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PurposeMetabolic syndrome (MetS) is associated with several degenerative diseases, including retinal degeneration. Previously, we reported on progressive retinal degeneration in a spontaneous obese rat (WNIN/Ob) model. In this study, we investigated the additional effect of impaired glucose tolerance (IGT), an essential component of MetS, on retinal degeneration using the WNIN/GR-Ob rat model.MethodsThe retinal morphology and ultrastructure of WNIN/GR-Ob and age-matched littermate lean rats were studied by microscopy and immunohistochemistry. The retinal transcriptome of WNIN/GR-Ob was compared with the respective lean controls and with the WNIN/Ob model using microarray analysis. Expression of selected retinal marker genes was studied via real-time PCR.ResultsProgressive loss of photoreceptor cells was observed in WNIN/GR-Ob rats with an onset as early as 3 months. Similarly, thinning of the inner nuclear layer was observed from 6 months in these rats. Immunohistochemical analysis showed decreased levels of rhodopsin and postsynaptic density protein-95 (PSD-95) proteins and increased levels of glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and calretinin in WNIN/GR-Ob rats compared with the age-matched lean controls, further supporting cellular stress/damage and retinal degeneration. The retinal transcriptome analysis indicated altered expression profiles in both the WNIN/GR-Ob and WNIN/Ob rat models compared to their respective lean controls; these pathways are associated with activation of pathways like cellular oxidative stress response, inflammation, apoptosis, and phototransduction, although the changes were more prominent in WNIN/GR-Ob than in WNIN/Ob animals.ConclusionsWNIN/GR-Ob rats with added glucose intolerance developed retinal degeneration similar to the parent line WNIN/Ob. The severity of retinal degeneration was greater in WNIN/GR-Ob rats compared to WNIN/Ob, suggesting a possible role for IGT in this model. Hence, the WNIN/GR-Ob model could be a valuable tool for investigating the impact of MetS on retinal degeneration pathology.

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized. Supplementary Material Supplementary Material File [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases. [ABSTRACT FROM AUTHOR]

Deficiencies of vitamin B12 (B12) and folate (FA) are of particular interest due to their pleiotropic role in 1-carbon metabolism. In addition to adverse birth outcomes, deficiencies of B12 and FA, or an imbalance in FA/B12 status, are linked to metabolic disorders. Indian diets that are predominantly plant food-based could be deficient in these vitamins, but there are no national estimates of the prevalence of B12 and FA deficiency in Indian children and adolescents, nor their associations with age, sex and growth indicators. The recent Comprehensive National Nutrition Survey (CNNS-2016-18) provided estimates of the prevalence of B12 and FA deficiency at the national and state levels among preschool (1–4 years: 9976 and 11,004 children, respectively), school-age children (5–9 years: 12,156 and 14,125) and adolescents (10–19 years: 11,748 and 13,621). Serum B12 and erythrocyte FA were measured by the direct chemiluminescence method and their deficiency was defined using WHO cut-offs. The prevalence of B12 and FA deficiency was high among adolescents (31.0%, CI: 28.7–33.5 and 35.6%, CI: 33.1–8.2) compared to school-age (17.3%, CI: 15.4–19.3 and 27.6%, CI: 25.5–29.9) and preschool children (13.8%, CI: 11.7–16.2 and 22.8%, CI: 20.5–25.2, respectively). The prevalence of both B12 and FA deficiency was significantly higher by 8% and 5%, respectively, in adolescent boys compared to girls. There was no association between anthropometric undernutrition and B12 and FA deficiency. There was wide regional variation in the prevalence of B12 and FA deficiency, but no rural–urban differences were observed across all age groups. The national prevalence of B12 deficiency among preschool or school-age children was <20% (the cut-off that indicates a public health problem). However, FA deficiency in these age groups and both FA and B12 deficiencies in adolescents were >20%, warranting further investigation. [ABSTRACT FROM AUTHOR]

β-Glucogallin 1 (BGG), a major component isolated from the Indian gooseberry ( Emblica officinalis) medicinal plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). Structurally, BGG is a glucosyl-1-ester, wherein gallic acid is linked to the β- d-glucose ring through an ester functionality. Susceptibility of the easily hydrolysable ester functional group in aqueous solution has been a cause of concern. Isosteric replacement of glucosyl- O- with - NH- has offered the more stable and potent analogue 2; however, the C-analogue 3, wherein a -CH2- unit replaces the glucosyl- O, remains unexplored. Synthesis of C-analogues 3 and 4 and their aldose reductase inhibition (ARI) constitutes the work presented herein. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic syndrome (MetS) is associated with several degenerative diseases, including retinal degeneration. Previously, we reported on progressive retinal degeneration in a spontaneous obese rat (WNIN/Ob) model. In this study, we investigated the additional effect of impaired glucose tolerance (IGT), an essential component of MetS, on retinal degeneration using the WNIN/GR-Ob rat model., Methods: The retinal morphology and ultrastructure of WNIN/GR-Ob and age-matched littermate lean rats were studied by microscopy and immunohistochemistry. The retinal transcriptome of WNIN/GR-Ob was compared with the respective lean controls and with the WNIN/Ob model using microarray analysis. Expression of selected retinal marker genes was studied via real-time PCR., Results: Progressive loss of photoreceptor cells was observed in WNIN/GR-Ob rats with an onset as early as 3 months. Similarly, thinning of the inner nuclear layer was observed from 6 months in these rats. Immunohistochemical analysis showed decreased levels of rhodopsin and postsynaptic density protein-95 (PSD-95) proteins and increased levels of glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and calretinin in WNIN/GR-Ob rats compared with the age-matched lean controls, further supporting cellular stress/damage and retinal degeneration. The retinal transcriptome analysis indicated altered expression profiles in both the WNIN/GR-Ob and WNIN/Ob rat models compared to their respective lean controls; these pathways are associated with activation of pathways like cellular oxidative stress response, inflammation, apoptosis, and phototransduction, although the changes were more prominent in WNIN/GR-Ob than in WNIN/Ob animals., Conclusions: WNIN/GR-Ob rats with added glucose intolerance developed retinal degeneration similar to the parent line WNIN/Ob. The severity of retinal degeneration was greater in WNIN/GR-Ob rats compared to WNIN/Ob, suggesting a possible role for IGT in this model. Hence, the WNIN/GR-Ob model could be a valuable tool for investigating the impact of MetS on retinal degeneration pathology.

The rapid increase in global diabetes burden with its associated morbidity and mortality is a major health concern for humans. Prediabetes is a condition which predispose a person not only to diabetes but also to the associated complications including morbidity even in the absence of an apparant hyperglycemia. However, appropriate dietary intervention may not only prevent but also improve one’s condition as diet is the major contributor to such metabolic disorders. Here, we investigated the effect of dietary ginger (Zingiber officinale Roscoe) on the markers of insulin resistance and pathophysiology in a diet-induced prediabetic rat model. Male Sprague-Dawley (SD) rats were fed the following diets: control (5% groundnut oil + 65 % corn starch), high fat high fructose (HFHF; 25% beef tallow + 35 % fructose) and HFHF with 3 % ginger (HFHFG) for eight months. Plasma markers of insulin resistance, lipid profile, oral glucose tolerance (OGTT; 2nd and 5th month), intraperitoneal insulin tolerance (ITT), plasma total antioxidant capacity (TAC), liver histology and pancreatic immunohistochemistry (IHC) were examined. The impaired OGTT, ITT and insulin sensitivity indices with observed hyperinsulinemia and hypertriglyceridemia suggest that HFHF feeding resulted in prediabetes in rats. HFHF feeding also decreased insulin secretion in the pancreas, increased lipid accumulation in liver and total oxidants in plasma. The effects of HFHF feeding on glucose regulation, pathophysiology of pancreas and liver; total oxidative stress were improved by ginger feeding. The present study demonstrated thatlong-term HFHF feeding induces prediabetes in experimental rats while dietary ginger neutralizes the HFHF induced impairment in glucose regulation, dyslipidemia, and oxidative stress.

Aberrant activation of oncogenic signaling pathways plays a central role in tumor development and progression. The aim of this present study was to investigate the chemopreventive effects of the neem limonoid gedunin in the hamster model of oral cancer based on its ability to modulate aldose reductase (AR), phosphatidyl inositol-3-kinase (PI3K)/Akt, and nuclear factor kappa B (NF-κB) pathways to block angiogenesis. Administration of gedunin suppressed the development of HBP carcinomas by inhibiting PI3K/Akt and NF-κB pathways through the inactivation of Akt and inhibitory kappa B kinase (IKK), respectively. Immunoblot and molecular docking interactions revealed that inhibition of these signaling pathways may be mediated via inactivation of AR by gedunin. Gedunin blocked angiogenesis by downregulating the expression of miR-21 and the pro-angiogenic factors vascular endothelial growth factor and hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, the results of the present study provide compelling evidence that gedunin prevents progression of hamster buccal pouch (HBP) carcinomas via inhibition of the kinases Akt, IKK, and AR, and the oncogenic transcription factors NF-κB and HIF-1α to block angiogenesis.

Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications.

Cataract, loss of eye lens transparency, is the leading cause of blindness worldwide. alpha-Crystallin, initially known as one of the major structural proteins of the eye lens, is composed of two homologous subunits alphaA- and alphaB-crystallins. It is convincingly established now that alpha-crystallin functions like a chaperone and plays a decisive role in the maintenance of eye lens transparency. The functional ability of alpha-crystallin subunits is to act in cooperation as molecular chaperones to prevent the cellular aggregation and/or inactivation of client proteins under variety of stress conditions. However, chaperone-like activity of alpha-crystallin could be deteriorated or lost during aging or under certain clinical conditions because of various genetic and environmental factors. This review will focus specifically on relevance of alpha-crystallin chaperone function to lens transparency. In particular, we reviewed the studies that demonstrate the modulation of alpha-crystallin chaperone-like activity and discussed the possibility of chaperone-like activity of alpha-crystallin as a potential target to prevent or delay the cataractogenesis.

Background: There is increasing evidence that complications related to diabetes are associated with increased oxidative stress. Curcumin, an active principle of turmeric, has several biological properties, including antioxidant activity. The protective effect of curcumin and turmeric on streptozotocin (STZ)-induced oxidative stress in various tissues of rats was studied., Material/methods: Three-month-old Wistar-NIN rats were made diabetic by injecting STZ (35 mg/kg body weight) intraperitoneally and fed either only the AIN-93 diet or the AIN-93 diet containing 0.002% or 0.01% curcumin or 0.5% turmeric for a period of eight weeks. After eight weeks the levels of oxidative stress parameters and activity of antioxidant enzymes were determined in various tissues., Results: STZ-induced hyperglycemia resulted in increased lipid peroxidation and protein carbonyls in red blood cells and other tissues and altered antioxidant enzyme activities. Interestingly, feeding curcumin and turmeric to the diabetic rats controlled oxidative stress by inhibiting the increase in TBARS and protein carbonyls and reversing altered antioxidant enzyme activities without altering the hyperglycemic state in most of the tissues., Conclusions: Turmeric and curcumin appear to be beneficial in preventing diabetes-induced oxidative stress in rats despite unaltered hyperglycemic status.