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The present study was conducted to explore the allele frequencies of MICA gene Exon-5 transmembrane and to measure the circulatory MICA levels in various histologic grades of patients with oral submucous fibrosis (OSF) compared to healthy individuals.We enrolled a total of 595 patients for this cross-sectional study and divided them into 2 groups: healthy controls (n = 320) and patients with OSF (n = 275). Further, patients with OSF were subdivided based on their histologic gradings. The genomic DNA was extracted followed by a polymerase chain reaction and genotyping using the ABI Prism DNA Sequencer (ThermoFisher Scientific, Inc., Waltham, MA, USA).Our study showed that the A5 allele of the MICA gene in the Exon-5 region conferred significant risk for patients with OSF. With reference to the histologic gradings of OSF, we found that the MICA gene conferred statistically significant risk among patients with grade III OSF. On the other hand, the A8 allele of MICA gene in the Exon-5 region conferred significant protection among the overall OSF cohort and in the grade III of histologic grade. Finally, the circulatory human MICA levels were found to have a stepwise increase from grade I toward grade III in patients with OSF.Our results suggested that the A5 allele in MICA might confer risk for the progression of OSF among the South Indian ethnic population.

The wide anatomical distribution of macrophages and their vast array of functions match various polarization states and their involvement in homeostasis and disease. The confluence of different cellular signaling networks, including direct involvement in inflammation, at the doorstep of the transcription factor Nuclear Factor- erythroid (NF-E2) p45-related factor 2 (Nrf2) activation raises the importance of deciphering the molecular circuitry at the background of multiple-discrete and antagonistic yet flexible and contextual pathways. While we primarily focus on wound healing and repair mechanisms that are affected in diabetic foot ulcers (DFUs), we strive to explore the striking similarities and differences in molecular events including inflammation, angiogenesis, and fibrosis during tissue injury and wound persistence that accumulates pro-inflammatory senescent macrophages, as a means to identify possible targets or cellular mediators to lessen DFU disease burden. In addition, the role of iron in the modulation of Nrf2 response in macrophages is crucial and reviewed here. Targeted approaches, unlike conventional treatments, in DFU management will require the review and re-assessment of mediators with relevance to other pathological conditions.

Vitamin D is an essential vitamin indispensable for calcium and phosphate metabolism, and its deficiency has been implicated in several extra-skeletal pathologies, including cancer and chronic kidney disease. Synthesized endogenously in the layers of the skin by the action of UV-B radiation, the vitamin maintains the integrity of the bones, teeth, and muscles and is involved in cell proliferation, differentiation, and immunity. The deficiency of Vit-D is increasing at an alarming rate, with nearly 32% of children and adults being either deficient or having insufficient levels. This has been attributed to Vit-D resistant genes that cause a reduction in circulatory Vit-D levels through a set of signaling pathways. CYP24A1, SMRT, and SNAIL are three genes responsible for Vit-D resistance as their activity either lowers the circulatory levels of Vit-D or reduces its availability in target tissues. The hydroxylase CYP24A1 inactivates analogs and prohormonal and/or hormonal forms of calcitriol. Elevation of the expression of CYP24A1 is the major cause of exacerbation of several diseases. CYP24A1 is rate-limiting, and its induction has been correlated with increased prognosis of diseases, while loss of function mutations cause hypersensitivity to Vit-D. The silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and its corepressor are involved in the transcriptional repression of VDR-target genes. SNAIL1 (SNAIL), SNAIL2 (Slug), and SNAIL3 (Smuc) are involved in transcriptional repression and binding to histone deacetylases and methyltransferases in addition to recruiting polycomb repressive complexes to the target gene promoters. An inverse relationship between the levels of calcitriol and the epithelial-to-mesenchymal transition is reported. Studies have demonstrated a strong association between Vit-D deficiency and chronic diseases, including cardiovascular diseases, diabetes, cancers, autoimmune diseases, infectious diseases

The regulation of angiogenesis by nuclear factor erythroid 2-related factor 2 (Nrf2), a master redox transcription factor, is well established. In the present study, we aimed to activate Nrf2 by mangiferin (MG) and investigate its potential to regulate angiogenesis under a hyperglycemic (HG) environment in human endothelial cells. The mRNA expression of Nrf2 and its downstream targets HO-1, SOD-1, and CAT were observed to be decreased at 72 h of HG (33.3 mM glucose) exposure, and was ameliorated in MG (24 h) pretreated endothelial cells. ROS generation was assessed using an DCFDA assay, where we found the ROS generated at HG exposure was quenched by MG in a dose-dependent manner. The angiogenic markers HIF-1α and VEGF were also decreased in HG-induced endothelial cells, which significantly increased in the cells pretreated with MG. In addition, we have observed substantially more closed tube network formation in MG pretreated cells, which was low in HG-induced endothelial cells. The cell migration potential was monitored using a scratch assay, where the cells activated by MG showed a more significant movement than those under HG stress. Furthermore, to understand the role of Nrf2 in regulating angiogenesis, we knocked out the Nrf2 using CRISPR/Cas9 in endothelial cells. The wild-type endothelial cells exposed to MG alone showed a cytoprotective effect under a hyperglycemic environment. Our findings collectively demonstrated that MG helps regulate impaired angiogenesis under a hyperglycemic environment through Nrf2 signaling.

Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose–exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance. [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12192-020-01176-z.

Diabetic non healing wounds often result in significant morbidity and mortality. The number of effective targets to detect these wounds are meagre. Slow lymphangiogenesis is one of the complex processes involved in impaired healing of wounds. Long non coding RNAs (lncRNAs) have been importantly recognized for their role in pathological conditions. Multiple studies highlighting the role of lncRNAs in the regulation of several biological processes and complex diseases. Herein, we investigated the role of lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of diabetic foot ulcer (DFU). We report a significant reduction in the expression of lncRNA MALAT1 in the infected DFU subjects which was positively correlated with the expression of angiogenic factors such as Nrf2, HIF-1α and VEGF. Further, expression of pro-inflammatory markers TNF-α and IL-6 were found to be increased while, the expression of anti-inflammatory marker IL-10 was decreased in infected DFU tissues. Involvement of lncRNA MALAT1 in angiogenesis in EA.hy926 cells was demonstrated by silencing the expression of Nrf2, HIF-1α, and VEGF through interference mediated by MALAT1. In addition, its inflammatory role was demonstrated by decreased expression of TNF-α, IL-6 and not affecting the expression of IL-10. Further, CRISPR-Cas9 knock out of Nrf2 decreased the expression of lncRNA MALAT1, HIF-1α and VEGF which revealed the association of Nrf2 in regulating MALAT1/HIF-1α loop through positive feedback mechanism. Collectively, our results suggested the role of Nrf2 on MALAT1/HIF-1α loop in the regulation of angiogenesis, which could act as a novel target in the treatment of diabetic wounds.

Plasma leakage is a major pathogenic manifestation of severe dengue and is a precursor of life-threatening complications associated with dengue. Accumulating evidence indicates the role of Matrix Metalloproteinases (MMPs) in mediating vascular permeability and plasma leakage following induction by the dengue virus. This study aims to investigate the utility of MMP-2, MMP-3, and MMP-9 in predicting the severity of dengue infection and further explore the relationship of these markers with the pathogenic factors associated with plasma leakage.The dengue-positive subjects were classified into mild and severe dengue groups based on the manifestation of warning signs. The samples in each group and healthy controls were quantified for basic laboratory characteristics. The levels of MMP-2, MMP-3, MMP-9, and Macrophage migration inhibitory factor (MIF) were estimated in all serum samples using a multiplex bead-based assay.MMP-2 and MMP-9 were markedly elevated in severe dengue patients compared to mild dengue patients and healthy controls. No alteration in the circulating levels of MMP-3 was observed between the study groups. ROC curve analysis indicated that MMP-2 and MMP-9 exhibited good potential for predicting severe dengue. Notably, an increase in MMP-9 was associated with increased MIF and Hematocrit levels in severe dengue patients.MMP-2 and MMP-9 could serve as prognostic biomarkers for severe dengue. These findings also identify the association of MMP-9 with markers of plasma leakage, thereby encouraging further studies to explore the therapeutic potential of targeting MMP-9 in managing plasma leakage in severe dengue.

Severe dengue is associated with a considerable risk of mortality, and there is currently a lack of appropriate prognostic biomarkers to predict its severity. Pathogenesis of severe dengue is characterized by overt inflammation, endothelial activation, and increased vascular permeability. The current study investigates the utility of endothelial, inflammatory, and vascular permeability factors as biomarkers to identify dengue severity, which could improve disease prognosis and management.The dengue-positive subjects were classified based on seropositivity for NS1, IgM, and IgG. The samples in each group were quantified for basic clinical investigations. The levels of Interleukin-6 (IL-6), Tumor necrosis factor receptor 1 (TNFR1), EOTAXIN, Monocyte chemoattractant protein-1 (MCP-1), Monokine induced by interferon-gamma (MIG), Intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Thrombomodulin, and Angiopoietin-2 were estimated in all serum samples using the multiplex bead-based assay.IgG seropositive dengue patients showed abnormal laboratory characteristics and severe dengue symptoms. Among the studied markers, only IL-6, TNFR1, ICAM-1, VCAM-1, Thrombomodulin, and Angiopoietin-2 were significantly elevated in IgG seropositive patients compared to healthy controls. Increased IL-6 and TNFR1 levels were associated with decreased platelet count and elevated Hematocrit levels in IgG seropositive patients. Furthermore, ROC curve analysis indicated that IL-6, TNFR1, Thrombomodulin, and Angiopoietin-2 showed good potential for predicting dengue severity.Inflammatory markers IL-6 and TNFR1, and endothelial factors Angiopoietin-2 and Thrombomodulin, could serve as prognostic markers for severe dengue. These findings also encourage the future study of these biomarkers in the pathogenesis of severe dengue infection.

Abstract: Chronic hyperglycemia damages the nerves, blood vessels, culminating in other vascular complications. Such complications enhance cytokine, oxidative and endoplasmic reticulum (ER) stress. ER is the primary organelle where proteins are synthesised and attains confirmatory changes before its site of destination. Perturbation of ER homeostasis activates signaling sensors within its lumen, the unfolded protein response (UPR) that orchestrates ER stress and is extensively studied. Increased ER stress markers are reported in diabetic complications in addition to lncRNA that acts as an upstream marker inducing ER stress response. This review focuses on the mechanisms of lncRNA that regulate ER stress markers, especially during the progression of diabetic complications. Through this systemic review, we showcase the dysfunctional lncRNAs that acts as a leading cause of ER stress response on the progression of diabetic complications.

Circular RNA (circRNA) is a neoteric researched transcript that involves gene regulation by serving as a micro-RNA (miRNA) sponge. This circRNA-miRNA-mRNA interaction is being recently explored, and its dysregulation is associated with disease pathogenesis and progression. Studies have demonstrated the involvement of this regulatory network in endothelium dysfunction-mediated regulation of pathology in vascular diseases. The disturbances or imbalance of vasodilation and vasoconstriction factors due to changes in oxidative stress, inflammatory markers, and nitric oxide signaling leads to endothelial dysfunction. These disturbances cause impermeability of blood through the endothelial barrier, thus developing atherosclerotic lesions. Advancements in high-throughput techniques like genome and RNA sequencing have made us understand this complex regulatory network causing endothelial dysfunction. In this review, we emphasize the network of interactions between circRNA, miRNA, and mRNA that mediates gene regulation and is linked to endothelial dysfunction in various pathological conditions.

Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment due to its antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. The molecular mechanism underlying HBO therapy particularly the involvement of Nrf2 in the wound healing process was investigated in the present study. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with standard therapy (Non-HBO) for DFU. A total of 32 Patients were recruited and randomized to standard wound care procedure alone (n = 17) or HBO therapy in combination with standard wound care procedure (n = 15) for 20 days. Our results showed that the tissue levels of Nrf2 along with its downstream targets were significantly increased in patients who underwent HBO therapy when compared to Non-HBO therapy. Further, HBO therapy induced angiogenesis as assessed by increased levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The expressions of eNOS and nitrite concentrations were also significantly increased in HBO therapy when compared to Non-HBO therapy subjects. Moreover, HBO therapy sensitises the macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further, it increased the levels of neutrophil attractant CXCL-8 thereby promotes the release of chemokine CCL2, a well-known mediator of neovascularization. The Pearson correlation showed that Nrf2 has a positive correlation with EGF, VEGF and PDGF. In conclusion, the findings of the present study suggest that HBO therapy promotes wound healing by increasing oxygen supply and distribution to damaged tissues, stimulating angiogenesis, decreasing inflammation, and increasing the nitrite levels. Increased levels of Nrf2 transiently regulate the expression of angiogenic genes in wound biopsies, which may result in accelerated healing of chronic wounds.

Enhanced and prolonged expression of tumor necrosis factor alpha (TNF-α), a potent pro-inflammatory cytokine is evidenced during the chronic wound healing process of infected diabetic foot ulcer (IDFU). B-cell activating factor (BAFF) is the member of TNF-α family, which implicit in B-cell dysfunction. This study was aimed to evaluate the role of BAFF in diabetic foot ulcer (DFU) patients and to correlate its association with other family of inflammatory cytokines. Circulating levels of BAFF and other cytokines were measured in IDFU (n = 44) and non-IDFU patients (n = 40) using multiplexed bead-based cytokine immunoassay. A stepwise significant increase was observed in both circulatory BAFF and C-reactive protein (CRP) during the disease progression. The area under the receiver operating characteristic curve (AUCROC ) for BAFF was found to be high (0.89; [95% CI: 0.73-1.0]), when compared to CRP (0.68; [95% CI: 0.61-0.76]). Optimum diagnostic cutoff level for BAFF was found to be ≥2.35 pg/mL with 62.0% sensitivity and 85.7% specificity. Further, BAFF levels showed a significant positive correlation with CRP among IDFU patients. With respect to other family cytokines, BAFF levels were positively correlated with TNF-α, interferon family cytokines such as IFN-α2, IL-28A/IFN-λ2, IFN-γ, and IL-10 family cytokines such as IL-19, IL-22, and IL-26 and negatively correlated with IL-6 receptor family such as gp130/sIL-6Rβ. Hence, our data suggest that devising therapeutic strategies to reduce the levels of BAFF may contribute in amelioration of IDFU.

The loss of function or dysfunction of β-cells in the pancreas, attributed to the development of diabetes, involve alterations in genetic and epigenetic signatures. Recent evidences highlight the pathophysiological role of histone deacetylases (HDACs) in type 1 and type 2 diabetes. Indeed, most HDAC members have been linked to critical pathogenic events in diabetes, including redox imbalance, endoplasmic reticulum (ER) homeostasis perturbation, onset of oxidative stress and inflammation, which ultimately deteriorate β-cell function. Accumulating evidence highlights the inhibition of HDACs as a prospective therapeutic strategy. Several chemically synthesized small molecules have been investigated for their specific ability to inhibit HDACs (reffered as HDAC inibitors) in various experimental studies. This review provides insights into the critical pathways involved in regulating different classes of HDACs. Further, the intricate signaling networks between HDACs and the stress mediators in diabetes are also explored. We exhaustively sum up the inferences from various investigations on the efficiency of HDAC inhibitors in managing diabetes and its associated complications.

Adipose tissue is instrumental in maintaining metabolic homeostasis by regulating energy storage in the form of triglycerides. In the case of over-nutrition, adipocytes favorably regulate lipogenesis over lipolysis and accumulate excess triglycerides, resulting in increased adipose tissue mass. An abnormal increase in hypertrophic adipocytes is associated with chronic complications such as insulin resistance, obesity, diabetes, atherosclerosis and nonalcoholic fatty liver disease. Experimental studies indicate the occurrence of oxidative stress in the pathogenesis of obesity. A common underlying link between increasing adipose tissue mass and oxidative stress is the Nuclear Factor Erythroid 2-related factor 2 (Nrf2), Keap1-Nrf2-ARE signaling, which plays an indispensable role in metabolic homeostasis by regulating oxidative and inflammatory responses. Additionally, Nrf2 also activates CCAAT/enhancer-binding protein α, (C/EBP-α), C/EBP-β and peroxisome proliferator-activated receptor γ (PPARγ) the crucial pro-adipogenic factors that promote de novo adipogenesis. Hence, at the forefront of research is the quest for prospecting novel compounds to modulate Nrf2 activity in the context of adipogenesis and obesity. This review summarizes the molecular mechanism behind the activation of the Keap1-Nrf2-ARE signaling network and the role of Nrf2 activators in adipocyte pathophysiology.

Endothelial cell (EC) dysfunction is the underlying cause for the development of several pathologies, and the interdependency between the pancreatic β-cells and ECs has been established in the pathophysiology of diabetes. ECs release several factors that govern the expression of genes involved in the proliferation, physiology, and survival of the β-cells. Of the known factors that collapse this intricately balanced system, endothelial dysfunction is the crucial condition that manifests as the causative factor for micro and macrovascular diseases. Our earlier studies demonstrated that activation of nuclear factor erythroid-related factor (Nrf2) renders protection to the ECs experiencing ER stress. In this study, using a co-culture system, the crosstalk between pancreatic cells under ER stress and ECs and the effect of a novel Nrf2 activator Rosolic Acid (RA), on the crosstalk was investigated. ECs pre-treated with different concentrations RA and co-cultured with thapsigargin-induced ER stressed pancreatic β-cells showed increased levels of Nrf2 and its downstream targets such as heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1), and reduction of ER stress evinced by the decreased levels of glucose-regulated protein (GRP) 78 and C/ERB homologous protein (CHOP). The sensitization of ECs using RA, offered protection to pancreatic cells against ER stress as displayed by increased intracellular insulin and upregulated expression of cell survival and proliferative genes BCl2 and PDX-1. In addition, RA treatment resulted in elevated levels of various angiogenic factors, while inflammatory (TNF-α and IL-1β) and apoptotic markers (CXCL10 and CCL2) decreased. RA treatment normalized the levels of 115 proteins of the 277, which were differentially regulated as revealed by proteomic studies of ER stressed pancreatic β-cells in co-culture conditions. These findings clearly indicate the role of small molecule activators of Nrf2 not only in restoring the functioning of pancreatic cells but also in increasing the cell mass. Further, the study impinges on the strategies that can be developed to balance the pancreatic microenvironment, leading to the restoration of β-cell mass and their normophysiology in diabetic patients.

Studies have identified dysregulated long non-coding RNA (lncRNA) in several diseases at transcriptional, translational, and post-translational levels. Although our mechanistic knowledge on the regulation of lncRNAs is still limited, one of the mechanisms of action attributed is binding and regulating transcription factors, thus controlling gene expression and protein function. One such transcription factor is nuclear factor erythroid 2-related factor 2 (Nrf2), which plays a critical biological role in maintaining cellular homeostasis at multiple levels in physiological and pathophysiological conditions. The levels of Nrf2 were found to be down-regulated in many chronic diseases, signifying that Nrf2 can be a key therapeutic target. Few lncRNAs like lncRNA ROR, ENSMUST00000125413, lncRNA ODRUL, Nrf2-lncRNA have been associated with the Nrf2 signaling pathway in response to various stimuli, including stress. This review discusses the regulation of Nrf2 in different responses and the potential role of specific lncRNA in modulating its transcriptional activities. This review further helps to enhance our knowledge on the regulatory role of the critical antioxidant transcription factor, Nrf2.

Cellular stress and inflammation, establishing as disease pathology, have reached great heights in the last few decades. Stress conditions such as hyperglycemia, hyperlipidemia and lipoproteins are known to disturb proteostasis resulting in the accumulation of unfolded or misfolded proteins, alteration in calcium homeostasis culminating in unfolded protein response. Protein disulfide isomerase and endoplasmic reticulum oxidase-1 are the key players in protein folding. The protein folding process assisted by endoplasmic reticulum oxidase-1 results in the production of reactive oxygen species in the lumen of the endoplasmic reticulum. Production of reactive oxygen species beyond the quenching capacity of the antioxidant systems perturbs ER homeostasis. Endoplasmic reticulum stress also induces the production of cytokines leading to inflammatory responses. This has been proven to be the major causative factor for various pathophysiological states compared to other cellular triggers in diseases, which further manifests to increased oxidative stress, mitochondrial dysfunction, and altered inflammatory responses, deleterious to cellular physiology and homeostasis. Numerous studies have drawn correlations between the progression of several diseases in association with endoplasmic reticulum stress, redox protein folding, oxidative stress and inflammatory responses. This review aims to provide an insight into the role of protein disulfide isomerase and endoplasmic reticulum oxidase-1 in endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, and inflammatory responses, which exacerbate the progression of various diseases.

Background The pivotal role of Nuclear factor erythroid-2-related factor 2 (NRF2) in redox homeostasis and wound healing has been well documented. However, the genetic mechanisms that regulate NRF2 in type 2 diabetes and diabetic foot ulcers remain unexplored. The present study investigated the association of single nucleotide polymorphism rs182428269 (–127 C/T) in subjects with type 2 diabetes and diabetic foot ulcers. Methods This cross-sectional study comprised 400 participants that included group I: normal glucose tolerant subjects (NGT, n = 150), group II: type 2 diabetes mellitus subjects (T2DM, n = 150) and group III: infected diabetic foot ulcer subjects (DFU, n = 100). The non-synonymous SNP rs182428269 was selected based on in silico analysis and genotyped by PCR-restriction fragment length polymorphism (RFLP) followed by bidirectional Sanger sequencing. In addition, the gene expression of NRF2 in patients with polymorphism was analyzed by qPCR to evaluate the functional impact of the SNP. Results NRF2 expression was significantly decreased among the T2DM and DFU subjects when compared to the NGT subjects. Of particular interest, the homozygous mutant (TT) genotype of rs182428269 polymorphism was significantly associated with an increased risk for the development of T2DM (OR = 1.95 (1.02–3.72), p = 0.04) and DFU (OR = 5.66 (2.98–10.76), p = 0.0001). Furthermore, a progressive decline in NRF2 expression was observed among the T2DM and DFU subjects with “TT” genotype compared to the “CC” and “CT” genotypes. Conclusion NRF2 polymorphism rs182428269 is associated with the pathogenesis of T2DM and DFU.

Endoplasmic Reticulum (ER) stress has been established to play a key pathophysiological role in developing metabolic diseases such as Diabetes Mellitus (DM). The complications of DM have been closely associated with deregulation of the unfolded protein response (UPR) signaling pathways, which are critically responsible for restoring homeostasis following ER stress. Chronic ER stress in the background of persistent hyperglycemia, as observed in DM, overwhelms the UPR signaling and commits the cells to apoptosis. The factors such as hyperglycemia, increased reactive oxygen species (ROS), disrupted calcium homeostasis, and overt inflammation serve as major UPR signal transduction pathways, including PKR like ER kinase (PERK), Activating transcription factor 6α/β (ATF6), and Inositol requiring enzyme1α/β (IRE1). The constantly developing understanding of these ER stress mediators has also unraveled their potential as therapeutic targets of small molecules termed ER stress inhibitors. A wide range of both naturally occurring and synthetic compounds have been screened and studied for their properties to inhibit ER stress in various experimental models. This review article elucidates the critical signaling pathways associated with response to ER stress. We shed light on the crosstalk between ER stress mediators with oxidative and inflammatory stress mediators in the background of DM. We extensively summarize the pieces of evidence sourced from preclinical and clinical research about the role of ER stress inhibitors and their pharmacological mechanism of action in alleviating ER stress in diabetes.

Diabetic Nephropathy (DN) is an important cause of morbidity and death amongst diabetes. Persistent micro and macroalbuminuria are well known predictors of DN leading to progressive end-stage renal disease. However, albuminuria has several limitations. Increasing evidences show that YKL-40 is highly expressed in variety of inflammatory diseases and also recognized as a non-invasive prognostic biomarker for inflammation. In the present study, we measured plasma YKL-40 levels in different stages of albuminuria and assessed its diagnostic accuracy as a biomarker for DN and correlated with different families of circulatory cytokines. A total of 306 subjects were recruited and divided into three groups [Group-I, control (n = 83), Group-II, Normoalbuminuria (n = 81), Group-III, DN (n = 142)]. Group-III is further subdivided into: Group-IIIa, microalbuminuria (n = 73), Group-IIIb, macroalbuminuria (n = 69). The median levels of YKL-40 (p = 0.001) showed a marked stepwise increase from normo to macroalbuminuria and positively correlated with eGFR. The AUCROC for YKL-40 was found to be high [0.95; (95% CI: 0.88–1.0)], when compared to other acute phase markers. Plasma YKL-40 showed a positive correlation with LIGHT/TNFSF14, sIL-6Ra, gp130/sIL-6Rβ, IFN-β, IL-8, TNFSF14, sCD-30 and eGFR meanwhile a negative correlation with TWEAK/TNFSF12, IL-7 like cytokine and IFN-λ2. Plasma YKL-40 could be a potential biomarker for early diagnosis of incipient DN among South Indian population.

Toxicoproteomic analysis of steel industry ambient particulate matter (PM) that contain high concentrations of PAHs and metals was done by treating human lung cancer cell-line, A549 and the cell lysates were analysed using quantitative label-free nano LC-MS/MS. A total of 18,562 peptides representing 1576 proteins were identified and quantified, with 196 proteins had significantly altered expression in the treated cells. Enrichment analyses revealed that proteins associated to redox homeostsis, metabolism, and cellular energy generation were inhibited while, proteins related to DNA damage and repair and other stresses were over expressed. Altered activities of several tumor associated proteins were observed. Protein-protein interaction network and biological pathway analysis of these differentially expressed proteins were carried out to obtain a systems level view of proteome changes. Together it could be inferred that PM exposure induced oxidative stress which could have lead into DNA damage and tumor related changes. However, lowering of cellular metabolism, and energy production could reduce its ability to overcome these stress. This kind of disequilibrium between the DNA damage and ability of the cells to repair the DNA damage may lead into genomic instability that is capable of acting as the driving force during PM induced carcinogenesis.

Background Circulatory Fetuin-A has been well reported to elevate the risk for Diabetic Nephropathy (DN) and is associated with many vascular complications. Compelling reports have well documented that the circulatory levels of Fetuin-A directly have an impact on its AHSG (α2- Heremans- Schmid Glycoprotein) gene single nucleotide polymorphisms (SNP). Thus, in this study among the South Indian T2DM population, we aim to explore the association of AHSG Thr256Ser (rs4918) SNP in subjects with DN and correlate with the circulatory levels of Fetuin-A at various stages of DN patients. Methods A total of 975 subjects were recruited, such as Group-I, consisting of Controls (n = 300), Group-II, with normoalbuminuria (n = 300), Group-IIIa, with incipient microalbuminuria (n = 195), Group-IIIb, with persistent macroalbuminuria (n = 180)] and were subjected for genotyping using PCR-restriction fragment length polymorphism (RFLP). Circulatory Fetuin-A was measured using sandwich enzyme-linked immunosorbent assay (ELISA). Results The ‘G’ allele of AHSG exon-7 (C/G) SNP is significantly concomitant and conferred significant risk for normoalbuminuria subjects. In the DN subjects, the ‘G' allele showed the risk for persistent macroalbuminuria. A noticeable stepwise decrease was evidenced in the circulatory Fetuin-A among persistent macroalbuminuria over incipient microalbuminuria from normoalbuminuria. Further, the circulatory Fetuin-A was lowered in DN subjects with mutant GG genotype than the wild CC. Conclusion AHSG Thr256Ser (rs4918) SNP is associated with renal complications among South Indian T2DM subjects.

Long non-coding RNAs (lncRNAs) are the novel class of transcripts involved in transcriptional, post-transcriptional, translational, and post-translational regulation of physiology and the pathology of diseases. Studies have evidenced that the impairment of endothelium is a critical event in the pathogenesis of atherosclerosis and its complications. Endothelial dysfunction is characterized by an imbalance in vasodilation and vasoconstriction, oxidative stress, proinflammatory factors, and nitric oxide bioavailability. Disruption of the endothelial barrier permeability, the first step in developing atherosclerotic lesions is a consequence of endothelial dysfunction. Though several factors interfere with the normal functioning of the endothelium, intrinsic epigenetic mechanisms governing endothelial function are regulated by lncRNAs and perturbations contribute to the pathogenesis of the disease. This review comprehensively addresses the biogenesis of lncRNA and molecular mechanisms underlying and regulation in endothelial function. An insight correlating lncRNAs and endothelial dysfunction-associated diseases can positively impact the development of novel biomarkers and therapeutic targets in endothelial dysfunction-associated diseases and treatment strategies.

Background Nuclear factor erythroid 2-related factor (Nrf2), a stress-activated transcription factor, has been documented to induce a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway a key pharmacological target for the treatment of liver diseases. Purpose The present review highlights the role of phytochemical compounds in activating Nrf2 and mitigate toxicant-induced stress on liver injury. Methods A comprehensive search of published articles was carried out to focus on original publications related to Nrf2 activators against liver disease using various literature databases, including the scientific Databases of Science Direct, Web of Science, Pubmed, Google, EMBASE, and Scientific Information (SID). Results Nrf2 activators exhibited promising effects in resisting a variety of liver diseases induced by different toxicants in preclinical experiments and in vitro studies by regulating cell proliferation and apoptosis as well as an antioxidant defense mechanism. We found that the phytochemical compounds, such as curcumin, naringenin, sulforaphane, diallyl disulfide, mangiferin, oleanolic acid, umbelliferone, daphnetin, quercetin, isorhamnetin-3-O-galactoside, hesperidin, diammonium glycyrrhizinate, corilagin, shikonin, farrerol, and chenpi, had the potential to improve the Nrf2-ARE signaling thereby combat hepatotoxicity. Conclusion Nrf2 activators may offer a novel potential strategy for the prevention and treatment of liver diseases. More extensive studies are essential to identify the underlying mechanisms and establish future therapeutic potentials of these signaling modulators. Further clinical trials are warranted to determine the safety and effectiveness of Nrf2 activators for hepatopathy.

ER stress is provoked by the accumulation of unfolded and misfolded proteins in the ER lumen leading to perturbations in ER homeostasis. ER stress activates a signaling cascade called the Unfolded Protein Response (UPR) which triggers a set of transcriptional and translational events that restore ER homeostasis, promoting cell survival and adaptation. If this adaptive response fails, a terminal UPR program commits such cells to apoptosis. Existing preclinical and clinical evidence testify that prolonged ER stress escalates the risk of several metabolic disorders including diabetes, obesity and dyslipidemia. There have been considerable efforts to develop small molecules that are capable of ameliorating ER stress. Few naturally occurring and synthetic molecules have already been demonstrated for their efficacy in abrogating ER stress in both in vitro and in vivo models of metabolic disorders. This review provides a broad overview of the molecular mechanisms of inhibition of ER stress and its association with various metabolic diseases.

Oxidative stress is an important factor contributing to the pathogenesis of diabetes and its complications. In our earlier study, we demonstrated the antidiabetic efficacy of morin by regulating key enzymes of carbohydrate metabolism in diabetic rats. The present study was designed to assess the antigenotoxic potential of morin in pancreatic β-cells, using the COMET assay. To explore its potential mechanisms of action, three genotoxic agents, H2O2 which induces DNA damage by the generation of reactive oxygen species, streptozotocin (STZ) by RNS and Methyl methanesulfonate (MMS) by DNA alkylation was used. We found that STZ and H2O2- induced genotoxicity was dose dependently reduced by morin as assessed by DNA tail length, tail moment, DNA content and olive moment. Since the protective property was found to be specific against oxidative DNA damage, we explored the molecular mechanism underlying morin-induced Nuclear factor erythroid 2-related factor 2 (Nrf2) activation in pancreatic β-cells as assessed by ARE-driven downstream target genes with Luciferase reporter assay. In addition, morin inhibited intracellular free radical generation as assessed by using DCFDA and increased the intra cellular antioxidants viz, superoxide dismutase and catalase in INS-1E cells. In addition, morin attenuated glucose-stimulated insulin secretion following exposure to oxidative stress by STZ (P

The failure in timely healing of wounds is a central feature in chronic wounds that leads to physiological, psychological and economic burdens. Macrophages have been demonstrated to have various functions in wounds including host defense, the promotion and resolution of inflammation, the removal of apoptotic cells and tissue restoration following injury. Accumulated evidence suggests that macrophage dysfunction is a component of the pathogenesis of non-healing wounds. While the overall signaling cascades have been well understood, their complex interplay and a detailed characterization of events that are disrupted in chronic wounds have still not emerged satisfactorily. The existing literature was reviewed to summarize the regulation of macrophage polarization in wound closure and dysregulation in non-healing wounds. Further, the review also underscored the role of Nrf2 in promoting macrophage-mediated regulation in wound responses and in particular, macrophage involvement in iron homeostasis that is impaired in chronic wounds such as in diabetes. The mechanisms involved in the reprogramming of macrophage subtypes in chronic wounds are still emerging. Furthermore, treating non-healing wounds has increasingly been shifting focus from generic treatments to the development of targeted therapies. Increasing evidence suggests the need for modeling wound tissue in vitro which may very well serve a critical aspect to characterize the relevant factors that sustain chronic wounds in vivo such as the constant iron overload at the wound site from recurrent infection and bleeding. The development of targeted therapies and also developing a reliable means to monitor assisted healing of chronic wounds are two major goals to be pursued. In addition, identifying molecular targets that can regulate macrophages to aid tissue restoration in chronic wounds would serve the crucial step in realizing both aforementioned goals.