>5a−f</b> with 2-cyanothioacetamide or guanidine hydrochloride, respectively. Both pyridines and pyrimidines were tested as anti-inflammatory agents to compare the difference in activity of the pyridine and pyrimidine scaffolds as part of a comparative study. With a percentage of live cells greater than 80%, the pyridines (<b>7a−f</b>) and pyrimidines (<b>9a−e</b>) were found to be safe for RAW cells. Moreover, the anti-inflammatory activity of these compounds was evaluated in lipopolysaccharide (LPS)-stimulated RAW macrophages by performing nitric oxide (NO) assays. Among pyridines, <b>7a</b> and <b>7f</b> showed significant inhibition with 65.48% and 51.19%, with IC<sub>50</sub> values (IC<sub>50</sub> = 76.6 and 96.8 µM), respectively. The pyrimidine derivatives showed promising results as well, <b>9a</b> and <b>9d</b> ranking the best activity with 55.95% and 61.90%, respectively, and IC<sub>50</sub> values (IC<sub>50</sub> = 83.1 and 88.7 µM, respectively). The gene expression levels were assessed for the most promising compounds <b>7a</b> and <b>9d</b> using real-time reverse transcription-polymerase chain reaction analysis to measure the mRNA and protein expression levels of inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-ɑ), nuclear factor kappa β (NF-kβ), and inducible nitric oxide synthase (INOS). The expression levels of IL-1, IL-6, TNF-<i>ɑ</i>, NF-kβ, and INOS genes were decreased significantly in RAW-treated cells with <b>7a</b> by 43%, 32%, 61%, 26%, and 53% respectively, compared with negative RAW cells. The expression levels of IL-1, IL-6, NF-k<i>β</i>, and INOS genes were decreased significantly in RAW-treated cells with <b>9d</b> by 71%, 48%, 61%, and 65%, respectively, compared with negative RAW cells. However, the expression levels of the TNF-ɑ gene were decreased without significant differences in RAW treated with <b>9d</b> by 83% (<i>p</i> > 0.05) compared with negative RAW cells. These findings exhibited that <b>7a</b> was more effective compared with <b>9d</b> as an anti-inflammatory agent.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuroactive Steroids Hold Promise as Innovative Anesthetics","authors":"Lu Liu, Yubao Li, Tian Mao, Ting Li, Ruilou Zhu, Xuhui Cong, Lulu Jiang, Mingyang Sun, Jiaqiang Zhang","doi":"10.1002/ddr.70137","DOIUrl":"10.1002/ddr.70137","url":null,"abstract":"<div>\u0000 \u0000 <p>Previous studies have shown that general anesthetics have neurotoxic effects on developing brains. Reducing the toxicity of anesthetics or finding nonneurotoxic anesthetics is a major challenge in anesthetic research. Neuroactive steroids (NASs) are active steroids in nervous tissue that regulate the excitability of the nervous system, γ-Aminobutyric acid subtype A receptors (GABA<sub>A</sub>Rs) serve as key targets in this regulatory process. NASs have many advantages in anesthesia, including rapid onset, mild cardiopulmonary inhibition, and neuroprotection, especially in recent studies showing that NASs do not cause neurotoxicity in the developing brain. NASs have the potential to return to human clinical applications, thereby assisting in clinical anesthesia. This article discusses the application prospects of NASs from the perspectives of action targets, drug characteristics, and neuroprotective effects, with a particular analysis of the possible mechanisms by which NASs do not induce neurotoxicity in anesthesia.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ethyl Linoleate Ameliorates Synovial Cell Proliferation and Inflammatory Cell Infiltration in Rheumatoid Arthritis Through DKK1/Wnt-OPG Signal Axis and Autophagy","authors":"Zong Jiang, XiaoLing Yao, Xin Cai, WeiYa Lan, WuKai Ma, XueMing Yao, Fang Tang","doi":"10.1002/ddr.70135","DOIUrl":"10.1002/ddr.70135","url":null,"abstract":"<div>\u0000 \u0000 <p>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting synovial joints. <i>Jinwu Jiangu Capsules</i> (JJC) has been shown to be effective in treating RA. However, the primary active components and the underlying molecular mechanisms of JJC in RA treatment remain unclear. This study investigates how the monomers of JJC regulate the DKK1/Wnt-OPG signaling axis and autophagy in RA, both in vivo and in vitro. Evaluate the antiarthritis effects of JJC using a Type II collagen-induced arthritis (CIA) rat model. Histopathological analysis is conducted using HE staining, while qPCR, Western blot, ELISA, and GFP-LC3 are used to assess the DKK1/Wnt-OPG signaling pathway and autophagy status. Key components of the capsule are identified through network pharmacology. The effects of these components on osteoblasts are evaluated using CCK-8, alizarin red staining, ALP activity assay, EdU staining, MDC detection, and TRAP staining. JJC effectively reduced the expression of DKK1, RANKL, β-catenin, and p-β-catenin, while increasing the levels of autophagy-related proteins such as Beclin-1, LC3, and Atg5, thus positively affecting the progression of RA. Network pharmacology analysis revealed that ethyl linoleate (EL), a key component of JJC, targeted DKK1. RA model rats showed a dose-dependent response to EL. It significantly reduced cell proliferation and inflammatory cell infiltration in knee joint synovium and improved tissue structure. EL lowered DKK1 and RANKL levels in knee joint synovium and bone tissue, and increased OPG and LC3 expression. Additionally, it enhanced ALP activity and survival of osteoblasts, promoted cell proliferation and autophagy, protected osteoblast function, and inhibited the differentiation of PBMCs into osteoclasts, demonstrating its potential therapeutic effects on RA pathology. EL, a key component of JJC, exhibits significant therapeutic potential and positive effects in the treatment of RA by influencing the DKK1/Wnt-OPG signaling axis and autophagic processes.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhenfei Yu, Ying Li, Peng An, Xiaoling Qian, Yakun Wang, Bo Wang
{"title":"Betulinic Acid Alleviates Acute Pancreatitis by Promoting SIRT1-PINK1-Mediated Mitophagy in Acinar Cells","authors":"Zhenfei Yu, Ying Li, Peng An, Xiaoling Qian, Yakun Wang, Bo Wang","doi":"10.1002/ddr.70140","DOIUrl":"10.1002/ddr.70140","url":null,"abstract":"<div>\u0000 \u0000 <p>Betulinic acid (BA) has the potential to ameliorate acute pancreatitis (AP); however, the mechanisms have not been fully elucidated. This study aimed to identify the effect of BA on mitophagy and its mediated acetylation. Rat pancreatic acinar AR42J cells were treated with cerulein to simulate AP-induced injury, and then inflammation and mitophagy were evaluated after BA treatment. The molecular mechanisms were analyzed using molecular docking, immunoprecipitation, immunoblotting, and cycloheximide chase assay. The roles of BA and SIRT1 in vivo were assessed by HE staining and enzyme-linked immunosorbent assay. The results showed that BA inhibited inflammation and promoted mitophagy in cerulein-induced AR42J cells. BA combined with SIRT1 and reduced SIRT1-mediated acetylation. Knockdown of SIRT1 counteracted the inflammation and mitophagy caused by BA. Moreover, interference with SIRT1 promoted acetylation of PINK1 to degrade PINK1 protein, which knockdown reversed the inhibition of inflammation and the promotion of mitophagy induced by SIRT1. Additionally, BA inhibited pancreatic tissue injury and inflammation levels in the pancreas in AP mice by regulating SIRT1. In conclusion, BA decelerates the progression of AP by promoting mitophagy and inhibiting inflammation in pancreatic acinar cells. Mechanically, BA increased SIRT1 expression, which knockdown degraded PINK1 protein by inducing acetylation of PINK1.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}