Role of ferroptosis inhibitors in the management of diabetes.

Ferroptosis, the iron-dependent, lipid peroxide-mediated cell death, has garnered attention due to its critical involvement in crucial physiological and pathological cellular processes. Indeed, several studies have attributed its role in developing a range of disorders, including diabetes. As accumulating evidence further the understanding of ferroptotic mechanisms, the impact this specialized mode of cell death has on diabetic pathogenesis is still unclear. Several in vivo and in vitro studies have highlighted the association of ferroptosis with beta-cell death and insulin resistance, supported by observations of marked alterations in ferroptotic markers in experimental diabetes models. The constant improvement in understanding ferroptosis in diabetes has demonstrated it as a potential therapeutic target in diabetic management. In this regard, ferroptosis inhibitors promise to rescue pancreatic beta-cell function and alleviate diabetes and its complications. This review article elucidates the key ferroptotic pathways that mediate beta-cell death in diabetes, and its complications. In particular, we share our insight into the cross talk between ferroptosis and other hallmark pathogenic mediators such as oxidative and endoplasmic reticulum stress regulators relevant to diabetes progression. Further, we extensively summarize the recent developments on the role of ferroptosis inhibitors and their therapeutic action in alleviating diabetes and its complications.

Association between Tumor Prognosis Marker Visfatin and Proinflammatory Cytokines in Hypertensive Patients.

Visfatin has been reported as a risk factor and a potential diagnostic marker in cancer. It is an adipokine, secreted by visceral fat and associated with the pathogenesis of arterial hypertension. We investigated the circulatory levels of visfatin in hypertensive patients with hypertriglyceridemia, which are the risk factors for various cancers and its association with proinflammatory cytokines. A total of 81 (male/female: 33/48) subjects with or without hypertension were enrolled for this study. Group 1 was normotensive, Group 2 hypertensive, and Group 3 with hypertension with hypertriglyceridemia. Data on anthropometric and biochemical data were recorded. Plasma visfatin levels were measured using an ELISA kit. The plasma inflammatory cytokines were estimated using a multiplex bead-based assay. The results revealed that the hypertension with hypertriglyceridemia group has the highest levels of visfatin compared to the hypertension and control groups with a significant difference (p < 0.001). Besides, circulatory visfatin showed the strongest possible correlation with proinflammatory cytokines among hypertensive patients with hypertriglyceridemia. We found a positive correlation between visfatin and diastolic blood pressure as well as high-density lipoproteins. In conclusion, the outcomes of the present study demonstrate that plasma visfatin levels were found to be elevated in hypertensive patients with hypertriglyceridemia and associated with proinflammatory cytokines. Since hypertension has been documented as the most common comorbidity observed in cancer patients, visfatin may be a novel potential therapeutic target for hypertension in cancer patients and survivors.

Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells.

Endoplasmic reticulum (ER) plays a key role in the folding, modification, and trafficking of proteins. When the homeostasis of the ER is disturbed, un/misfolded proteins accumulate in the ER which leads to ER stress. Sustained ER stress results in apoptosis, which is associated with various diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor in redox homeostasis by regulating various genes associated with detoxification and cell-protective mechanisms. We found that Rosolic acid (RA) treatment dose-dependently activates Nrf2 in endothelial cells using the enzyme fragment complementation assay. The cytoprotective role of RA against ER stress-induced endothelial apoptosis and its molecular mechanism was explored in the present study. The Nrf2 and its target genes, as well as ER stress marker expressions, were measured by qPCR in ER stress-exposed endothelial cells. The contribution of Nrf2 in RA-mediated defense mechanism in endothelial cells was established by knockout studies using Nrf2-CRISPR/Cas9. The treatment with RA to ER stress-induced endothelial cells exhibited activation of Nrf2, as demonstrated by Nrf2 translocation and reduction of ER stress markers. We found that the Nrf2 knockout sensitized the endothelial cells against ER stress, and further, RA failed to mediate its cytoprotective effect. Proteomic studies using LC-MS/MS revealed that among the 1370 proteins detected, we found 296 differentially regulated proteins in ER stress-induced endothelial cells, and RA administration ameliorated 71 proteins towards the control levels. Of note, the ER stress in endothelial cells was attenuated by the treatment with the RA, suggesting the role of the Nrf2 activator in the pathological conditions of ER stress-associated diseases.

miR-23c regulates wound healing by targeting stromal cell-derived factor-1α (SDF-1α/CXCL12) among patients with diabetic foot ulcer.

Diabetic Foot Ulcer (DFU) is the most common in patients who have diabetic peripheral neuropathy and angiopathy as well as a foot deformity. The delayed process of wound healing in diabetic condition is mainly due to reduced expression of the growth factors, persistent inflammatory response and endothelial dysfunction. Emerging evidence indicate that miRNAs play a crucial role in regulating angiogenesis, collectively called as "angiomiRs". The present study aimed to screen the expressions of angiomiRs particularly miR23 family and its association with the various angiogenic factors including SDF-1α in the tissue biopsies isolated from DFU patients. Among the 40 enrolled subjects for this study, 10 were subjected in each group as healthy controls, type 2 diabetic subjects (T2DM), T2DM subjects with uninfected DFU, and T2DM subjects with infected DFU. The expression of both the miR23 family such as hsa-miR-23a, hsa-miR-23b, hsa-miR-23c and angiogenic factors such as SDF-1α, HIF-1α, VEGF, eNOS were investigated in peripheral blood mononuclear cells and tissue biopsy samples using qPCR. We found that the angiogenic factor SDF-1α was significantly decreased in both the circulation and tissue biopsies of patients with T2DM and infected DFU. The SDF-1α at the 3'-untranslated region pairs with target miRNAs namely hsa-miR-23a-3p, hsa-miR-23b-3p and hsa-miR-23c as established using miRNA target prediction algorithm. Further, the tissue-specific expressions of miR-23a and miR-23b were found to be low whereas miR-23c was increased in patients with infected DFU. Moreover, correlation analysis showed that SDF-1α was found to have a significant inverse association with miR-23c. In conclusion, miR-23c may function as a new regulator to inhibit angiogenesis by targeting SDF-1α.

Association of SNP rs7181866 in the nuclear respiratory factor-2 beta subunit encoding GABPB1 gene with obesity and type-2 diabetes mellitus in South Indian population.

GABPB1, known as nuclear respiratory factor 2 (Nrf2), activates mitochondrial genes that are responsible for oxidative phosphorylation. Earlier studies on GABPB1 reported that two single nucleotide polymorphisms (SNPs) such as rs7181866 and rs8031031, to be associated with increased endurance in athletes. In the present study, a cohort of 302 South Indians, including normoglycemic healthy controls, T2DM with and without obesity were genotyped for the two SNPs by PCR-RFLP method and correlated with serum adipokines. The 'G' allele of rs7181866 was found to be associated with obesity whereas rs8031031 didn't show any significant association with obese individuals. The increased levels of adipokines such as Leptin, IL-6 and TNF-α and decreased adiponectin were found among obese-T2DM, when compared to non-obese T2DM subjects. Further, Factor analysis on metabolic components revealed four factors which accounts for 71.5% for non-obese control and 88.3% for obese T2DM of variance. The bias-corrected and accelerated bootstrap analysis revealed GG genotype to have significant positive and negative correlation with both TNF-α and adiponectin. In conclusion, the G allele of (rs7181866 A/G) was found to be significantly associated with risk for obesity among T2DM subjects.

The tip link protein Cadherin-23: From Hearing Loss to Cancer.

Cadherin-23 is an atypical member of the cadherin superfamily, with a distinctly long extracellular domain. It has been known to be a part of the tip links of the inner ear mechanosensory hair cells. Several studies have been carried out to understand the role of Cadherin-23 in the hearing mechanism and defects in the CDH23 have been associated with hearing impairment resulting from defective or absence of tip links. Recent studies have highlighted the role of Cadherin-23 in several pathological conditions, including cancer, suggesting the presence of several unknown functions. Initially, it was proposed that Cadherin-23 represents a yet unspecified subtype of Cadherins; however, no other proteins with similar characteristics have been identified, till date. It has a unique cytoplasmic domain that does not bear a ß-catenin binding region, but has been demonstrated to mediate cell-cell adhesions. Several protein interacting partners have been identified for Cadherin-23 and the roles of their interactions in various cellular mechanisms are yet to be explored. This review summarizes the characteristics of Cadherin-23 and its roles in several pathologies including cancer.

Potential of circulatory procalcitonin as a biomarker reflecting inflammation among South Indian diabetic foot ulcers.

OBJECTIVE: Diabetic foot ulcer (DFU), the major complication associated with diabetes mellitus, has been shown to precede amputation in up to 90% of cases. Recent data reveal that procalcitonin (PCT) is a valid marker for the diagnosis of bacterial infections compared with traditional markers like white blood cell count, C-reactive protein levels, and erythrocyte sedimentation rate in DFU patients. Furthermore, cytokines are proposed to act as modulators and mediators for the expression and release of PCT into the circulation. Hence, this preliminary study was conducted to evaluate the diagnostic accuracy of PCT compared with other traditional markers and to predict the association of PCT plasma levels with inflammatory cytokines and clinical parameters of incident diabetes among South Indian DFU subjects. METHODS: There were 185 subjects with type 2 diabetes mellitus (T2DM) selected in this cross-sectional study, subdivided into three groups: group I, control/T2DM subjects free from DFU (n = 75; male, 43; female, 32); group II, T2DM subjects with noninfected DFU (n = 34; male, 19; female, 15); and group III, T2DM subjects with infected DFU (IDFU; n = 76; male, 46; female, 30). Patients with IDFU were further divided into three subgroups as per the Infectious Diseases Society of America-International Working Group on the Diabetic Foot classification criteria: grade 2 (n = 27), grade 3 (n = 38), and grade 4 (n = 11). Subjects with type 1 diabetes, gestational diabetes, pneumonia, sepsis, inflammatory bowel disease, meningitis, or hematologic diseases and those who underwent surgery in the past 2 to 3 weeks were excluded from this study. For investigation of clinical parameters, blood samples were drawn from all the study subjects; plasma samples were used for estimating PCT by the enzyme-linked immunosorbent assay method. The profiling of plasma cytokines was carried out using a multiplex bead-based assay. Data are presented as mean ± standard deviation for clinical and biochemical variables and as geometric mean with 95% confidence interval (CI) for cytokines. All analysis was done using the Statistical Package for the Social Sciences (version 20.0; IBM Corp, Armonk, NY); P < .05 was considered to be statistically significant. RESULTS: We found PCT to be a valid diagnostic marker for IDFU with higher sensitivity and specificity than other traditional markers. For PCT, the area under the receiver operating characteristic curve was found to be high (0.99; 95% CI, 0.96-1.0), followed by C-reactive protein levels (0.78; 95% CI, 0.65-0.81), white blood cell count (0.76; 95% CI, 0.67-0.86), and erythrocyte sedimentation rate (0.74; 95% CI, 0.68-0.80) in IDFU subjects. We found the cutoff value of ≥0.5 ng/mL to have 54% sensitivity and 100% specificity for PCT with a positive predictive value of 100% and a negative predictive value of 12% for IDFU diagnosis. Moreover, PCT circulatory levels showed a positive correlation with helper T-cell subtype 1 cytokines, such as interferon γ (r = 0.21; P = .03) and interleukin 28A (r = 0.31; P = .003), and subtype 17 cytokines, such as interleukin 29/interferon λ1 (r = 0.20; P = .037). CONCLUSIONS: PCT could be a valuable marker for diagnosis of T2DM patients with IDFU.

Genetic portrait of Tamil non-tribal and Irula tribal population using Y chromosome STR markers.

The 17 Y chromosomal short tandem repeat loci included in the AmpFlSTR® Yfiler™ PCR Amplification Kit were used to analyse the genetic diversity of 517 unrelated males representing the non-tribal and Irula tribal population of Tamil Nadu. A total of 392 unique haplotypes were identified among the 400 non-tribal samples whereas 111 were observed among the 117 Irula tribal samples. Rare alleles for the loci DYS458, DYS635 and YGATAH4.1 were also observed in both population. The haplotype diversity for the non-tribal and Irula tribal population were found to be 0.9999, and the gene diversity ranged from 0.2041 (DYS391) to 0.9612 (DYS385). Comparison of the test population with 26 national and global population using principal coordinate analysis (PCoA) and determination of the genetic distance matrix using phylogenetic molecular analysis indicate a clustering of the Tamil Nadu non-tribal and Irula tribal population away from other unrelated population and proximity towards some Indo-European (IE) and Asian population. Data are available in the Y chromosome haplotype reference database (YHRD) under accession number YA004055 for Tamil non-tribal and YA004056 for the Irula tribal group.

Pathophysiological insights of methylglyoxal induced type-2 diabetes.

Diabetes mellitus is a metabolic disorder constituting a major health problem whose prevalence has gradually increased worldwide over the past few decades. Type 2 diabetes mellitus (T2DM) remains more complex and heterogeneous and arises as a combination of insulin resistance and inadequate functional ß-cell mass and comprises about 90% of all diabetic cases. Appropriate experimental animal models are essential for understanding the molecular basis, pathogenesis of complications, and the utility of therapeutic agents to abrogate this multifaceted disorder. Currently, animal models for T2DM are obtained as spontaneously developed diabetes or diabetes induced by chemicals or dietary manipulations or through surgical or genetic methods. The currently used diabetogenic agents have certain limitations. Recently, methylglyoxal (MG), a highly reactive compound derived mainly from glucose and fructose metabolism has been implicated in diabetic complications. MG is a major precursor of the advanced glycation end product (AGE) and promotes impaired functions of insulin signaling, GLUT transporters, anion channels, kinases, and endothelial cells and is finally involved in apoptosis. Recent array of literature also cited that higher concentrations of MG causes rapid depolarization, elevated intracellular Ca(2+) concentration, and acidification in pancreatic ß-cells. This review henceforth highlights the mechanism of action of MG and its implications in the pathophysiology of experimental diabetes.