IUBMB Life最新文献

{"title":"Pyrimidine–triazole-tethered tert-butyl-piperazine-carboxylate suppresses breast cancer by targeting estrogen receptor signaling and β-catenin activation","authors":"Jie Yuan,&nbsp;Li Yang,&nbsp;Zhi Li,&nbsp;Hua Zhang,&nbsp;Qun Wang,&nbsp;Bei Wang,&nbsp;Arunachalam Chinnathambi,&nbsp;Chandramohan Govindasamy,&nbsp;Shreeja Basappa,&nbsp;Omantheswara Nagaraja,&nbsp;Mahendra Madegowda,&nbsp;Narasimha M. Beeraka,&nbsp;Vladimir N. Nikolenko,&nbsp;Minghua Wang,&nbsp;Geng Wang,&nbsp;Kanchugarakoppal S. Rangappa,&nbsp;Basappa Basappa","doi":"10.1002/iub.2913","DOIUrl":"10.1002/iub.2913","url":null,"abstract":"<p>Several chemotherapeutics against breast cancer are constrained by their adverse effects and chemoresistance. The development of novel chemotherapeutics to target metastatic breast cancer can bring effective clinical outcomes. Many breast cancer patients present with tumors that are positive for estrogen receptors (ERs), highlighting the importance of targeting the ER pathway in this particular subtype. Although selective estrogen receptor modulators (SERMs) are commonly used, their side effects and resistance issues necessitate the development of new ER-targeting agents. In this study, we report that a newly synthesized compound, TTP-5, a hybrid of pyrimidine, triazole, and <i>tert</i>-butyl-piperazine-carboxylate, effectively binds to estrogen receptor alpha (ERα) and suppresses breast cancer cell growth. We assessed the impact of TTP-5 on cell proliferation using MTT and colony formation assays and evaluated its effect on cell motility through wound healing and invasion assays. We further explored the mechanism of action of this novel compound by detecting protein expression changes using Western blotting. Molecular docking was used to confirm the interaction of TTP-5 with ERα. The results indicated that TTP-5 significantly reduced the proliferation of MCF-7 cells by blocking the ERα signaling pathway. Conversely, although it did not influence the growth of MDA-MB-231 cells, TTP-5 hindered their motility by modulating the expression of proteins associated with epithelial–mesenchymal transition (EMT), possibly via the Wnt/β-catenin pathway.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1309-1324"},"PeriodicalIF":3.7,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248614","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":"CircSLC4A7 in resistant-cells-derived exosomes promotes docetaxel resistance via the miR-1205/MAPT axis in prostate cancer","authors":"Anhua Lin,&nbsp;Junhe Li,&nbsp;Wenjing He","doi":"10.1002/iub.2915","DOIUrl":"10.1002/iub.2915","url":null,"abstract":"<p>Prostate cancer (PCa) is a high-mortality cancer. Docetaxel (DCT) combined with second-generation anti-androgens is considered the golden standard therapy for PCa, whose application is limited for DCT resistance (DR). Therefore, exploring the mechanism of DR is of great importance. In this study, PCa cell lines of PC3 and DU145 were employed, and DR cells were constructed by treatment with graded DCT. CircSLC4A7, miR-1205, and microtubule-associated protein tau (MAPT) transfections were established. Cell counting kit-8 assay was performed to evaluate the cell activity and IC₅₀ of DCT. After being treated with DCT, DR was assessed by colony formation assay, flow cytometry analysis, and terminal transferase-mediated UTP nick end-labeling assay. Real-time quantitative PCR and western blotting analysis evaluated the expression levels of genes. The dual-luciferase reporter gene assay verified the miR-1205 binding sites with circSLC4A7 and MAPT. An animal experiment was performed to assess the tumor growth influenced by circSLC4A7. After conducting DR cells and isolated exosomes, we found that not only co-culture with DR cells but also treatment with DR cells' exosomes would promote the DR of normal cells. Moreover, circSLC4A7 was highly expressed in DR cells and their exosomes. CircSLC4A7 overexpression enhanced DR, represented as raised IC50 of DCT, increased colony formation, and decreased cell apoptosis after DCT treatment, while circSLC4A7 knockdown had the opposite effect. MiR-1205 was confirmed as a circSLC4A7-sponged miRNA and miR-1205 inhibitor reversed the effect of sh-circSLC4A7. MAPT was further identified as a target of miR-1205 and had a similar effect with circSLC4A7. The effect of circSLC4A7 on DR was also confirmed by xenograft experiments. Collectively, circSLC4A7 in resistant-cells-derived exosomes promotes DCT resistance of PCa via miR-1205/MAPT axis, which may provide a new treatment strategy for DR of PCa.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1342-1355"},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248605","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":"SNHG14 promotes triple-negative breast cancer cell proliferation, invasion, and chemoresistance by regulating the ERK/MAPK signaling pathway","authors":"Bin Wang,&nbsp;Ai-Yan Xing,&nbsp;Guang-Xin Li,&nbsp;Long Liu,&nbsp;Chungen Xing","doi":"10.1002/iub.2910","DOIUrl":"10.1002/iub.2910","url":null,"abstract":"<p>The functional role and molecular mechanisms of small-nucleolar RNA host gene 14 (SNHG14) in triple-negative breast cancer (TNBC) progression remain unclear. The expression levels of SNHG14 in breast cancer samples and cell lines were determined using real-time quantitative polymerase chain reaction. Cell proliferation, migration, and invasion abilities were detected using MTS and transwell assays. By RNA sequencing, differentially expressed genes were identified between the SNHG14 siRNA and the negative control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to predict the targets and pathways regulated by SNHG14. pRAF, pMEK, and pERK expression were measured by western blot. The xenograft model was constructed to access the biological function of SNHG14 in vivo. A minimal patient-derived xenograft model was established to evaluate the sensitivity to chemotherapy drugs. Our data indicated that SNHG14 expression was increased in TNBC tissues and cell lines. SNHG14 knockdown attenuated the proliferation, migration, and invasion abilities of TNBC cells both in vivo and in vitro. High SNHG14 expression was associated with lymph node metastasis and a high Ki67 index. The targets of SNHG14 were mainly enriched in the MAPK signaling pathway. pRAF, pMEK, and pERK expression were downregulated after being transfected with SNHG14 siRNA. Compared with the negative control group, the expression of CACNA1I, DUSP8, FGF17, FGFR4, FOS, PDGFRB, and DDIT3 was increased, and the expression of MKNK1 was decreased in the SNHG14 siRNA group. Minimal patient-derived xenograft model demonstrated that knockdown of SNHG14 enhanced the sensitivity to Docetaxel in vivo. Compared with the DMSO group, the proliferation of Docetaxel-resistant MDA-MB-231 cells was decreased in Dabrafenib, PD184352, and FR180204 treatment groups. SNHG14 knockdown inhibits TNBC progression by regulating the ERK/MAPK signaling pathway, which provides evidence for SNHG14 as a potential target for TNBC therapy.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1295-1308"},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248606","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":"Thiouracil and triazole conjugate induces autophagy through the downregulation of Wnt/β-catenin signaling pathway in human breast cancer cells","authors":"Bada Yoon,&nbsp;Basappa Basappa,&nbsp;Shreeja Basappa,&nbsp;Omantheswara Nagaraju,&nbsp;Mahendra Madegowda,&nbsp;K. S. Rangappa,&nbsp;Gautam Sethi,&nbsp;Kwang Seok Ahn","doi":"10.1002/iub.2917","DOIUrl":"10.1002/iub.2917","url":null,"abstract":"<p>Autophagy is vital for maintaining cellular homeostasis by breaking down unnecessary organelles and proteins within cells. Its activity varies abnormally in several diseases, including cancer, making it a potential target for therapeutic strategies. The Wnt/β-catenin signaling pathway significantly impacts cancer by stabilizing β-catenin protein and promoting the transcription of its target genes. Therefore, we aimed to identify candidate substances targeting this signaling pathway. We designed and tested a thiouracil conjugate, discovering that TTP-8 had anti-tumor effects on human breast cancer cell lines MCF-7 and MDA-MB231. Our findings showed that TTP-8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP-8 might induce autophagy. Further analysis confirmed an increase in autophagy-related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP-8 was even more pronounced in MCF-7 and MDA-MB231 cells transfected with β-catenin siRNA. Thus, our research supports the idea that the Wnt/β-catenin signaling pathway influences the regulation of autophagy-related proteins, thereby inducing autophagy. This suggests that TTP-8 could serve as a novel agent for treating breast cancer.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1377-1391"},"PeriodicalIF":3.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.2917","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223185","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":"AARS Online: A collaborative database on the structure, function, and evolution of the aminoacyl-tRNA synthetases","authors":"Jordan Douglas,&nbsp;Haissi Cui,&nbsp;John J. Perona,&nbsp;Oscar Vargas-Rodriguez,&nbsp;Henna Tyynismaa,&nbsp;Claudia Alvarez Carreño,&nbsp;Jiqiang Ling,&nbsp;Lluís Ribas de Pouplana,&nbsp;Xiang-Lei Yang,&nbsp;Michael Ibba,&nbsp;Hubert Becker,&nbsp;Frédéric Fischer,&nbsp;Marie Sissler,&nbsp;Charles W. Carter Jr,&nbsp;Peter R. Wills","doi":"10.1002/iub.2911","DOIUrl":"10.1002/iub.2911","url":null,"abstract":"<p>The aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various translational and non-translational activities beyond aminoacylation, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the 22 coded amino acids are handled by 16 evolutionary families of Class I aaRS and 21 families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like tool curated by an international consortium of field experts. This platform systematizes existing knowledge about the aaRS by showcasing a taxonomically diverse selection of aaRS sequences and structures. Through its graphical user interface, AARS Online facilitates a seamless exploration between protein sequence and structure, providing a friendly introduction to the material for non-experts and a useful resource for experts. Curated multiple sequence alignments can be extracted for downstream analyses. Accessible at www.aars.online, AARS Online is a free resource to delve into the world of the aaRS.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1091-1105"},"PeriodicalIF":3.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154132","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":"Microglia synchronizes with the circadian rhythm of the glymphatic system and modulates glymphatic system function","authors":"Ting Yang,&nbsp;Yan Tang,&nbsp;Xinghua Liu,&nbsp;Song Gong,&nbsp;Ensheng Yao","doi":"10.1002/iub.2903","DOIUrl":"10.1002/iub.2903","url":null,"abstract":"<p>Microglia, as immune cells in the central nervous system, possess the ability to adapt morphologically and functionally to their environment. Glymphatic system, the principal waste clearance system in the brain, exhibits circadian rhythms. However, the impact of microglia on the glymphatic system function remains unknown. In this study, we explored the intricate relationship between microglia and the glymphatic system. Examining diurnal patterns, we identified synchronized behaviors in glymphatic activity and microglial morphology, peaking during sleep and exhibiting distinct changes in branching complexity. Depleting microglia using PLX5622 or in P2Y12 knockout mice enhanced glymphatic function. Chemogenetic manipulation of microglia demonstrated that activating HM3D improved glymphatic function, while inhibiting HM4D unexpectedly increased microglial complexity. These findings highlight the dynamic influence of microglia on the glymphatic system.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1209-1222"},"PeriodicalIF":3.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119849","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":"Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway","authors":"Vahid Pourbarkhordar,&nbsp;Sohrab Rahmani,&nbsp;Ali Roohbakhsh,&nbsp;A. Wallace Hayes,&nbsp;Gholamreza Karimi","doi":"10.1002/iub.2900","DOIUrl":"10.1002/iub.2900","url":null,"abstract":"<p>Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1035-1049"},"PeriodicalIF":3.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107572","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":"Lectins CGL and MTL, representatives of mytilectin family, exhibit different antiproliferative activity in Burkitt's lymphoma cells","authors":"Alexandra S. Kuzmich,&nbsp;Alina P. Filshtein,&nbsp;Galina N. Likhatskaya,&nbsp;Tatiana Y. Gorpenchenko,&nbsp;Irina V. Chikalovets,&nbsp;Tatyana O. Mizgina,&nbsp;Kuo-Feng Hua,&nbsp;Gunhild von Amsberg,&nbsp;Sergey A. Dyshlovoy,&nbsp;Oleg V. Chernikov","doi":"10.1002/iub.2909","DOIUrl":"10.1002/iub.2909","url":null,"abstract":"<p>Lectins are carbohydrate-binding proteins, whose biological effects are exerted via binding to glycoconjugates expressed on the surface of cells. Exposure to lectins can lead not only to a change in the structure and properties of cells but also to their death. Here, we studied the biological activity of lectins from the mussels <i>Crenomytilus graynus</i> (CGL) and <i>Mytilus trossulus</i> (MTL) and showed that these proteins can affect the proliferation of human lymphoma cells. Both lectins suppressed the formation of colonies as well as cell cycle progression. The mechanism of action of these lectins was not mediated by reactive oxygen species but included damaging of mitochondria, inhibition of key cell cycle points, and activation of MAPK signaling pathway in tumor cells. Computer modeling suggested that various effects of CGL and MTL on lymphoma cells may be due to the difference in the energy of binding of these lectins to carbohydrate ligands on the cell surface. Thus, molecular recognition of residues of terminal carbohydrates on the surface of tumor cells is a key factor in the manifestation of the biological action of lectins.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1279-1294"},"PeriodicalIF":3.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017555","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":"Neuroprotective effects of resveratrol through modulation of PI3K/Akt/GSK-3β pathway and metalloproteases","authors":"Lütfiye Ozpak,&nbsp;Bakiye Göker Bağca","doi":"10.1002/iub.2902","DOIUrl":"10.1002/iub.2902","url":null,"abstract":"<p>To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular Alzheimer's Disease (AD) model with the effect of antioxidant resveratrol. Neuron-like cells were obtained by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the amyloid beta peptide 25–35 (Aβ25-35) to the cell culture mimicked the environmental toxicity observed in AD. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, the expressional changes in genes in the cellular AD model with the effect of resveratrol were analyzed by Real-Time PCR. The analysis in silico was assessed using the STRING V12.0 database in each group. Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by Differentiated+Resveratrol (RES) and RES when compared to control but no significant difference was observed between RES and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (<i>p</i> &lt; .001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62-fold, respectively) in the Differentiated+Aβ + RES groups compared to the Differentiated+Aβ group (<i>p</i> &lt; .001). Network analysis shows the functional enrichment of 23 Alzheimer-related GO terms in the Wnt signaling, proteolysis, and extracellular matrix organization pathways. Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1199-1208"},"PeriodicalIF":3.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004226","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":"Irisin alleviates the pyroptosis of β cells in T2DM by inhibiting NLRP3 inflammasome through regulating miR-19b-3p/SOCS3/STAT3 axis mediated autophagy","authors":"Jingjing Yang,&nbsp;Anjun Tan,&nbsp;Tianrong Li,&nbsp;Hewen Chen","doi":"10.1002/iub.2907","DOIUrl":"10.1002/iub.2907","url":null,"abstract":"<p>The purpose of this study was to analyze the mechanism by which irisin affects β-cell pyroptosis in type 2 diabetes mellitus (T2DM). The in vivo T2DM model was established by raised with high-fat diet and intraperitoneally injection of streptozocin. Min6 cells were divided into four groups: negative control (NC), high glucose (HG), HG + irisin, and HG + irisin+3-MA. The cell viability was determined by CCK-8 assay. Dual-luciferase gene reporter assay was conducted to confirm the binding between miR-19b-3p and SOCS3. The expression level of FNDC5 and GSDMD was visualized using the immunofluorescence assay. The protein level of FNDC5, Beclin1, LC3II/I, NLRP3, cleaved-caspase-1, GSDMD-N, STAT3, p-STAT3, and SOCS3 was determined by Western blotting. The secretion of irisin, lactate dehydrogenase (LDH), and insulin was checked by ELISA. In vivo results showed that pathological changes in islet tissues with declined number of β cells, elevated FBG value, decreased FIN and HOMA-β value, elevated autophagy-associated proteins expressions, and activated NLRP3 signaling in T2DM mice, which were dramatically reversed by FNDC5 overexpression. Furthermore, the declined level of miR-19b-3p and p-STAT3, as well as the upregulation of SOCS3, was greatly rescued by FNDC5 overexpression. The in vitro data confirmed the binding site between SOCS3 and miR-19b-3p. SOCS3 was downregulated and p-STAT3 was upregulated in miR-19b-3p mimic-treated Min6 cells. In HG-stimulated Min6 cells, the elevated cell viability, increased production of insulin, decreased release of LDH, and inactivated NLRP3 signaling induced by irisin were abolished by miR-19b-3p inhibitor and STAT3 inhibitor. The increased level of autophagy-related proteins and activated SOCS3/STAT3 axis induced by irisin in HG-stimulated Min6 cells were abolished by miR-19b-3p inhibitor. The inhibitory effect of irisin against NLRP3 signaling in HG-stimulated Min6 cells was abrogated by 3-MA. In conclusion, irisin alleviated the pyroptosis of β cells in T2DM by inhibiting NLRP3 signaling through miR-19b-3p/SOCS3/STAT3 axis mediated autophagy.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"76 12","pages":"1264-1278"},"PeriodicalIF":3.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982331","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}