{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:13:33Z","timestamp":1790709213840,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019535","name":"Texas Tech University Health Sciences Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019535","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001027","name":"CH Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001027","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000928","name":"Robert A. Welch Foundation","doi-asserted-by":"crossref","award":["B1-0028"],"award-info":[{"award-number":["B1-0028"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007917","name":"USDA-ARS","doi-asserted-by":"crossref","award":["#3062-10700-002-000D"],"award-info":[{"award-number":["#3062-10700-002-000D"]}],"id":[{"id":"10.13039\/100007917","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["R01NS038261"],"award-info":[{"award-number":["R01NS038261"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Growing evidence highlights the links between diabetic neuropathy (DNP), gut dysbiosis, mitochondrial dysfunction and neuroinflammation in colon and bone microstructure deterioration. Geranylgeraniol (GG) shows neuroprotective and osteoprotective capacity. Our study examines GG\u2019s effects on pain-associated behaviors, glucose homeostasis, gut microbiota, mitochondrial homeostasis, and bone microstructure in DNP rats. We randomly assigned 27 male Sprague Dawley rats to three groups (n = 8\u201310\/group): a control group (regular low-fat diet), a DNP group (high-fat diet + a single dose of 35 mg\/kg streptozotocin), and a GG-treated DNP group (a single dose of 35 mg\/kg streptozotocin + GG at 800 mg\/kg in diet) for 6 weeks. Nocifensive response was assessed via the von Frey test and an open field test, and the elevated plus maze was used to assess anxio-depressive behaviors. The mRNA expression levels of tight junction protein, mitochondrial homeostasis, and neuroinflammation were measured in the colon using qRT-PCR. We collected fecal samples for microbiota composition analysis with 16S rRNA gene sequencing and analyzed by QIIME 2. All other data were analyzed via one-way ANOVA followed by post hoc Tukey\u2019s multiple comparison. p &lt; 0.05 was defined as statistical significance. Our study showed GG\u2019s ability to mitigate mechanical hypersensitivity and anxio-depressive behavior in rats with DNP. GG supplementation did not improve glucose homeostasis (i.e., glucose intolerance, insulin sensitivity, pancreatic \u03b2-cell dysfunction) and bone microstructure. GG increased alpha-diversity without changing microbial abundance. DNP rats exhibited elevated Clostridium sensu stricto and reduced Eubacterium coprostanoligenes, Lachnospiraceae, Oscillospiraceae, and Peptococcaceae compared with controls. GG did not reverse DNP-induced gut dysbiosis but increased colonic claudin-3 (tight junction), MFN1 (mitochondria fusion), and TFAM (mitochondria biogenesis), while reducing FIS1 (mitochondria fission), GFAP (glial activation), P62 and PINK1 (mitophagy), and TNF\u03b1 (inflammation). Functionally, GG reduced pain behaviors, improved intestinal integrity and mitochondrial homeostasis, increased alpha-diversity, and suppressed neuroinflammation, but did not improve glucose homeostasis or bone microstructure in obese DNP rats.<\/jats:p>","DOI":"10.3390\/ijms262412133","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T12:13:03Z","timestamp":1765973583000},"page":"12133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dietary Geranylgeraniol Mitigates Pain-Associated Behaviors via Improving Mitochondrial Function and Colon Integrity and Suppressing Neuroinflammation in Male Diabetic Neuropathy Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-6598","authenticated-orcid":false,"given":"Chwan-Li","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2492-4537","authenticated-orcid":false,"given":"Xiaobo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay J.","family":"Cao","sequence":"additional","affiliation":[{"name":"Grand Forks Human Nutrition Research Center, U.S. Department of Agriculture-Agricultureal Research Service (USDA-ARS), Grand Forks, ND 58202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Neugebauer","sequence":"additional","affiliation":[{"name":"Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moamen M.","family":"Elmassry","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale M.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5623-519X","authenticated-orcid":false,"given":"Jannette M.","family":"Dufour","sequence":"additional","affiliation":[{"name":"Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.pcd.2019.12.005","article-title":"Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis","volume":"14","author":"Sun","year":"2020","journal-title":"Prim. Care Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic \u03b2-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure","volume":"16","author":"Eizirik","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lee, J.H., and Lee, J. (2022). Endoplasmic Reticulum (ER) Stress and Its Role in Pancreatic beta-Cell Dysfunction and Senescence in Type 2 Diabetes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094843"},{"key":"ref_5","first-page":"e68083","article-title":"Gut-Brain Axis: Unveiling the Interplay Between Diabetes Mellitus and Alzheimer\u2019s Disease","volume":"16","author":"Haripriya","year":"2024","journal-title":"Cureus J. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tanase, D.M., Gosav, E.M., Neculae, E., Costea, C.F., Ciocoiu, M., Hurjui, L.L., Tarniceriu, C.C., Maranduca, M.A., Lacatusu, C.M., and Floria, M. (2020). Role of Gut Microbiota on Onset and Progression of Microvascular Complications of Type 2 Diabetes (T2DM). Nutrients, 12.","DOI":"10.3390\/nu12123719"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Xu, Y.H., Zhou, H., and Zhu, Q. (2017). The Impact of Microbiota-Gut-Brain Axis on Diabetic Cognition Impairment. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00106"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Iheagwam, F.N., Joseph, A.J., Adedoyin, E.D., Iheagwam, O.T., and Ejoh, S.A. (2025). Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight. Pathophysiology, 32.","DOI":"10.3390\/pathophysiology32010009"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, Y., Miao, Y.H., Feng, Q., Zhu, W.X., Chen, Y.J., Kang, Q.Q., Wang, Z., Lu, F., and Zhang, Q. (2024). Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: A multi-omics Mendelian randomization and colocalization study. Front Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1401531"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/s13098-025-01884-5","article-title":"Curcumin as a promising therapeutic agent for diabetic neuropathy: From molecular mechanisms to functional recovery","volume":"17","author":"Barati","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10654-015-0094-6","article-title":"The epidemiology and risk factors of chronic polyneuropathy","volume":"31","author":"Hanewinckel","year":"2016","journal-title":"Eur. J. Epidemiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.diabres.2018.08.020","article-title":"A new look at painful diabetic neuropathy","volume":"144","author":"Sloan","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e32653","DOI":"10.1097\/MD.0000000000032653","article-title":"Mechanism of Schwann cells in diabetic peripheral neuropathy: A review","volume":"102","author":"Li","year":"2023","journal-title":"Medicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5345269","DOI":"10.1155\/2022\/5345269","article-title":"Plasticity of the Central Nervous System Involving Peripheral Nerve Transfer","volume":"2022","author":"Shen","year":"2022","journal-title":"Neural Plast."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/jbmr.4517","article-title":"Bone Microarchitecture and Strength in Long-Standing Type 1 Diabetes","volume":"37","author":"Sewing","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_16","first-page":"153","article-title":"Diabetic neuropathy: Past, present, and future","volume":"14","author":"Rojas","year":"2023","journal-title":"Casp. J. Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.cell.2016.02.023","article-title":"The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia","volume":"165","author":"Okin","year":"2016","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nutres.2021.07.001","article-title":"Beneficial effect of dietary geranylgeraniol on glucose homeostasis and bone microstructure in obese mice is associated with suppression of proinflammation and modification of gut microbiome","volume":"93","author":"Chung","year":"2021","journal-title":"Nutr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrendo.2010.155","article-title":"PPARgamma: A circadian transcription factor in adipogenesis and osteogenesis","volume":"6","author":"Kawai","year":"2010","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1139\/cjpp-2016-0528","article-title":"Geraniol promotes functional recovery and attenuates neuropathic pain in rats with spinal cord injury","volume":"95","author":"Lv","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"C1016","DOI":"10.1152\/ajpcell.00277.2008","article-title":"Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation","volume":"295","author":"Ishikura","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19909","DOI":"10.1073\/pnas.1009523107","article-title":"Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells","volume":"107","author":"Sun","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1002\/jcsm.13061","article-title":"Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity","volume":"13","author":"Wang","year":"2022","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giriwono, P.E., Shirakawa, H., Ohsaki, Y., Sato, S., Aoyama, Y., Ho, H.J., Goto, T., and Komai, M. (2019). Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFkappaB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092320"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Saputra, W.D., Shono, H., Ohsaki, Y., Sultana, H., Komai, M., and Shirakawa, H. (2021). Geranylgeraniol Inhibits Lipopolysaccharide-Induced Inflammation in Mouse-Derived MG6 Microglial Cells via NF-\u03baB Signaling Modulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910543"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Spano, M., Di Matteo, G., Ingallina, C., Ambroselli, D., Carradori, S., Gallorini, M., Giusti, A.M., Salvo, A., Grosso, M., and Mannina, L. (2022). Modulatory properties of food and nutraceutical components targeting NLRP3 inflammasome activation. Nutrients, 14.","DOI":"10.3390\/nu14030490"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.21873\/invivo.12998","article-title":"Geranylgeraniol Supplementation Mitigates Soleus Muscle Atrophy via Changes in Mitochondrial Quality in Diabetic Rats","volume":"36","author":"Jiwan","year":"2022","journal-title":"In Vivo"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jung, J., Park, J.S., Chun, J., Al-Nawas, B., Ziebart, T., and Kwon, Y.-D. (2023). Geranylgeraniol Application in Human Osteoblasts and Osteoclasts for Reversal of the Effect of Bisphosphonates. Life, 13.","DOI":"10.3390\/life13061353"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.ejphar.2017.11.010","article-title":"A new promising simultaneous approach for attenuating type II diabetes mellitus induced neuropathic pain in rats: iNOS inhibition and neuroregeneration","volume":"818","author":"Ahlawat","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1111\/pme.12387_1","article-title":"Establishment of a Rat Model of Type II Diabetic Neuropathic Pain","volume":"15","author":"Dang","year":"2014","journal-title":"Pain Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"307285","DOI":"10.1155\/2015\/307285","article-title":"Rat Models of Diet-Induced Obesity and High Fat\/Low Dose Streptozotocin Type 2 Diabetes: Effect of Reversal of High Fat Diet Compared to Treatment with Enalapril or Menhaden Oil on Glucose Utilization and Neuropathic Endpoints","volume":"2015","author":"Holmes","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Spindola, H.M., Servat, L., Denny, C., Rodrigues, R.A., Eberlin, M.N., Cabral, E., Sousa, I.M., Tamashiro, J.Y., E Carvalho, J., and A Foglio, M. (2010). Antinociceptive effect of geranylgeraniol and 6alpha,7beta-dihydroxyvouacapan-17beta-oate methyl ester isolated from Pterodon pubescens Benth. BMC Pharmacol., 10.","DOI":"10.1186\/1471-2210-10-1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejphar.2011.01.025","article-title":"Geranylgeraniol and 6\u03b1,7\u03b2-dihydroxyvouacapan-17\u03b2-oate methyl ester isolated from Benth: Further investigation on the antinociceptive mechanisms of action","volume":"656","author":"Spindola","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4351327","DOI":"10.1155\/2019\/4351327","article-title":"Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study","volume":"2019","author":"Fliefel","year":"2019","journal-title":"Stem. Cells Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"627","DOI":"10.3892\/etm.2012.669","article-title":"Antidepressant effect of geranylgeranylacetone in a chronic mild stress model of depression and its possible mechanism","volume":"4","author":"Zhong","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1007\/s40200-024-01447-x","article-title":"Diabetic neuropathy: Understanding the nexus of diabetic neuropathy, gut dysbiosis and cognitive impairment","volume":"23","author":"Babu","year":"2024","journal-title":"J. Diabetes Metab. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12974-025-03352-3","article-title":"Probiotics alleviate painful diabetic neuropathy by modulating the microbiota-gut-nerve axis in rats","volume":"22","author":"Jiang","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e220197","DOI":"10.1590\/0074-02760220197","article-title":"Impact of gut-peripheral nervous system axis on the development of diabetic neuropathy","volume":"118","author":"Carvalho","year":"2023","journal-title":"Mem. I Oswaldo Cruz"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bai, Y., Shu, C., Hou, Y., and Wang, G.H. (2024). Adverse childhood experience and depression: The role of gut microbiota. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1309022"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5186","DOI":"10.1128\/AEM.68.10.5186-5190.2002","article-title":"Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine","volume":"68","author":"Duncan","year":"2002","journal-title":"Appl. Environ. Microb."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nrmicro3344","article-title":"The gut microbiota, bacterial metabolites and colorectal cancer","volume":"12","author":"Louis","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Goudman, L., Demuyser, T., Pilitsis, J.G., Billot, M., Roulaud, M., Rigoard, P., and Moens, M. (2024). Gut dysbiosis in patients with chronic pain: A systematic review and meta-analysis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1342833"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Herfindal, A.M., Nilsen, M., Aspholm, T.E., Schultz, G.I.G., Valeur, J., Rudi, K., Thoresen, M., Lundin, K.E.A., Henriksen, C., and B\u00f8hn, S.K. (2024). Effects of fructan and gluten on gut microbiota in individuals with self-reported non-celiac gluten\/wheat sensitivity-a randomised controlled crossover trial. BMC Med., 22.","DOI":"10.1186\/s12916-024-03562-1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103.e1","DOI":"10.1016\/j.ajog.2025.01.013","article-title":"Gut, vaginal, and urinary microbiota as potential biomarkers of sensitization in women with chronic pelvic pain","volume":"233","author":"Cardaillac","year":"2025","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"529","DOI":"10.5056\/jnm20004","article-title":"The Role of Intestinal Microbiota and Mast Cell in a Rat Model of Visceral Hypersensitivity","volume":"26","author":"Li","year":"2020","journal-title":"J. Neurogastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e0328622","DOI":"10.1128\/spectrum.03286-22","article-title":"Protective Effect of Clostridium butyricum on Escherichia coli-Induced Endometritis in Mice via Ameliorating Endometrial Barrier and Inhibiting Inflammatory Response","volume":"10","author":"Wang","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Xu, X., Yang, S.L., Olajide, J.S., Qu, Z.G., Gong, Z.X., Wang, J., Zhang, Y., Wang, H., Xiong, L., and Zhang, K. (2021). Supplement Can Ameliorate the Intestinal Barrier Roles in Broiler Chickens Experimentally Infected with. Front Physiol., 12.","DOI":"10.3389\/fphys.2021.737481"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e0136822","DOI":"10.1128\/spectrum.01368-22","article-title":"Clostridium butyricum and Its Derived Extracellular Vesicles Modulate Gut Homeostasis and Ameliorate Acute Experimental Colitis","volume":"10","author":"Ma","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chen, J., Wang, Q., Wang, A., and Lin, Z. (2019). Structural and Functional Characterization of the Gut Microbiota in Elderly Women with Migraine. Front. Cell Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00470"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.anaerobe.2013.06.002","article-title":"High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis\/chronic fatigue syndrome patients","volume":"22","author":"Fremont","year":"2013","journal-title":"Anaerobe"},{"key":"ref_51","first-page":"274","article-title":"Streptozotocin as a tool for induction of rat models of diabetes: A practical guide","volume":"22","author":"Ghasemi","year":"2023","journal-title":"EXCLI J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.2337\/db22-0623","article-title":"NRF2 and diabetes: The good, the bad, and the complex","volume":"71","author":"Dodson","year":"2022","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12967-023-03878-1","article-title":"Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer","volume":"21","author":"Liu","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3390\/ijms16010378","article-title":"Oxidative Stress in Obesity: A Critical Component in Human Diseases","volume":"16","author":"Marseglia","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/EC-14-0092","article-title":"Mitochondrial dysfunction and insulin resistance: An update","volume":"4","author":"Montgomery","year":"2015","journal-title":"Endocr Connect"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Vezza, T., Abad-Jim\u00e9nez, Z., Marti-Cabrera, M., Rocha, M., and V\u00edctor, V.M. (2020). Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes. Antioxidants, 9.","DOI":"10.3390\/antiox9090848"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"101265","DOI":"10.1016\/j.xcrm.2023.101265","article-title":"Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain","volume":"4","author":"Willemen","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Allen, J., Romay-Tallon, R., Brymer, K.J., Caruncho, H.J., and Kalynchuk, L.E. (2018). Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front Neurosci., 12.","DOI":"10.3389\/fnins.2018.00386"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"610","DOI":"10.2174\/1570159X14666160229114755","article-title":"Mitochondrial Dysfunction in Depression","volume":"14","author":"Bansal","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Li, W.H., Zhu, L.Q., Chen, Y., Zhuo, Y.D., Wan, S.R., and Guo, R.J. (2023). Association between mitochondrial DNA levels and depression: A systematic review and meta-analysis. BMC Psychiatry, 23.","DOI":"10.1186\/s12888-023-05358-8"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Al Ojaimi, M., Salah, A., and El-Hattab, A.W. (2022). Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders. Membranes, 12.","DOI":"10.3390\/membranes12090893"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"102012","DOI":"10.1016\/j.jsps.2024.102012","article-title":"A detailed review of pharmacology of MFN1 (mitofusion-1)-mediated mitochondrial dynamics: Implications for cellular health and diseases","volume":"32","author":"Alghamdi","year":"2024","journal-title":"Saudi Pharm. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1093\/hmg\/ddz008","article-title":"MFN2 mutations in Charcot\u2013Marie\u2013Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics","volume":"28","author":"Larrea","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1038\/s41467-022-29945-7","article-title":"Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis","volume":"13","author":"Sidarala","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105380","DOI":"10.1016\/j.jbc.2023.105380","article-title":"Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission","volume":"299","author":"Nolden","year":"2023","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zerihun, M., Sukumaran, S., and Qvit, N. (2023). The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065785"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Gabrielson, M., Bj\u00f6rklund, M., Carlson, J., and Shoshan, M. (2014). Expression of Mitochondrial Regulators PGC1\u03b1 and TFAM as Putative Markers of Subtype and Chemoresistance in Epithelial Ovarian Carcinoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107109"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1002\/1873-3468.12989","article-title":"The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms","volume":"592","author":"Kang","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/cvr\/cvn098","article-title":"Transcriptional control of mitochondrial biogenesis: The central role of PGC-1\u03b1","volume":"79","author":"Garnier","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.brainresbull.2016.12.004","article-title":"Parkin and PINK1 functions in oxidative stress and neurodegeneration","volume":"133","author":"Barodia","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/ncb2012","article-title":"PINK1\/Parkin-mediated mitophagy is dependent on VDAC1 and p62\/SQSTM1","volume":"12","author":"Geisler","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1093\/ibd\/izac024","article-title":"Role of Energy Metabolism and Mitochondrial Function in Inflammatory Bowel Disease","volume":"28","author":"Stummer","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic Neuropathy: A Position Statement by the American Diabetes Association","volume":"40","author":"Boulton","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110765","DOI":"10.1016\/j.diabres.2023.110765","article-title":"Conventional management and current guidelines for painful diabetic neuropathy","volume":"206","author":"Tesfaye","year":"2023","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6773662","DOI":"10.1155\/2022\/6773662","article-title":"Painful Diabetic Neuropathy Is Associated with Compromised Microglial IGF-1 Signaling Which Can Be Rescued by Green Tea Polyphenol EGCG in Mice","volume":"2022","author":"Chen","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Khan, I., Kaur, S., Rishi, A.K., Boire, B., Aare, M., and Singh, M. (2024). Cannabidiol and Beta-Caryophyllene Combination Attenuates Diabetic Neuropathy by Inhibiting NLRP3 Inflammasome\/NF\u03baB through the AMPK\/sirT3\/Nrf2 Axis. Biomedicines, 12.","DOI":"10.20944\/preprints202404.1827.v1"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Silva, G.S.D., Santana, T.D.M., Velozo, A.C.L., Macedo, A.P.A., Goncalves, M.D., Couto, R.D., Soares, M.B.P., Viana, M.D.M., and Villarreal, C.F. (2025). Green Tea Intake Reduces High-Fat Diet-Induced Sensory Neuropathy in Mice by Upregulating the Antioxidant Defense System in the Spinal Cord. Antioxidants, 14.","DOI":"10.3390\/antiox14040452"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.phrs.2005.05.004","article-title":"Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening","volume":"52","author":"Srinivasan","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1744806918804441","DOI":"10.1177\/1744806918804441","article-title":"Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats","volume":"14","author":"Ji","year":"2018","journal-title":"Mol. Pain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.nutres.2024.01.014","article-title":"Ginger alleviates mechanical hypersensitivity and anxio-depressive behavior in rats with diabetic neuropathy through beneficial actions on gut microbiome composition, mitochondria, and neuroimmune cells of colon and spinal cord","volume":"124","author":"Shen","year":"2024","journal-title":"Nutr. Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Shen, C.L., Dufour, J.M., Miranda, J.M., Kaur, G., Chung, E., Ramalingam, L., Moustaid-Moussa, N., and Cao, J.J. (2023). Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24020979"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Deshmukh, H., Mendoza, R., Santos, J.M., Sivaprakasam, S., Elmassry, M.M., Miranda, J.M., Pham, P.Q., Driver, Z., Bender, M., and Dufour, J.M. (2025). Effect of Peanut Shell Extract and Luteolin on Gut Microbiota and High-Fat Diet-Induced Sequelae of the Inflammatory Continuum in a Metabolic Syndrome-like Murine Model. Nutrients, 17.","DOI":"10.3390\/nu17142290"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12133\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:12:32Z","timestamp":1766121152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":83,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262412133"],"URL":"https:\/\/doi.org\/10.3390\/ijms262412133","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]}}}