Archives of biochemistry and biophysics最新文献

{"title":"Runx2 silencing sensitized human renal cell carcinoma cells to ABT-737 apoptosis","authors":"Yen-Chuan Ou ,&nbsp;Tung-Min Yu ,&nbsp;Jian-Ri Li ,&nbsp;Chih-Cheng Wu ,&nbsp;Jiaan-Der Wang ,&nbsp;Su-Lan Liao ,&nbsp;Wen-Ying Chen ,&nbsp;Yu-Hsiang Kuan ,&nbsp;Chun-Jung Chen","doi":"10.1016/j.abb.2024.110173","DOIUrl":"10.1016/j.abb.2024.110173","url":null,"abstract":"<div><div>The prognostic value of Runt-related transcription factor 2 (Runx2) and its involvement in cell growth and motility have been reported in patients diagnosed with renal cell carcinoma (RCC). Since Runx2 may have the potential to be a target for the purpose of antitumor intervention, there is an urgent need to gain insight into its oncogenic properties. Using human 786-O, Caki-1 and ACHN RCC cells as models, the silencing of cellular Runx2 expression brought about a reduction in cyclin D1 and β-catenin expression, cell growth and migration without any significant cell death. Runx2-silenced cells turned into apoptosis vulnerable in the presence of ABT-737, a BH3 mimetic Bcl-2 inhibitor. Data from biochemical and molecular studies have revealed a positive correlation between Runx2 expression and Akt phosphorylation, Mcl-1 expression, and fibronectin expression. Results of genetic silencing studies have indicated the potential involvement of Mcl-1 and fibronectin in the decision of RCC cell ABT-737 resistance and sensitivity. The regulatory roles of the PI3K/Akt axis in the expression of Mcl-1 and fibronectin were suggested by means of the results taken from experiments involving pharmacological study of the PI3K/Akt. Since overexpression and prognostic roles of Runx2, activated Akt, Mcl-1, fibronectin, cyclin D1, and β-catenin have been revealed in RCC, it is important to explore the precise mechanisms underlying Runx2 oncogenic effects. Although the linking details between Runx2 and PI3K/Akt have yet to be identified, our findings suggest that Mcl-1 and fibronectin are downstream effectors of Runx2 via a regulatory axis of the PI3K/Akt and their promotion of cell growth, migration, and ABT-737 resistance in RCC cells.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110173"},"PeriodicalIF":3.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of short-chain fatty acids in cancer prevention and cancer treatment","authors":"Balaraman Kalyanaraman ,&nbsp;Gang Cheng ,&nbsp;Micael Hardy","doi":"10.1016/j.abb.2024.110172","DOIUrl":"10.1016/j.abb.2024.110172","url":null,"abstract":"<div><div>Short-chain fatty acids (SCFAs) are microbial metabolites in the gut that may play a role in cancer prevention and treatment. They affect the metabolism of both normal and cancer cells, regulating various cellular energetic processes. SCFAs also inhibit histone deacetylases, which are targets for cancer therapy. The three main SCFAs are acetate, propionate, and butyrate, which are transported into cells through specific transporters. SCFAs may enhance the efficacy of chemotherapeutic agents and modulate immune cell metabolism, potentially reprogramming the tumor microenvironment. Although SCFAs and SCFA-generating microbes enhance therapeutic efficacy of several forms of cancer therapy, published data also support the opposing viewpoint that SCFAs mitigate the efficacy of some cancer therapies. Therefore, the relationship between SCFAs and cancer is more complex, and this review discusses some of these aspects. Clearly, further research is needed to understand the role of SCFAs, their mechanisms, and applications in cancer prevention and treatment.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110172"},"PeriodicalIF":3.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing high potential benzothiazole chalcones against dengue virus NS5 protein: A multi-faceted theoretical study through molecular docking, ADME, and DFT","authors":"Ahmad Badreddin Musatat ,&nbsp;Tülay Durmuş ,&nbsp;Alparslan Atahan","doi":"10.1016/j.abb.2024.110171","DOIUrl":"10.1016/j.abb.2024.110171","url":null,"abstract":"<div><div>Chalcones bearing tetralone, indanone and benzothiazole cores were synthesized successfully using a general Claisen-Schmidt condensation protocol. The prepared compounds were purified and structurally analyzed by ¹H, ¹³C NMR, and FT-IR techniques. A multi-faceted theoretical approach, combining Density Functional Theory (DFT), molecular docking, and ADME predictions, was employed to evaluate their therapeutic potential. DFT calculations at the B3LYP/def2-TZVP level revealed key electronic properties, with TD3 compound demonstrating the highest chemical reactivity. Molecular Electrostatic Potential (MEP) and Reduced Density Gradient (RDG) analyses provided insights into the compounds' non-covalent interactions and charge distributions. Molecular docking studies against the NS5 protein (PDB: <span><span>6KR2</span><svg><path></path></svg></span>) showed superior binding affinities for all three compounds compared to the control ligand SAH, with TD3 exhibiting the lowest binding energy (−8.41 kcal/mol) and theoretical inhibition constant (689.31 nM). ADME predictions indicated favorable drug-like properties with concerns regarding aqueous solubility and potential P-glycoprotein interactions. Toxicity evaluations highlighted challenges, particularly in hepatotoxicity and carcinogenicity. The study identified TD3 as a promising lead compound for Dengue Virus NS5 inhibition, while also emphasizing the need for targeted modifications to address toxicity concerns. This research not only contributes to anti-dengue drug discovery efforts but also provides a robust methodological framework for the theoretical evaluation of similar small compounds in future investigations.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110171"},"PeriodicalIF":3.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The LINC00319 binding to STAT3 promotes the cell proliferation, migration, invasion and EMT process in oral squamous cell carcinoma","authors":"Xiao Jiang ,&nbsp;Xueyi Liang ,&nbsp;Simin Li,&nbsp;Yinshen Yang,&nbsp;Xiaoheng Xu,&nbsp;Wenli Gu,&nbsp;Wenxia Meng,&nbsp;Fanping Cheng","doi":"10.1016/j.abb.2024.110170","DOIUrl":"10.1016/j.abb.2024.110170","url":null,"abstract":"<div><h3>Background</h3><div>Long non-coding RNA LINC00319 has been implicated in the progression of various cancers, including oral squamous cell carcinoma (OSCC). While our previous work has revealed some aspects of LINC00319's role in OSCC, including its upregulation and involvement in a competing endogenous RNA (ceRNA) mechanism, the full extent of its functions and regulatory mechanisms in OSCC progression remain to be fully elucidated.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the function of LINC00319 in OSCC and its potential interaction with the STAT3 signaling pathway, thus uncovering novel regulatory mechanisms and therapeutic targets.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was performed using TCGA data to evaluate LINC00319 expression in OSCC tissues and its correlation with STAT3 signaling. The direct binding between LINC00319 and STAT3 was examined by RNA pull-down, FISH, and RIP assays. Functional experiments, including CCK-8, transwell migration and invasion assays, and western blot analysis of EMT markers and STAT3 pathway activation, were conducted to assess the effects of LINC00319 on OSCC cell behaviors and its interaction with the STAT3 signaling pathway. In vivo xenograft models were established to validate the role of LINC00319 in tumor growth and STAT3 activation.</div></div><div><h3>Results</h3><div>LINC00319 expression was significantly upregulated in OSCC tissues compared to normal tissues, and high LINC00319 expression correlated with STAT3 signaling activation. Mechanistically, LINC00319 directly bound to STAT3 protein and promoted its phosphorylation at Tyr705. LINC00319 overexpression enhanced, while its knockdown suppressed, the proliferation, migration, invasion, and EMT of OSCC cells. These oncogenic effects were mediated through STAT3 activation and could be reversed by the STAT3 inhibitor stattic. In vivo experiments further confirmed that LINC00319 silencing inhibited tumor growth and STAT3 phosphorylation.</div></div><div><h3>Conclusion</h3><div>This study uncovers that LINC00319 promotes OSCC tumorigenesis by directly binding to and activating STAT3 signaling. These findings provide new insights into the regulatory mechanisms of STAT3 by long non-coding RNAs and highlight the potential of LINC00319 as a biomarker and therapeutic target in OSCC.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110170"},"PeriodicalIF":3.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt3a-induced LRP6 phosphorylation enhances osteoblast differentiation to alleviate osteoporosis through activation of mTORC1/β-catenin signaling","authors":"Xiang Shen ,&nbsp;Shuolin Feng ,&nbsp;Shanbin Chen ,&nbsp;Bin Gong ,&nbsp;Suiyuan Wang ,&nbsp;Huan Wang ,&nbsp;Deye Song ,&nbsp;Jiangdong Ni","doi":"10.1016/j.abb.2024.110169","DOIUrl":"10.1016/j.abb.2024.110169","url":null,"abstract":"<div><h3>Objective</h3><div>Osteoporosis (OP) is a common cause of morbidity and mortality in older individuals. The importance of Wnt3a in osteogenic activity and bone tissue homeostasis is well known. Here, we explored the possible molecular mechanism by which Wnt3a mediates the LRP6/mTORC1/β-catenin axis to regulate osteoblast differentiation in OP.</div></div><div><h3>Methods</h3><div>OP-related key genes were identified through a bioinformatics analysis. A ROS17/2.8 cell differentiation system for rat osteogenic progenitors and a rat model of senile OP were constructed for <em>in vitro</em> and <em>in vivo</em> mechanism verification.</div></div><div><h3>Results</h3><div>Bioinformatics analysis revealed that LRP6 was poorly expressed in OP and may play a key role in the occurrence of OP by affecting osteoblast differentiation. LRP6 knockdown inhibited osteoblast differentiation in an <em>in vitro</em> model. In addition, Wnt3a promoted osteoblast differentiation by inducing LRP6 phosphorylation. Moreover, LRP6 promoted mTORC1 expression, which indirectly promoted β-catenin expression, thus promoting osteoblast differentiation. Finally, an <em>in vivo</em> assay revealed that LRP6 inhibition improved OP.</div></div><div><h3>Conclusion</h3><div>Our study provides evidence that Wnt3a induces phosphorylation of LRP6 to activate the mTORC1/β-catenin axis, thus promoting osteoblast differentiation and ultimately improving OP in aged rats.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110169"},"PeriodicalIF":3.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heightened TPD52 linked to metabolic dysfunction and associated abnormalities in zebrafish","authors":"Hsin-Hung Lai ,&nbsp;Kuo-Shyang Jeng ,&nbsp;Chung-Tsui Huang ,&nbsp;An-Ju Chu ,&nbsp;Guor Mour Her","doi":"10.1016/j.abb.2024.110166","DOIUrl":"10.1016/j.abb.2024.110166","url":null,"abstract":"<div><div>The tumor protein D52 (TPD52) gene encodes a proto-oncogene protein associated with various medical conditions, including breast and prostate cancers. It plays a role in multiple biological pathways such as cell growth, differentiation, and apoptosis. The function of TPD52 in lipid droplet biosynthesis has been investigated <em>in vitro</em>. However, its precise role in lipid metabolism in animal models is not fully understood. To investigate the functions of TPD52 in vivo, we performed a conditional TPD52 protein expression analysis using a Tet-off transgenic system to establish conditionally expressed Tpd52 transgenic zebrafish. The effect of Tpd52 on lipogenesis was assessed using various methods, including whole-mount Oil Red O staining, histological examination, and measurement of inflammatory markers and potential targets using real-time quantitative polymerase chain reaction and immunoblotting in Tpd52 fish. Zebrafish with increased Tpd52 levels exhibited notable weight gain and the enlargement of fat deposits, which were mainly attributed to an increase in the volume of adipocytes. Moreover, Tpd52 overexpression was correlated with the triggering of the adipocyte differentiation signaling pathway. During adipocytic differentiation in response to nutrient status, our observations revealed adipogenesis, nonalcoholic fatty liver disease, and metabolic cardiomyopathy (MCM) in Tpd52 transgenic zebrafish. To gain a deeper understanding of the contribution of these proteins to the regulation of cellular growth, we investigated the expression of their corresponding genes and proteins in zebrafish. In the present study, the activated protein kinase pathway was identified as the primary target of TPD52. Adult Tpd52 zebrafish showed increased lipid accumulation, resulting in the development of visceral obesity, nonalcoholic fatty liver disease, and MCM. These findings strongly suggest that TPD52 actively contributes to adipose tissue expansion and its subsequent effects. This investigation provides compelling evidence that Tpd52 facilitates adipocyte development and related metabolic comorbidities in zebrafish.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110166"},"PeriodicalIF":3.8,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic mechanisms, diagnostic, and therapeutic potential of microvesicles in diabetes and its complications","authors":"Alaa Abbas ,&nbsp;Heba Almaghrbi ,&nbsp;Roberta Giordo ,&nbsp;Hatem Zayed ,&nbsp;Gianfranco Pintus","doi":"10.1016/j.abb.2024.110168","DOIUrl":"10.1016/j.abb.2024.110168","url":null,"abstract":"<div><div>Extracellular vesicles (EVs), particularly microvesicles (MVs), have gained significant attention for their role as mediators of intercellular communication in both physiological and pathological contexts, including diabetes mellitus (DM) and its complications. This review provides a comprehensive analysis of the emerging roles of MVs in the pathogenesis of diabetes and associated complications such as nephropathy, retinopathy, cardiomyopathy, and neuropathy. MVs, through their cargo of proteins, lipids, mRNAs, and miRNAs, regulate critical processes like inflammation, oxidative stress, immune responses, and tissue remodeling, all of which contribute to the progression of diabetes and its complications. We examine the molecular mechanisms underlying MVs' involvement in these pathological processes and discuss their potential as biomarkers and therapeutic tools, particularly for drug delivery. Despite promising evidence, challenges remain in isolating and characterizing MVs, understanding their molecular mechanisms, and validating them for clinical use. Advanced techniques such as single-cell RNA sequencing and proteomics are required to gain deeper insights. Improved isolation and purification methods are essential for translating MVs into clinical applications, with potential to develop novel diagnostic and therapeutic strategies to improve patient outcomes in diabetes.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110168"},"PeriodicalIF":3.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizations of angiotensin-converting enzyme-2 (ACE2) peptidase activity","authors":"Nathalie M. Saulnier,&nbsp;Devyn M. Thorne,&nbsp;Fariha E. Bablu,&nbsp;Alessia M. Suzuki,&nbsp;Rafa L. Khan,&nbsp;Katelin X. Oliveira,&nbsp;Yuichiro J. Suzuki","doi":"10.1016/j.abb.2024.110167","DOIUrl":"10.1016/j.abb.2024.110167","url":null,"abstract":"<div><div>Angiotensin (Ang) II (1–8) is a potent vasoconstrictor known for its role in hypertension. Angiotensin-converting enzyme (ACE2) converts Ang II (1–8) to a vasodilator Ang (1–7) by removing the carboxy-terminal Phe. ACE2 more recently gained attention as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic. Given the pathophysiological importance of ACE2, the present study examined the mechanism of ACE2 catalytic activity by comparing the ability of angiotensin molecules of various lengths to compete with the artificial fluorogenic substrate. The Fluorimetric SensoLyte 390 ACE2 Activity Assay uses an Mca/Dnp fluorescence resonance energy transfer peptide as the substrate. Results showed that the natural substrate Ang II (1–8) competed with the fluorogenic substrate, reducing the fluorescence signals. Deletion of C-terminal Phe resulted in the loss of the ability to compete with the artificial substrate, as shown by the actions of Ang (1–7), Ang (2–7), and Ang (5–7). By contrast, the loss of N-terminal Asp potentiated the ability to compete with the substrate as seen by the action of Ang III (2–8). However, the loss of two amino acids (Asp-Arg) from the N-terminus reduced the ability to compete with the substrate as observed by the actions of Ang IV (3–8) and Ang (5–8). Ang I (1–10) and Ang (1–9) did not strongly compete with the substrate. Interestingly, shorter peptides Ang (1–5) and Ang (1–4) potentiated the ACE2 activity. These results suggest that Ang II and Ang III are the best natural substrates for ACE2.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110167"},"PeriodicalIF":3.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anionic cardiolipin stabilizes the transmembrane region of hyaluronan synthase and promotes catalysis-relevant dynamics","authors":"Kaiyi Zhu,&nbsp;Yilei Han,&nbsp;Yupei Jian,&nbsp;Guoqiang Jiang,&nbsp;Diannan Lu,&nbsp;Zheng Liu","doi":"10.1016/j.abb.2024.110165","DOIUrl":"10.1016/j.abb.2024.110165","url":null,"abstract":"<div><div>Hyaluronic acid (HA) is a glycosaminoglycan essential for cellular processes and finding increasingly applications in medicine, pharmaceuticals, and cosmetics. While membrane-integrated Class I hyaluronan synthase (HAS) catalyzes HA synthesis in most organisms, the molecular mechanisms by which HAS-lipid interactions impact HAS catalysis remain unclear. This study employed coarse-grained molecular dynamics simulation combined with dimensionality reduction to uncover the interplay between lipids and <em>Streptococcus equisimilis</em> HAS (SeHAS). A minimum of 67 % cardiolipin is necessary for HA synthesis, as determined through simulations using gradient-composed membranes. The anionic cardiolipin stabilizes the cationic transmembrane regions of SeHAS and thereby maintains its conformation. Moreover, the highly dynamic cardiolipin is required to modulate the catalysis-relevant motions in HAS and thus facilitate HA synthesis. These findings provide molecular insights essential not only for understanding the physiological functions of HAS, but also for the development of cell factories and enzyme catalysts for HA production.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110165"},"PeriodicalIF":3.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing marine natural products to inhibit PAD4 triple mutant: A structure-based virtual screening approach for rheumatoid arthritis therapy","authors":"Santhiya Panchalingam ,&nbsp;Manikandan Jayaraman ,&nbsp;Jeyakanthan Jeyaraman ,&nbsp;Govindaraju Kasivelu","doi":"10.1016/j.abb.2024.110164","DOIUrl":"10.1016/j.abb.2024.110164","url":null,"abstract":"<div><div>Peptidylarginine deiminase type4 (PAD4) is a pivotal pro-inflammatory protein within the human immune system, intricately involved in both inflammatory processes and immune responses. Its role extends to the generation of diverse immune cell types, including T cells, B cells, natural killer cells, and dendritic cells. PAD4 has recently garnered attention due to its association with a spectrum of inflammatory and autoimmune disorders, notably rheumatoid arthritis (RA). Mutations in the PAD4 gene, leading to the conversion of arginine to citrulline, have emerged as significant factors in the pathogenesis of RA and related conditions. As a calcium-dependent enzyme, PAD4 is central to the citrullination process, a crucial post-translational modification implicated in disease pathophysiology. Its critical role in autoimmune disorders and inflammation makes PAD4 a prime candidate for therapeutic intervention in RA. Inhibiting PAD4 presents a promising avenue for mitigating inflammatory responses and curtailing joint degradation and impairment. To explore its therapeutic potential, a structure-based virtual screening (SBVS) approach was employed, harnessing an array of marine natural products (MNPs) sourced from databases such as CMNPD, MNPD, and Seaweed. Notably, MNPD10752, CMNPD12680, and CMNPD2751 emerged as potential hit molecules, exhibiting adherence to essential pharmacokinetic properties and favorable toxicity profiles. Quantum mechanics studies using density functional theory (DFT) calculations revealed the inhibitory potential of these identified natural products. Further structural elucidation through molecular dynamics simulations (MDS) and principal component-based free energy landscape (FEL) analysis shed light on the stability of MNP-bound PAD4 complexes. In conclusion, this computational study serves as a stepping stone for further experimental evaluation, aiming to explore the potential of MNPs in addressing PAD4-related human pathologies.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110164"},"PeriodicalIF":3.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}