{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:26:41Z","timestamp":1789586801016,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to explore the targets and mechanisms by which metformin (MET) exacerbates diabetic amyotrophy (DA) using a streptozotocin (STZ)-induced diabetic SD rat model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      The targets of MET were acquired from 10 databases, including\n                      <jats:italic>HIT<\/jats:italic>\n                      and\n                      <jats:italic>TCMSP<\/jats:italic>\n                      . The DA targets were obtained from the\n                      <jats:italic>GeneCards<\/jats:italic>\n                      database. The associated targets were imported into the Venn analysis platform to draw Venn diagrams, and their intersections were visualized. A target protein\u2013protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes\/Proteins (STRING) and Database for Annotation, Visualization, and Integrated Discovery (DAVID) databases and Cytoscape software, and the core targets were identified. GO enrichment and KEGG pathway analyses were performed on the targets, and the construction of the \u201cMET exacerbated DA target-pathway\u201d network was carried out. Molecular docking was performed using Schr\u00f6dinger Maestro 13.5 software to determine the binding free energy and binding mode of MET with the target protein. The expression of NOS1 and 3-nitrotyrosine proteins in gastrocnemius muscle tissue was detected by WB. The expression of 3-nitrotyrosine protein in gastrocnemius muscle tissue was detected using an enzyme-linked immunosorbent assay (ELISA). The localization of NOS1 in the gastrocnemius muscle tissue was detected using immunohistochemistry (IHC). 16S rDNA gene sequencing was performed to detect structural changes in the fecal microbiota.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network toxicology analysis revealed 19 intersecting proteins. GO functional enrichment and KEGG pathway analyses demonstrated that the obtained targets were involved in molecular functions, biological processes, and cellular components and were involved in pathways such as drug metabolism\u2014other enzymes, peroxisomes, and nucleotide metabolism. Based on the crystal structures of potential target proteins, complex structural models of target\u2013MET were constructed through molecular docking (extra precision [XP] mode of flexible docking), followed by MM-GBSA analysis. The IHC results indicated that MET significantly promoted the redistribution of NOS1 from the membrane region to the cytoplasm. WB results showed that MET significantly (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) promoted the expression of 3-nitrotyrosine in the diabetic SD rat model but had no significant effect on the expression of NOS1. ELISA results demonstrated that MET significantly (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) promoted the expression of 3-nitrotyrosine in the diabetic SD rat model. The 16S rDNA gene sequencing results showed that MET led to a significant (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.05) increase in the abundance of\n                      <jats:italic>Desulfovibrio<\/jats:italic>\n                      in the intestinal tract of rats.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      MET exacerbates diabetic amyotrophy by promoting the increased relative abundance of\n                      <jats:italic>Desulfovibrio<\/jats:italic>\n                      , inducing muscle oxidative stress, and causing NOS1 dysregulation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1778515","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:47:34Z","timestamp":1776059254000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Metformin exacerbates diabetic amyotrophy via oxidative stress and gut microbiota alterations"],"prefix":"10.3389","volume":"17","author":[{"given":"Hejie","family":"Wang","sequence":"first","affiliation":[{"name":"School of Public Health, Changzhi Medical College","place":["Changzhi, Shanxi, China"]},{"name":"Laboratory of Environmental Factors and Population Health, Shanxi Higher Education Institutions of Science and Technology Innovation Plan Platform","place":["Changzhi, China"]},{"name":"Key Laboratory of Environmental Pathogenic Mechanisms and Prevention of Chronic Diseases, Changzhi Medical College","place":["Changzhi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Public Health, Changzhi Medical College","place":["Changzhi, Shanxi, China"]},{"name":"Laboratory of Environmental Factors and Population Health, Shanxi Higher Education Institutions of Science and Technology Innovation Plan Platform","place":["Changzhi, China"]},{"name":"Key Laboratory of Environmental Pathogenic Mechanisms and Prevention of Chronic Diseases, Changzhi Medical College","place":["Changzhi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa","family":"Yousaf","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Shanxi Agricultural University","place":["Taigu, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Haseeb","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Shanxi Agricultural University","place":["Taigu, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of TCM, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangang","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Public Health, Changzhi Medical College","place":["Changzhi, Shanxi, China"]},{"name":"Laboratory of Environmental Factors and Population Health, Shanxi Higher Education Institutions of Science and Technology Innovation Plan Platform","place":["Changzhi, China"]},{"name":"Key Laboratory of Environmental Pathogenic Mechanisms and Prevention of Chronic Diseases, Changzhi Medical College","place":["Changzhi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"4813","DOI":"10.1242\/jcs.154229","article-title":"The role of nNOS and PGC-1\u03b1 in skeletal muscle cells","volume":"127","author":"Baldelli","year":"2014","journal-title":"J. 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