Pancreatic Β-cell Damage Research Articles

β-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory β-Cell Destruction.

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1tg/+ mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1tg/+ mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1tg/+ mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1tg/+ islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.

AKTIVITAS GLUTATION PEROKSIDASE DAN KADAR GULA DARAH TIKUS DIABETES YANG DIBERI EKSTRAK DAUN KAPULAGA (<em>Amomum cardamomum</em>)

Oxidative stress in a patient with diabetes known to decrease the activity of GSH-PX and increase the level of blood glucose. Glibenclamide is commonly used by patients with diabetes to lower the blood glucose. However, the long-term use of glibenclamide may induce the damage of pancreatic β-cells. The extract containing flavonoids and vitamin C of cardamoms leaf can reduce free radicals. The effect of cardamoms leaf extract on the enzymes activity and the level of blood glucose in diabetic rats is yet unknown. The aim of this study was to examine the effect of cardamoms leaf extract administration in the GSH-PX activities and the level of blood glucose of diabetic rats. The method used in this study was experimental with completely randomized design (CRD). There were three groups with five replicates for each. The first group, diabetic rats as control group were given no treatment; the second group, diabetic rats were given cardamoms leaf extract at the dose of 100 mg/kg of body weight; the third group, the diabetic rat were given glibenclamide at the dose of 2 mg/kg of body weight. Blood samples were taken three times at 0, 7, and 14 days after each treatment. Parameters measured were GSH-PX activity and the level of blood glucose. The data were analyzed using ANOVA F-test with a confidence level of 95%. The result of this study showed that the cardamoms leaf extract treatment decreased the activity of GSH-PX activity and decreased the level of blood glucose at a significant level (p < 0.05) from 278.8 to 101.4 mg/dl.

Nrf2 Protects Pancreatic β-Cells From Oxidative and Nitrosative Stress in Diabetic Model Mice

Transcription factor Nrf2 (NF-E2-related factor 2) regulates wide-ranging cytoprotective genes in response to environmental stress. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for Cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. The Keap1-Nrf2 system plays important roles in the oxidative stress response and metabolism. However, the roles Nrf2 plays in prevention of pancreatic β-cell damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic β-cells, we used four genetically engineered mouse models: 1) β-cell-specific Keap1-conditional knockout mice, 2) β-cell-specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) β-cell-specific Nrf2-conditional knockout mice. We found that Nrf2 induction suppressed the oxidative DNA-adduct formation in pancreatic islets of iNOS-Tg mice and strongly restored insulin secretion from pancreatic β-cells in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic β-cell lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic β-cell apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and β-cell-specific Nrf2-conditional knockout mice strongly aggravated pancreatic β-cell damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic β-cells and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic β-cells.

Hyperbaric Oxygen Treatment in a Diabetic Rat Model Is Associated with a Decrease in Blood Glucose, Regression of Organ Damage and Improvement in Wound Healing

Diabetes leads to widespread complications including pancreatic β-cell damage, nephropathy and impaired wound healing. Hyperbaric oxygen therapy (HBOT) has been shown to improve wound healing through induction of stem cell recruitment and the potential to inhibit progression of diabetic complications. We aimed to determine the efficacy of HBOT in wound healing and organ preservation in a diabetic rat model. Diabetes was induced in male Wistar rats (n = 10/group) using streptozotocin (20 mg/kg sc) daily for 3 days. A wound was inflicted on the skin over the back and the rats were given HBOT (2.3 ATA for 1 h/day) for 1, 3, 5, 7 or 10 days or were not treated. Blood glucose, pancreatic β-cell damage, diabetic nephropathy and wound healing progression were assessed. Diabetic rats not treated with HBOT had significantly higher blood glucose levels compared to controls (26.7 ± 3.3 mmol/L vs. 5.8 ± 0.4 mmol/L; P ≤ 0.05). This was associated with significant increase in the percentage of β-cell damage (72% ± 9% vs. 10% ± 2%; P ≤ 0.05) and diabetic nephropathy. HBOT for 3 days and longer in diabetic rats reduced hyperglycemia to control levels. Pancreatic β-cell damage was negligible in rats treated with HBOT for 5 days and longer while diabetic nephropathy was diminished in animals treated for 10 days. Similarly HBOT induced wound healing and accelerated epithelial closure from 5 days of HBOT. In summary, our findings show the efficacy of HBOT in this diabetic rat model. There was significant reduction of hyperglycemia and inhibition of diabetic complications in the form of preservation of pancreatic and kidney structure and accelerated wound healing.

Extracts of Hunteria umbellata reverses the effect of streptozotocin-induced pancreatic islet-cell destruction

The use of extracts of plant parts in the treatment and/or management of diabetes mellitus has formed the basis of health care in most African countries. The aim of this study was to investigate the possible effect of oral administration of extracts Hunteria umbellata (HU) leaves and seeds on streptozotocin- induced pancreatic β-cell damage. Twenty four (24) adult wistar rats were selected into two control group (negative control group A and positive control group B) and two treatment groups (C & D) each containing six animals each (n= 6 per group). Rats in the positive control group (B) were giving intraperitoneal injection of with 50 mg/kg body weight of Streptozotocin (STZ) prepared with 0.05M Citrate buffer solution while the negative control group A rats were injected with a corresponding volume of Citrate buffer without STZ. Rats in the treatment groups were treated with 250 mg/kg body weight aqueous extract of seeds of Hunteria umbellata (group C) and 250 mg/kg body weight aqueous extract of leaves of Hunteria umbellata (group D) respectively. Blood samples were taken by repeated needle puncture of their tail tip vein every 72 hours at the end of a 12 hrs fasting. Fasting blood glucose was determined using a fine test glucometer and compatible glucose test strips. Rats were sacrificed by cervical dislocation on the 15 th day and the pancreas was accessed and dissected out through a midline incision of the anterior abdominal wall of the rats. The pancreas was fixed in 10% buffered formal saline for routine histological examination. 5ml blood samples were collected in heparin coated tubes for serum anti-oxidant estimation. Results obtained showed that HU seeds and leaves extracts significantly (P < 0.05) increased Superoxide dismutase (SOD) and Catalase (CAT) activities and decrease in the activity of Thiobarbituric acid reactive species (TBARS) when compared streptozotocin injected rats. Histological sections showed marked distortion, vacoulation of the central part of the Islet. Treatment with Hunteria umbellata seed and leaf extracts reversed the cytoarchitectural distortion of pancreatic Islet cells caused by Streptozotocin. This suggests that extracts of HU seeds and leaves posses antidiabetic potential.

Mangiferin fromSalacia chinensisPrevents Oxidative Stress and Protects Pancreaticβ-Cells in Streptozotocin-Induced Diabetic Rats

Oxidative stress in diabetic tissues is a consequence of free radical accumulation with concurrently impaired natural antioxidants status and results in oxidative tissue damage. The present study investigated the protective effects of mangiferin against pancreatic β-cell damage and on the antioxidant defense systems in streptozotocin (STZ)-induced diabetic rats. Diabetes was experimentally induced by a single intraperitoneal injection of STZ. Oxidative stress biomarkers such as tissue malondialdehyde, hydroperoxides, reduced glutathione (GSH) content, and nonenzymatic antioxidants were measured. Biochemical observations were further substantiated with histological examination and ultrastructural studies in the pancreas of diabetic, glibenclamide and mangiferin-treated diabetic rats (dosage of 40 mg/kg body weight daily for 30 days). Oral administration of mangiferin and glibenclamide to diabetic rats significantly decreased the level of blood glucose and increased levels of insulin. Additionally, mangiferin treatment significantly modulated the pancreatic nonenzymatic antioxidants status (vitamin C, vitamin E, ceruloplasmin, and reduced GSH content) and other oxidative stress biomarkers. The histoarchitecture of diabetic rats showed degenerated pancreas with lower β-cell counts, but mangiferin treatment effectively regenerated insulin secreting islet cells. The electron microscopic study revealed damaged nuclear envelope and mitochondria and fewer secretory granules in pancreas of diabetic rats; however, mangiferin treatment nearly normalized pancreatic architecture. The present findings suggest that mangiferin treatment exerts a therapeutic protective nature in diabetes by decreasing oxidative stress and protecting against pancreatic β-cell damage, which may be attributable to its antioxidative properties.

Ku70 Functions in Addition to Nonhomologous End Joining in Pancreatic β-Cells

The genesis of β-cells predominantly occurs through self-replication; therefore, understanding the regulation of cell proliferation is essential. We previously showed that the lack of nonhomologous end joining (NHEJ) DNA repair factor ligase IV leads to an accumulation of DNA damage that permanently halts β-cell proliferation and dramatically decreases insulin production, causing overt diabetes in a hypomorphic p53R172P background. In the present study, to further delineate the function of NHEJ, we analyzed mice deficient for another key NHEJ factor, Ku70, to discover the effect of cellular responses to DNA damage in pancreatic β-cells on cellular proliferation and glucose homeostasis. Analysis of Ku70−/− pancreatic β-cells revealed an accumulation of DNA damage and activation of p53-dependent cellular senescence similar to the results found in our earlier ligase IV deficiency study. To our surprise, Ku70−/− mice had significantly increased β-cell proliferation and islet expansion, heightened insulin levels, and decreased glycemia. This augmented β-cell proliferation was accompanied by an increased β-catenin level, which we propose to be responsible for this phenotype. This study highlights Ku70 as an important player not only in maintaining genomic stability through NHEJ-dependent functions, but also in regulating pancreatic β-cell proliferation, a novel NHEJ-independent function.

Extracts of sweet potato leaves protect β cells from oxidative stress‐mediated injury

Pancreatic β‐cells are very sensitive to oxidative stress due to relatively low in the expression of antioxidant enzymes, which might play an important role in β‐cell death in diabetes. In the present study, we investigated whether the extracts of sweet potato leaves (SPL) have protective effects against hydrogen peroxide‐induced damage in INS‐1 pancreatic β‐cells. Total phenolic compounds, scavenging activity against DPPH radicals, reducing power method, and ferric chelating ability were evaluated for the antioxidant ability of SPL samples. INS‐1 cells were treated with SPL and/or H2O2 for various concentrations from 2mg/ml to 0.5mg/ml for 24 hours. The reduced cell proliferation after H2O2 toxicity is significantly recovered in the presence of SPL as evaluated by MTT assay (p&lt;0.05). The H2O2‐induced overproduction of intracellular reactive oxygen species is greatly inhibited by SPL extracts (p&lt;0.05), suggesting the free radical scavenging activity of SPL. In parallel, extracts of SPL increase activities of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase in H2O2 treated INS‐1 cells (p&lt;0.05). In summary, these results suggest that SPL might be used as potential nutraceutical agent which will protect the pancreatic β‐cells from oxidative stress associated with diabetes.

The Impact of Oxidative Stress on Islet Transplantation and Monitoring the Graft Survival by Non-Invasive Imaging

Islet transplantation is an attractive strategy to treat severe diabetic conditions in patients suffering from autoimmune derived diabetes, and it has currently been considered a forefront research arena in diabetes. Major aim of islet transplantation is to achieve successful insulin independent disease free survival. The key challenges in transplanted islets are the generation of reactive oxygen species (ROS) and associated oxidative stress, pro-inflammatory cytokine - (TNFα) mediated apoptotic induction, attack by immune cells, and achieving revascularization with minimal hypoxic microenvironment. Free radicals and their derivatives are constantly produced in living systems, but at relatively low level, and in a balanced state. Oxidative stress, which occurs as a result of an imbalance between the intracellular free radicals production and the cellular antioxidant defense mechanisms in the transplanted islets, can lead to cell death. The balance between oxidants and antioxidants in a cell can be easily disturbed by increase in ROS production or reduction in the level of cellular antioxidant defensive substances, which can cause many metabolic complications, including pancreatic β-cell damage. Antioxidants function as blockers of radical processes by eliminating harmful ROS produced during normal cellular metabolism. A complex antioxidant defense mechanism has been developed by nature in cells to protect the cellular homeostasis. This system mainly includes antioxidant enzymes, vitamins and minerals. As transplanted islet survival is crucial for achieving successful therapy, most of these antioxidants can be used as a supplement to scavenge the local ROS thereby improving the survival of transplanted islets. Currently, very few techniques have been routinely used to qualitatively and quantitatively assess the survival and function of islet grafts, especially to confirm the success of treatment, which includes metabolic parameters such as blood glucose, insulin and C-peptide levels. These biochemical measurements provide markers at only the late stages of islet rejection. Use of molecular imaging techniques has the potential for real-time non-invasive monitoring of the functional status and viability of transplanted islet grafts in living animals. This review mainly focuses on the current status of islet transplantations, potential preventive strategies used to reduce oxidative stress-mediated toxicity in islet grafts, and use of molecular imaging as a tool to quantitatively evaluate the functional status of the transplanted islets in living animals.

Effects of Sesamin on Streptozotocin (STZ)-Induced NIT-1 Pancreatic β-Cell Damage

The protective effect of sesamin (SES) from sesame meal on NIT-1 pancreatic β-cells damaged by streptozotocin (STZ) in vitro was investigated. The cell viability, insulin secretion, the activity of superoxide dismutase(SOD), glutathione peroxidase (GSHpx) and the content of reduced glutathione (GSH) increased significantly when incubated with SES (400, 200 μg mL−1). The content of malondialdehyde (MDA), nitric oxide (NO) production, and the activity of NO synthase (NOS), inducible NOS (iNOS), decreased significantly when incubated with SES. The destructive changes of NIT-1 cells were ameliorated when treated with SES under microscopic observation. These data suggested that SES had obvious protective effect on NIT-1 pancreatic β-cells damaged by STZ, which might be related to its effects of decreasing levels of β-cell-destroying factors such as oxidative stress and NO synthesis.

Anti-inflammatory action of Tamarind seeds reduces hyperglycemic excursion by repressing pancreatic β-cell damage and normalizing SREBP-1c concentration

Context: Tamarindus indica L. (Leguminosae) is widely used as a traditional medicine for the management of diabetes mellitus (DM) in India, in addition to its anti-inflammatory activity. The present study has been designed to understand the correlation involved between antidiabetic and anti-inflammatory action of aqueous seed extract of T. indica (TSE) in diabetic rats.Objective: In view of the fact that fatty acid synthesis and insulin release from islets of pancreas are regulated by sterol regulatory element-binding proteins (SREBP-1c) and cytosolic calcium, respectively, the objectives of present study were to determine the influence of TSE on SREBP-1c mRNA and to investigate the intracellular islets calcium [Ca2+]I involvement and β-cell mass preservation in insulin secretagogue action of TSE.Materials and methods: The effect of 4 weeks oral treatment (120 and 240 mg/kg) of high-performance liquid chromatography (HPLC) standardized TSE was studied in streptozotocin (STZ)-induced diabetic male Wistar rats. Reverse transcription-PCR (RT-PCR) and a spectrofluorometer were used for mRNA concentration and islets [Ca2+]I determination, respectively. The TUNEL assay was followed to study the pancreatic apoptosis.Results: TSE (120 and 240 mg/kg) showed positive correlation with [Ca2+]I and insulin release. The anti-inflammatory action of TSE was significant on nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in addition to a favorable effect on β-cell neogenesis and improved mRNA concentration of SREBP-1c.Discussion and conclusion: The results suggest that anti-inflammatory action of Tamarind seeds on β-cell cells of islets and cytokines contribute toward its antidiabetic activity by way of complex mechanisms of [Ca2+]I handling and through SREBP-1c gene in liver.

The protective effect of MT-α-glucan against streptozotocin (STZ)-induced NIT-1 pancreatic β-cell damage

The protective effect of an alpha-glucan (designated here as MT-α-glucan) from fruit body of maitake (Grifola frondosa) on NIT-1 pancreatic β-cells damaged by streptozotocin (STZ) in vitro was investigated. The cell viability, insulin secretion, the activity of superoxide dismutase (SOD), glutathione peroxidase (GSHpx) and the content of reduced glutathione (GSH) increased significantly when the cells were incubated with MT-α-glucan (400, 200μgml−1). The content of malondialdehyde (MDA), nitric oxide (NO) production, and the activity of NO synthase (NOS), inducible NOS (iNOS) decreased significantly when the cells were incubated with MT-α-glucan. The destructive changes of NIT-1 cells ameliorated when incubated with MT-α-glucan under microscopic observation. These data suggested that MT-α-glucan had obvious protective effect on NIT-1 pancreatic β-cells damaged by STZ, which might be related to its effects of decreasing levels of β-cell-destroying factors such as oxidative stress and NO synthesis.

Adverse Effect on Syngeneic Islet Transplantation by Transgenic Coexpression of Decoy Receptor 3 and Heme Oxygenase-1 in the Islet of NOD Mice

Decoy receptor 3 (DcR3) blocks both Fas ligand- and LIGHT-induced pancreatic β-cell damage in autoimmune diabetes. Heme oxygenase 1 (HO-1) possesses antiapoptotic, anti-inflammatory, and antioxidative effects that protect cells against various forms of attack by the immune system. Previously, we have demonstrated that transgenic islets overexpressing DcR3 or murine HO-1 (mHO-1) exhibit longer survival times than nontransgenic islets in syngeneic islet transplantation. In this study, we evaluated whether DcR3 and mHO-1 double-transgenic islets of NOD mice could provide better protective effects and achieve longer islet graft survival than DcR3 or mHO-1 single-transgenic islets after islet transplantation. We generated DcR3 and mHO-1 double-transgenic NOD mice that specifically overexpress DcR3 and HO-1 in islets. Seven hundred islets isolated from double-transgenic, single-transgenic, or nontransgenic NOD mice were syngeneically transplanted into the kidney capsules of newly diabetic female recipients. Unexpectedly, there was no significant difference in the survival time between double-transgenic or nontransgenic NOD islet grafts, and the survival times of double-transgenic NOD islet grafts were even shorter than those of DcR3 or mHO-1 single-transgenic islets. Our data indicate that transplantation of double-transgenic islets that coexpress HO-1 and DcR3 did not result in a better outcome. On the contrary, this strategy even caused an adverse effect in syngeneic islet transplantation.

Effects of the novel mitochondrial protein mimitin in insulin-secreting cells

Mimitin, a novel mitochondrial protein, has been shown to act as a molecular chaperone for the mitochondrial complex I and to regulate ATP synthesis. During Type 1 diabetes development, pro-inflammatory cytokines induce mitochondrial damage in pancreatic β-cells, inhibit ATP synthesis and reduce glucose-induced insulin secretion. Mimitin was expressed in rat pancreatic islets including β-cells and decreased by cytokines. In the ob/ob mouse, a model of insulin resistance and obesity, mimitin expression was down-regulated in liver and brain, up-regulated in heart and kidney, but not affected in islets. To further analyse the impact of mimitin on β-cell function, two β-cell lines, one with a low (INS1E) and another with a higher (MIN6) mimitin expression were studied. Mimitin overexpression protected INS1E cells against cytokine-induced caspase 3 activation, mitochondrial membrane potential reduction and ATP production inhibition, independently from the NF-κB (nuclear factor κB)-iNOS (inducible NO synthase) pathway. Mimitin overexpression increased basal and glucose-induced insulin secretion and prevented cytokine-mediated suppression of insulin secretion. Mimitin knockdown in MIN6 cells had opposite effects to those observed after overexpression. Thus mimitin has the capacity to modulate pancreatic islet function and to reduce cytokine toxicity.

Bioactive compounds extracted from Ecklonia cava by using enzymatic hydrolysis protects high glucose-induced damage in INS-1 pancreatic β-cells.

Pancreatic β-cells are very sensitive to oxidative stress and this might play an important role in β-cell death in diabetes. In the present study, we investigated whether the brown alga Ecklonia cava has protective effects against high glucose-induced damage in INS-1 pancreatic β-cells. For that purpose, we prepared an enzymatic hydrolysate from E. cava (EHE) by using the carbohydrase, Celluclast. High-glucose (30mM) treatment induced glucotoxicity, whereas EHE prevented cells from high glucose-induced damage then restoring cell viability was significantly increased. Furthermore, lipid peroxidation, intracellular reactive oxygen species (ROS) and nitric oxide (NO) were overproduced as the result of the treatment by high glucose; however, these lipid peroxidation, ROS and NO generations were effectively inhibited by addition of EHE in a dose-dependent manner. Moreover, EHE treatment increased activities of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) in high glucose pretreated INS-1 pancreatic β-cells. EHE slightly reduced the expression of pro-apoptotic protein Bax induced by high glucose but increased the expression of Bcl-2, an anti-apoptotic protein. These findings indicate that EHE might be used as potential nutraceutical agent which will protect the glucotoxicity caused by hyperglycemia-induced oxidative stress associated with diabetes.

Effect of Nigella sativa on pancreatic β-cell damage in streptozotocin-induced diabetic rats

BackgroundDiabetes mellitus is a metabolic disease characterized by chronic hyperglycemia. Nigella sativa (NS) is a medical plant used as a natural remedy for a variety of illness.Aim of the studyThe aim of this study was to demonstrate the effect of NS on pancreatic β-cell damage and serum levels o

Apigenin Attenuates 2-Deoxy-D-ribose-Induced Oxidative Cell Damage in HIT-T15 Pancreatic .BETA.-Cells

Glucose toxicity contributes to progressive β-cell failure and the development of overt diabetes. Oxidative stress is an important aspect of glucose toxicity in pancreatic β-cells. We investigated whether the flavonoid apigenin protects pancreatic β-cells from 2-deoxy-D-ribose (dRib)-induced oxidative cell damage. HIT-T15 pancreatic β-cells were cultured with or without apigenin in the presence of dRib. Time- and dose-dependent cell viability was monitored using a cell counting kit (CCK-8), while the induction of apoptosis was analyzed using a cell death enzyme-linked immunosorbent assay (ELISA) kit. Mitochondrial membrane potential (ΔΨ(m)) was determined using the JC-1 kit. Intracellular oxidative stress was measured by fluorometric analysis of DCFH oxidation using 2',7'-dichlorofluorescin diacetate (DCFH-DA) as the probe. In addition, the DNA binding activity of the oxidative stress-related transcriptional factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) were analyzed. dRib reduced cell survival and ΔΨ(m), while it markedly increased intracellular levels of reactive oxygen species (ROS), apoptosis, and the activity of the oxidative stress-related transcription factors NF-κB and AP-1. However, pretreatment of cells with apigenin attenuated all the dRib-induced effects. The anti-oxidants, N-acetyl-L-cysteine (NAC) and alpha lipoic acid (ALA), also prevented both dRib-induced oxidative damage and activation of NF-κB and AP-1. Taken together, these results suggest that apigenin attenuates dRib-induced cell damage in pancreatic β-cells via oxidative stress-related signaling.

Effect of PRX-1 Downregulation in the Type 1 Diabetes Microenvironment

Type 1 diabetes (T1D) is caused by dysregulation of the immune system in the pancreatic islets, which eventually leads to insulin-producing pancreatic β-cell death and destabilization of glucose homeostasis. One of the major characteristics of T1D pathogenesis is the production of inflammatory mediators by macrophages that result in destruction or damage of pancreatic β-cells. In this study the inflammatory microenvironment of T1D was simulated with RAW264.7 cells and MIN6 cells, acting as macrophages and pancreatic β-cells respectably. In this setting, peroxiredoxin-1, an anti-oxidant enzyme was knocked down to observe its functions in the pathogenesis of T1D. RAW264.7 cells were primed with lipopolysaccharide and co-cultured with MIN6 cells while PRX-1 was knocked down in one or both cell types. Our results suggest that hindrance of PRX-1 activity or the deficiency of this enzyme in inflammatory conditions negatively affects pancreatic β-cell survival. The observed decrease in viability of MIN6 cells seems to be caused by nitric oxide production. Additionally, it seems that PRX-1 affects previously reported protective activity of IL-6 in pancreatic β cells as well. These results signify new, undiscovered roles for PRX-1 in inflammatory conditions and may contribute toward our understanding of autoimmunity.

Syzygium cumini Ameliorates Insulin Resistance and β-Cell Dysfunction via Modulation of PPARγ, Dyslipidemia, Oxidative Stress, and TNF-α in Type 2 Diabetic Rats

Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin–induced (HFD–STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. Subsequently, after confirmation of hyperglycemia on the 14th day (fasting glucose level > 13.89 mM), diabetic rats were treated with SC for the next 21 days. Diabetic rats showed increased serum glucose, insulin, IR, TNF-α, dyslipidemia, and pancreatic thiobarbituric acid-reactive substances with a concomitant decrease in β-cell function and pancreatic superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzyme activities. Microscopic examination of their pancreas revealed pathological changes in islets and β-cells. These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD–STZ-induced type 2 diabetic rats.

KIOM-79 attenuated cell damage induced by endoplasmic reticulum stress by inhibiting apoptosis in RINm5F cells

Endoplasmic reticulum (ER) is a cellular compartment responsible for biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. ER stress plays a role in the pathogenesis of diabetes and is associated with pancreatic β-cell damage. The aim of this study was to examine the effect of KIOM-79, a mixture of plant extracts, on streptozotocin (STZ)-induced ER stress in pancreatic RINm5F β-cells. STZ induced characteristics of ER stress; the release of Ca2+ from ER, increased ER staining, induction of glucose-regulated protein-78, phosphorylation of PKR-like ER kinase, and eukaryotic initiation factor-2α, as well as cleavage of activating transcription factor-6, whereas KIOM-79 inhibited these changes. Moreover, KIOM-79 inhibited STZ-induced apoptotic cell death. STZ induced CCAAT/enhancer-binding protein-homologous protein (CHOP) and cleavage of caspase 12, which are ER stress-induced apoptosis regulatory proteins; however, KIOM-79 suppressed these effects. KIOM-79 suppressed apoptosis induced by STZ treatment in CHOP siRNA-transfected cells. Furthermore, KIOM-79 restored cell viability decreased by STZ treatment via ER-stressed apoptosis. The pancreatic β-cells damaged by STZ had decreased levels of insulin, and KIOM-79 restored the levels. Taken together, these results suggest that KIOM-79 had cytoprotective effects against STZ-induced apoptosis by interrupting the ER stress pathway.