{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:46:12Z","timestamp":1762177572219,"version":"build-2065373602"},"reference-count":76,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["GM 102631","GM 102631S"],"award-info":[{"award-number":["GM 102631","GM 102631S"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes is currently the fifth leading cause of death by disease in the USA. The underlying mechanisms for type 2 Diabetes Mellitus (DM2) and the enhanced susceptibility of such patients to inflammatory disorders and infections remain to be fully defined. We have recently shown that peripheral blood mononuclear cells (PBMCs) from non-diabetic people upregulate expression of inflammatory genes in response to proteasome modulators, such as bacterial lipopolysaccharide (LPS) and soybean lectin (LEC); in contrast, resveratrol (RES) downregulates this response. We hypothesized that LPS and LEC will also elicit a similar upregulation of gene expression of key signaling mediators in (PBMCs) from people with type 2 diabetes (PwD2, with chronic inflammation) ex vivo. Unexpectedly, using next generation sequencing (NGS), we show for the first time, that PBMCs from PwD2 failed to elicit a robust LPS- and LEC-induced gene expression of proteasome subunit LMP7 (PSMB8) and mediators of T cell signaling that were observed in non-diabetic controls. These repressed genes included: PSMB8, PSMB9, interferon-\u03b3, interferon-\u03bb, signal-transducer-and-activator-of-transcription-1 (STAT1), human leukocyte antigen (HLA DQB1, HLA DQA1) molecules, interleukin 12A, tumor necrosis factor-\u03b1, transporter associated with antigen processing 1 (TAP1), and several others, which showed a markedly weak upregulation with toxins in PBMCs from PwD2, as compared to those from non-diabetics. Resveratrol (proteasome inhibitor) further downregulated the gene expression of these inflammatory mediators in PBMCs from PwD2. These results might explain why PwD2 may be susceptible to infectious disease. LPS and toxins may be leading to inflammation, insulin resistance, and thus, metabolic changes in the host cells.<\/jats:p>","DOI":"10.3390\/ijms24032732","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T02:52:02Z","timestamp":1675219922000},"page":"2732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dysregulation of Gene Expression of Key Signaling Mediators in PBMCs from People with Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"24","author":[{"given":"Nilofer","family":"Qureshi","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Shock\/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"},{"name":"Department of Pharmacology\/Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Desousa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Shock\/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"},{"name":"Department of Pharmacology\/Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeela Z.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Shock\/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betty M.","family":"Drees","sequence":"additional","affiliation":[{"name":"Internal Medicine, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Shock\/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asaf A.","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Shock\/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.dsx.2020.04.004","article-title":"Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations","volume":"14","author":"Singh","year":"2020","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3389\/fcimb.2020.00364","article-title":"Immune parameters, and COVID-19 infection-associations with clinical severity and diseases prognosis","volume":"10","author":"Jesenak","year":"2020","journal-title":"Front. Cell. Infect. Microbiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1016\/S0140-6736(16)30163-5","article-title":"Trends in diabetes: Sounding the alarm","volume":"387","author":"Krug","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wing, S.S. (2008). The UPS in diabetes and obesity. BMC Biochem., 9.","DOI":"10.1186\/1471-2091-9-S1-S6"},{"key":"ref_5","first-page":"1","article-title":"Diabetes: Mechanism, pathophysiology, and management-A review","volume":"5","author":"Siddiqui","year":"2013","journal-title":"Int. J. Drug Dev. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jinf.2007.05.177","article-title":"Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia","volume":"55","author":"Leonidou","year":"2007","journal-title":"J. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1097\/CCM.0b013e3181b083f7","article-title":"Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis","volume":"37","author":"Falciglia","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10096-011-1337-4","article-title":"The impact of diabetes on the pathogenesis of sepsis","volume":"31","author":"Koh","year":"2012","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2174\/1871530315666150316124019","article-title":"Metformin and Inflammation: Its potential beyond glucose-lowering effect","volume":"15","author":"Saisho","year":"2015","journal-title":"Endocr. Metab. Immune Disord. Drug Targets."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s00125-015-3844-9","article-title":"Metformin and the gastrointestinal tract","volume":"59","author":"McCreight","year":"2016","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1152\/physiol.00041.2015","article-title":"Linking gut microbiota and inflammation to obesity and insulin resistance","volume":"31","author":"Saad","year":"2016","journal-title":"Physiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1196\/annals.1372.039","article-title":"Inflammatory process in type 2 diabetes: The role of cytokines","volume":"1084","author":"Alexandraki","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2337\/diabetes.52.3.812","article-title":"Inflammatory cytokines and the risk to develop type 2 diabetes: Results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study","volume":"52","author":"Spranger","year":"2003","journal-title":"Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1600-051X.2009.01498.x","article-title":"Effect of periodontal treatment on metabolic control, systemic inflammation, and cytokines in patients with type 2 diabetes","volume":"37","author":"Correa","year":"2010","journal-title":"J. Clin. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0024-3205(00)00622-6","article-title":"Plasma interleukin-6, tumour necrosis factor \u03b1 and blood cytokine production in type 2 diabetes","volume":"67","author":"Pickup","year":"2000","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.2337\/dc09-1315","article-title":"Unbalanced M1\/M2 phenotype of peripheral blood monocytes in obese diabetic patients: Effect of pioglitazone","volume":"33","author":"Satoh","year":"2010","journal-title":"Diabetes Care."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/cr.2015.68","article-title":"Metabolic reprogramming in macrophages and dendritic cells in innate immunity","volume":"25","author":"Kelly","year":"2015","journal-title":"Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cyto.2014.02.001","article-title":"Human monocytes produce interferon-gamma upon stimulation with LPS","volume":"67","author":"Kraaij","year":"2014","journal-title":"Cytokine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1093\/intimm\/5.11.1383","article-title":"Induction of IFN-\u03b3 in macrophages by lipopolysaccharide","volume":"5","author":"Fultz","year":"1993","journal-title":"Int. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1111\/j.0300-9475.2004.01500.x","article-title":"Interferon-\u03b3 mediates neuronal killing of intracellular bacteria","volume":"60","author":"Jin","year":"2004","journal-title":"Scand. J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1128\/AAC.43.5.1242","article-title":"Mechanism of the intracellular killing and modulation of antibiotic susceptibility of Listeria monocytogenes in THP-1 macrophages activated by gamma interferon","volume":"43","author":"Ouadrhiri","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Herbst, S., Schaible, U.E., and Schneider, B.E. (2011). Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019105"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1189\/jlb.0412214","article-title":"Regulation of inflammation by interleukin-4: A review of \u201calternatives\u201d","volume":"92","author":"Luzina","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/cdd.2016.3","article-title":"Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages","volume":"23","author":"Chen","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1681\/ASN.2006010083","article-title":"Protein degradation by the ubiquitin\u2013proteasome pathway in normal and disease states","volume":"17","author":"Lecker","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.4049\/jimmunol.171.3.1515","article-title":"The proteasome as a lipopolysaccharide-binding protein in macrophages: Differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events","volume":"171","author":"Qureshi","year":"2003","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"594599.5","DOI":"10.1097\/01.shk.0000209555.46704.2d","article-title":"Proteasome inhibitor, lactacystin blocks CpG DNA-and peptidoglycan induced inflammatory genes, cytokines and mitogen-activated protein kinases in macrophages","volume":"25","author":"Shen","year":"2006","journal-title":"Shock"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/01.shk.0000209554.46704.64","article-title":"Key inflammatory signaling pathways are regulated by the proteasome","volume":"25","author":"Shen","year":"2006","journal-title":"Shock"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1016\/j.bbamcr.2012.06.016","article-title":"Proteasome protease mediated regulation of cytokine induction and inflammation","volume":"1823","author":"Qureshi","year":"2012","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1097\/SHK.0000000000000743","article-title":"Of Mice and Men: Proteasome\u2019s role in LPS-induced inflammation and tolerance","volume":"47","author":"Silswal","year":"2017","journal-title":"Shock"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1159\/000336335","article-title":"A critical role for the inducible proteasomal subunits LMP7 and MECL1 in cytokine production by activated murine splenocytes","volume":"89","author":"Rockwell","year":"2012","journal-title":"Pharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1177\/1753425908096855","article-title":"A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model","volume":"14","author":"Reis","year":"2008","journal-title":"Innate Immun."},{"key":"ref_34","first-page":"22","article-title":"Levels of proteasome subunit expression provide information about host\u2019s immune system status","volume":"3","author":"Qureshi","year":"2017","journal-title":"Intern. Med. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s12013-011-9183-7","article-title":"The immunoproteasomes regulate LPS-induced TRIF\/TRAM signaling pathway in murine macrophages","volume":"60","author":"Reis","year":"2011","journal-title":"Cell Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s12013-011-9182-8","article-title":"LPS-induced formation of immunoproteasomes: TNF-\u03b1 and nitric oxide production are regulated by altered composition of proteasome-active sites","volume":"60","author":"Reis","year":"2011","journal-title":"Cell Biochem. Biophys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"761","DOI":"10.3389\/fonc.2019.00761","article-title":"Proteasomes and several aspects of their heterogeneity relevant to cancer","volume":"9","author":"Morozov","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/1476-511X-11-76","article-title":"Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor","volume":"11","author":"Qureshi","year":"2012","journal-title":"Lipids Health Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/1476-511X-10-177","article-title":"Suppression of nitric oxide induction and pro-inflammatory cytokines by novel proteasome inhibitors in various experimental models","volume":"10","author":"Qureshi","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1097\/SHK.0000000000001080","article-title":"Resveratrol downregulates biomarkers of sepsis Via inhibition of proteasome's proteases","volume":"50","author":"Silswal","year":"2018","journal-title":"Shock"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12944-018-0697-5","article-title":"Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs","volume":"17","author":"Qureshi","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.tiv.2012.06.015","article-title":"Modulation of NF-kB activation by resveratrol in LPS treated human intestinal cells results in downregulation of PGE2 production and COX-2 expression","volume":"26","author":"Cianciulli","year":"2012","journal-title":"Toxicol. Vitr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1096\/fj.04-2691fje","article-title":"Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-\u03baB-independent mechanism","volume":"19","author":"Birrell","year":"2005","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cho, C.E., Damle, S.S., Wancewicz, E.V., Mukhopadhyay, S., Hart, C.E., Mazur, C., Swayze, E.E., and Kamme, F.A. (2019). modular analysis of microglia gene expression, insights into the aged phenotype. BMC Genom., 20.","DOI":"10.1186\/s12864-019-5549-9"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/ki.2011.347","article-title":"Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury","volume":"81","author":"Holthoff","year":"2012","journal-title":"Kidney Int."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zong, Y., Sun, L., Liu, B., Deng, Y.S., Zhan, D., Chen, Y.L., He, Y., Liu, J., Zhang, Z.J., and Sun, J. (2012). Resveratrol inhibits LPS-induced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044107"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.biopha.2016.09.020","article-title":"Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation","volume":"84","author":"Jiang","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/S0006-2952(99)00002-7","article-title":"Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages","volume":"57","author":"Wadsworth","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_49","unstructured":"Liener, I. (2012). The Lectins: Properties, Functions, and Applications in Biology and Medicine, Elsevier."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1590\/S0100-879X1997000700009","article-title":"Inflammatory and anti-inflammatory effects of soybean agglutinin","volume":"30","author":"Benjamin","year":"1997","journal-title":"Braz. J. Med. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.4049\/jimmunol.1600145","article-title":"Plant lectins activate the NLRP3 inflammasome to promote inflammatory disorders","volume":"198","author":"Gong","year":"2017","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"356","DOI":"10.3389\/fendo.2019.00356","article-title":"Differential apoptotic and mitogenic effects of lectins in zebrafish","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"110827","DOI":"10.1016\/j.fct.2019.110827","article-title":"Structure-function, and application of plant lectins in disease biology and immunity","volume":"134","author":"Mishra","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Qureshi, N., Desousa, J., Siddiqui, A.Z., Morrison, D.C., and Qureshi, A.A. (2022). Reprograming of Gene Expression of Key Inflammatory Signaling Pathways in Human Peripheral Blood Mononuclear Cells by Soybean Lectin and Resveratrol. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112946"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14","DOI":"10.2337\/db11-1213","article-title":"Central role for interleukin-2 in type 1 diabetes","volume":"61","author":"Hulme","year":"2012","journal-title":"Diabetes"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.2147\/DMSO.S300048","article-title":"Gene expression profiling of apoptotic proteins in circulating peripheral blood mononuclear cells in type II diabetes mellitus and modulation by metformin","volume":"14","author":"Alshahrani","year":"2021","journal-title":"Diabetes Metab. Syndr. Obes. Targets Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"338","DOI":"10.4049\/jimmunol.1801651","article-title":"Metformin inhibits the type 1 IFN response in human CD4+ T cells","volume":"203","author":"Titov","year":"2019","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.numecd.2015.03.007","article-title":"Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial","volume":"25","author":"Ceolotto","year":"2015","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"874","DOI":"10.4049\/jimmunol.154.9.4874","article-title":"IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice","volume":"154","author":"Rabinovitch","year":"1995","journal-title":"J. Immunol."},{"key":"ref_60","unstructured":"(2021). Pharmacologic Approaches to Glycemic Treatment. Am. Diabetes Assoc. Diabetes Care, 44, S111\u2013S124."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2147\/JIR.S245064","article-title":"Impact of low interferon-\u03b3 and il-10 levels on TNF-\u03b1 and il-6 production by PHA-induced pbmcs in type 2 diabetes mellitus","volume":"13","author":"Kartika","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cyto.2005.02.011","article-title":"Correlation between intracellular interferon-\u03b3 (IFN-\u03b3) production by CD4+ and CD8+ lymphocytes and IFN-\u03b3 gene polymorphism in patients with type 2 diabetes mellitus and latent autoimmune diabetes of adults (LADA)","volume":"31","author":"Tsiavou","year":"2005","journal-title":"Cytokine"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"254","DOI":"10.5582\/bst.2017.01043","article-title":"The T-Box transcription factor 3 in development and cancer","volume":"11","author":"Willmer","year":"2017","journal-title":"Biosci. Trends"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/sj.mp.4001817","article-title":"Association of the NRG1 gene and schizophrenia: A meta-analysis","volume":"11","author":"Munafo","year":"2006","journal-title":"Mol. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/s00125-007-0654-8","article-title":"C3H\/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet","volume":"50","author":"Poggi","year":"2007","journal-title":"Diabetologia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E386","DOI":"10.1152\/ajpendo.00087.2001","article-title":"Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance","volume":"282","author":"Sugita","year":"2002","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.2337\/dc10-2197","article-title":"Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation","volume":"34","author":"Lassenius","year":"2011","journal-title":"Diabetes Care."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s11010-013-1911-4","article-title":"Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes","volume":"388","author":"Jayashree","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1101\/gad.381806","article-title":"The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic \u03b2 cells and intestinal endocrine cells","volume":"20","author":"Gierl","year":"2006","journal-title":"Genes Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/obr.12370","article-title":"Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: Implications for inflammation and obesity","volume":"17","author":"Hersoug","year":"2016","journal-title":"Obes. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1007\/s00125-012-2648-4","article-title":"Modulation of gut microbiota by antibiotics improves insulin signaling in high-fat fed mice","volume":"55","author":"Carvalho","year":"2012","journal-title":"Diabetologia"},{"key":"ref_72","first-page":"2258","article-title":"A novel mixture of d-tocotrienol, vitamin D3, and resveratrol significantly decreases diabetes biomarkers including inflammatory, in people with type 2 diabetes","volume":"5","author":"Qureshi","year":"2021","journal-title":"J. Diabetes Clin. Stud."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.2741\/2750","article-title":"Uses of plant lectins in bioscience and biomedicine","volume":"13","author":"Pusztai","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1016\/S0021-9258(18)37881-5","article-title":"Complete structural determination of lipopolysaccharide obtained from deep rough mutant of Escherichia coli. Purification by high performance liquid chromatography and direct analysis by plasma desorption mass spectrometry","volume":"263","author":"Qureshi","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"11808","DOI":"10.1016\/S0021-9258(18)33836-5","article-title":"Purification, and structural determination of nontoxic lipid A from the rough mutant of Salmonella typhimurium","volume":"257","author":"Qureshi","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"12947","DOI":"10.1016\/S0021-9258(17)44062-2","article-title":"Position of ester groups in the lipid A backbone of lipopolysaccharides obtained from Salmonella typhimurium","volume":"258","author":"Qureshi","year":"1983","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2732\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:20:36Z","timestamp":1760120436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,1]]},"references-count":76,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032732"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032732","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,2,1]]}}}