Injury In Diabetic Rats Research Articles

Potential cerebrovascular protective functions of lycium barbarum polysaccharide in alleviating hyperglycemia-aggravated cerebral ischemia/reperfusion injury in hyperglycemic rats.

Lycium barbarum polysaccharide (LBP) is the efficient primary compound of Lycium barbarum and has been shown to alleviate hyperglycemia-aggravated cerebral ischemia/reperfusion (I/R) injury. However, the cerebrovascular changes related to diabetes mellitus (DM) and the potential cerebrovascular protective effects of LBP are still unknown. This study aimed to explore the cerebrovascular protective functions of LBP on cerebral I/R injury in diabetic rats and its potential mechanisms. Sprague Dawley (SD) rats were separated into three groups: the normoglycemic (NG), diabetic hyperglycemic (HG), and HG + LBP (50 mg/kg) treatment groups. A 30 min transient middle cerebral artery occlusion (tMCAO) with 24 h reperfusion was established. The neurological deficits, cerebral water content, infarct volume, and cerebrovascular permeability were assessed to evaluate the extent of cerebral injury. Histopathological alterations were assessed by hematoxylin and eosin, Nissl, immunohistochemical, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. A transmission electron microscope was used to detect ultrastructural alterations, and a western blot was used to examine protein expression. The HG rats exhibited a significant increase in neurological deficits, cerebral water content, infarct volume, cerebrovascular permeability, neural cell death, and apoptosis compared with the NG rats, and the LBP treatment alleviated these effects. Cerebrovascular structure analysis showed that the cross-sectional area (CSA) and wall thickness were remarkably altered in the HG rats compared with the NG rats. The LBP treatment protected the cerebrovascular structure and vasoreactivity by decreasing the wall thickness and increasing the CSA, α-smooth muscle actin, and endothelial nitric oxide synthase expression of cerebral vessels. The intake of LBP benefits the cerebrovascular structure and vasoreactivity in diabetic rats. Our research provides a possible new strategy for treating stroke in patients with DM.

CD36 inhibition partially attenuates myocardial injury in diabetic rats with ischemic postconditioning

IntroductionTo investigate the role of CD36 (fatty acid translocation enzyme) in the myocardial ischemia reperfusion (IR) injury in diabetes with ischemic postconditioning (IPostC).Research design and methodsAdult male Sprague-Dawley rats received...

Protective Effect of Buckwheat Polysaccharide on Streptozotocin-Induced Kidney Injury in Diabetic Rats and the Possible Mechanism

We intend to explore the mechanism underlying the effect of Buckwheat polysaccharide on kidney damage in diabetics. In this study, rats received 5 week-STZ injection to induce type 2 diabetes and then were administered with 8-week buckwheat polysaccharide followed by analysis of the diabetes-index and kidney histopathological changes by immunohistochemistry and ELISA as well as the expression of kidney Col IV, Akt, TGF-β1, FN, FoxO1 and MnSOD by western blot and RT-qPCR. Diabetic nephropathy rats exhibited significantly increased blood glucose, kidney body mass index, Scr and glomerular mesangial index, with thickened glomerular basement membrane, and elevated BUN and urinary albumin excretion. Besides, podocyte was fused as demonstrated by significantly decreased expression of renal TGF-β1, FN, Col IV mRNA and renal MnSOD mRNA. In conclusion, Buckwheat polysaccharides significantly alleviate kidney injury in diabetes possibly through regulation of FoxO1/MnSOD axis.

FKN/NR Signaling Pathway Regulates Hippocampal Inflammatory Responses: the Survival of Hippocampal Neurons in Diabetic Rats with Chronic Unpredictable Mild Stress.

Aim To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1β, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1β, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.

Deposition of platelet-derived microparticles in podocytes contributes to diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN. The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot. PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.

Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD.

Activation of AMPK/p38/Nrf2 is involved in resveratrol alleviating myocardial ischemia-reperfusion injury in diabetic rats as an endogenous antioxidant stress feedback.

BackgroundMyocardial necrosis caused by myocardial ischemia-reperfusion (MI/R) in diabetic patients is prominently aggravated and can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensing transcription factor that protects against myocardial ischemia/reperfusion injury (MIRI). However, the mechanism of action of Nrf2 in resveratrol-pretreated cardiomyocytes is complex. We assumed that adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/p38 mitogen-activated protein kinases (p38)/Nrf2 might be involved in resveratrol alleviating MIRI in diabetic rats as an endogenous protective mechanism.MethodsA total of 50 type 2 diabetes mellitus (T2DM) rat models were randomly divided into 5 groups (n=10 in each group): sham group; MI/R group; AMPK inhibitor compound C + myocardial ischemia-reperfusion (C + MI/R) group; resveratrol + myocardial ischemia-reperfusion (RSV + MI/R) group; and resveratrol + AMPK inhibitor compound C + myocardium ischemia-reperfusion group (RSV + C + MI/R) group. Rats were fed a high fat diet, and the T2DM models were established by intraperitoneal injection of 1% streptozotocin (STZ). The MIRI models were established by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion for 120 minutes. The size of myocardial infarction was measured. Serum samples were collected to measure the concentrations of creatine kinase-MB (CK-MB). The levels of lactate dehydrogenase (LDH), glutathione (GSH), and superoxide dismutase (SOD) in myocardial tissues were determined. Immunofluorescence analysis of translocase of outer mitochondrial membrane 20 (TOMM20) was performed to observe the pathological changes in myocardial tissues. The protein expressions of AMPK, p-AMPK, p38, p-p38, Nrf2, and heme oxygenase 1 (HO-1) were determined by western blotting.ResultsCompared with the sham group, the expressions of AMPK, p38, Nrf2, and HO-1 in the myocardium were significantly increased in the MI/R group. Compared with the MI/R group, the RSV + MI/R group had a significantly lower oxidative stress level, milder myocardial injury, increased expressions of AMPK, Nrf2, and HO-1, and lower expression of p38. The protein expressions of Nrf2 and HO-1 were partially inhibited in the RSV + C + MI/R group.ConclusionsResveratrol can inhibit oxidative stress and alleviate MIRI by activating the AMPK/p38/Nrf2 signaling pathway. Meanwhile, AMPK/p38/Nrf2 is also an endogenous antioxidant stress pathway that protects against stress.

Mechanistic Research into the Effects of the Jianpi Xiaozhi Formula on Liver Injury in Diabetic Rats.

Objective The purpose of this study was to explore the mechanism of Jianpi Xiaozhi Formula (JPXZF) action in attenuating liver injury in a rat model of type 2 diabetes mellitus (T2DM). Methods A rat model of T2DM was established. Forty-eight male Sprague–Dawley (SD) rats were randomly allocated to six groups: healthy untreated rats (normal control (NC)), rats with diabetes mellitus (DM), diabetic rats treated with low-dosage JPXZF (DM + JL), diabetic rats treated with an intermediate JPXZF dosage (DM + JM), diabetic rats treated with high-dosage JPXZF (DM + JH), and diabetic rats treated with 4-phenylbutyric acid (PBA) (DM + PBA). The rats in each group were given the indicated drugs for 8 weeks, and pathological changes in the liver tissues of each rat group were observed by haematoxylin-eosin (HE) staining. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting (WB) were performed to determine the expression of glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), family with sequence similarity 134, member B (FAM134B), P62, Beclin-1, and light chain 3II/I (LC3II/I) genes and proteins in the liver tissues of the rats in each group. Immunofluorescence was used to observe changes in FAM134B expression. Results After successfully establishing the rat model, RT-PCR assays revealed that, compared with those in the NC group rats, the expression levels of GRP78, ATF6, and P62 mRNA in the livers of the DM group rats were significantly increased, and the relative expression levels of FAM134B and Beclin-1 mRNA were significantly decreased. Compared with that in the DM group, the relative expression of GRP78, ATF6, and P62 mRNA in the liver of the rats in each JPXZF intervention group was decreased in a dosage-dependent manner, and the relative expression of FAM134B and Beclin-1 mRNA was increased significantly (p < 0.05). WB indicated that, compared with that in the NC group rats, the LC3II/I protein expression ratio in the liver of the DM group rats was significantly reduced, and the LC3II/I protein expression ratio in the liver of the rats in each JPXZF intervention group was significantly increased. In addition, the expression of the other measured proteins was consistent with that of the corresponding mRNA measured by RT-PCR (p < 0.05). The immunofluorescence assay results showed that FAM134B changes were consistent with the results obtained by RT-PCR and WB (p < 0.05). Conclusion Jianpi Xiaozhi Formula may be effective in treating liver injury in diabetic rats by regulating autophagy induced by endoplasmic reticulum stress (ERS).

Interval training and Crataegus persica ameliorate diabetic nephropathy via miR-126/Nrf-2 mediated inhibition of stress oxidative in rats with diabetes after myocardial ischemia-reperfusion injury

Myocardial disorders are the most common cause of renal failure and mortality in diabetic patients, but the molecular mechanism of this process is not yet clear. The reduction of nuclear Erythroid2-related factor-2 (Nrf-2) and positive regulators of Nrf-2 proteins, such as DJ-1 and microRNA-126 (miR-126), after hypoxia and the promotion of reactive oxygen species, might be an intervention indicator in renal failure after myocardial ischemia-reperfusion. Therefore, this study evaluates the renoprotective effect of exercise training and Crataegus persica extract (CE) on myocardial ischemia-reperfusion-induced kidney injury in diabetic rats. Fifty rats were divided into five groups: healthy sedentary control (Con), sedentary diabetic (D), interval trained diabetic (TD), diabetic plus Crataegus persica extract treatment (CD), and interval trained diabetic plus Crataegus persica extract treatment (TCD) groups. The rats in the exercise groups were subjected to moderate-intensity interval training five days per week for ten weeks. The rats in CD and TCD groups received 300 mg/kg of Crataegus persica through gavage for ten weeks. Then, the subjects underwent 30 min of myocardial ischemia and subsequently reperfusion for 24 h. At the end of the experiment, insulin sensitivity, oxidative stress, renal function, histopathology of the kidney, Nrf-2, miR-126, and DJ-1 gene expression levels were evaluated. The results show that the treatments decreased elevated levels of renal oxidative stress, glomerular filtration rate, insulin sensitivity, and pathological score in diabetic rats. Also, the expression of Nrf-2 and miR-126, unlike DJ-1, decreased in diabetic rats due to interval training. Due to the results, diabetes aggravates acute myocardial ischemia-reperfusion-induced kidney injury, while moderate-intensity interval training and Crataegus persica treatment simultaneously ameliorate myocardial ischemia-reperfusion-induced renal injury via miR-126/Nrf-2 pathway and improve insulin sensitivity and renal function in type 1 diabetic rats.

The Effect of Curcumin on Renal Ischemia/Reperfusion Injury in Diabetic Rats.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are global health problems that affect over 850 million people, twice the number of diabetic individuals around the world. Diabetes mellitus (DM) is known to increase the susceptibility to AKI. Plants and foods, such as curcumin, are traditionally used as treatments for various diseases due to its wide range of bioactive compounds that exert antioxidative, anti-inflammatory, antimicrobial and anticancer properties. The aim of this study is to evaluate the effect of curcumin in diabetic rats with AKI. Adult male Wistar rats, weighing between 250 and 290 g, were randomized into four groups: Citrate (citrate buffer, i.v., single dose, on Day 1 of the protocol); DM (streptozotocin (STZ), 65 mg/k, single dose, i.v., on Day 1); DM + I/R (DM rats that, on Day 26, had the renal pedicle clamped for 30 min on both sides); DM + I/R + Curcumin (DM + I/R rats submitted to curcumin treatment). Results showed that IR worsened renal function and oxidative stress in DM rats, but the DM + IR + Curcumin group showed an increase in inulin clearance and a decrease in serum creatinine and in NGAL, in addition to an improvement in renal hemodynamics. These effects were accompanied by a reduction in oxidative and nitrosative metabolites and an increase in the thiol antioxidant reserve when curcumin was administered to the DM + IR group.

Antioxidative stress and nephroprotective activity of leaf fractions of Setaria megaphylla in alloxan-induced diabetic Wistar rats

Setaria megaphylla (Steud) Dur &amp; Schinz (Poaceae), a medicinal plant used traditionally to treat diabetes was investigated for antioxidative stress and renoprotective potentials against alloxan-induced kidney injuries in diabetic rats. Standard biochemical and histological methods were used to determine oxidative stress markers levels, kidney function indices and kidney histopathology, which were used as parameters to evaluate antioxidative stress and renoprotective activities of the leaf fractions (200 mg/kg). Significantly (p&lt;0.05 – 0.001) increased levels of kidney oxidative stress markers (SOD, CAT, GPx, GSH) and decreased MDA level were caused by the leaf fractions in the treated-diabetic rats. Creatinine and urea levels were also significantly (p&lt;0.05-0.001) reduced, while electrolytes levels were not significantly (p&gt;0.05) reduced when compared to control. Kidney histology revealed absence or significant reductions in pathological features in the treated diabetic rats relative to untreated diabetic rats. The results suggest that the leaf fractions of Setaria megaphylla possess antioxidative stress and nephroprotective potentials due to the antioxidant activities of their phytochemical constituents.

RJX Improves Wound Healing in Diabetic Rats.

BackgroundWe recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). The primary objective of the present study was to examine the effects of GMP-grade RJX on wound and burn injury healing in diabetic rats.MethodsIn the present study, a rat model of T2DM was used that employs HFD in combination with a single injection of STZ intraperitoneally (i.p) at a moderate dose level (45 mg/kg). Anesthetized diabetic rats underwent full-thickness skin excision on the back or were subjected to burn injury via a heated brass probe and then started on treatments with normal saline (NS = vehicle) or RJX administered via intraperitoneal injections for three weeks.FindingsNotably, diabetic rats treated with the 1.25 mL/kg or 2.5 mL/kg RJX (DM+RJX groups) rapidly healed their wounds as fast as non-diabetic control rats. Inflammatory cell infiltration in the dermis along with fibrin and cell debris on the epithelial layer persisted for up to 14 days in the DM+NS group but not in RJX-treated groups. The histopathological score of wound healing on days 7 and 14 was better in diabetic rats treated with RJX than diabetic rats treated with NS and comparable to the scores for non-diabetic healthy rats consistent with an accelerated healing process. The residual wound area of RJX-treated rats was significantly smaller than that of NS-treated diabetic rats at each evaluation time point (P<0.001). The accelerating effect of RJX on diabetic wound healing was dose-dependent. We obtained similar results in the burn injury model. Our results demonstrate that RJX – at a dose level >10-fold lower than its clinical maximum tolerated dose (MTD) – accelerates the healing of excision wounds as well burn injury in diabetic rats.

Regulatory effects and anti‐inflammatory activity of Trachyspermum ammi (L.) Sprague seeds extract on alleviation of kidney injury in diabetic rats

Diabetic nephropathy is a major cause of renal tissue damage and complications of diabetes. In this in-vitro experimental study, diabetes was induced by a single injection of Streptozotocin (55 mg/kg) in rats. STZ-diabetic rats were treated with oral doses of methanolic extract T. ammi seeds (300–400 mg/kg). After 8 weeks, serum levels of glucose, creatinine, urea, SOD, and MDA in the blood serum and protein levels in urine were measured. Also, changes in the expression of IL-18 and TNF-α genes in the renal tissue were examined. The results of this study showed that T. ammi seeds have anti-hyperglycemic and anti-hyperlipidemia effects. It can also increase SOD, decrease MDA, and inhibit IL-18 and TNF-α expression. T. ammi methanolic extract reduced blood glucose, oxidative stress, renal function biomarkers, and inflammatory cytokines caused by STZ in mice. Because of this, it could be used as a new treatment for diabetic nephropathy. Novelty impact statement The effect of T. ammi seed extract on rats with nephropathy was investigated. The real-time PCR technique was used to measure the expression of the genes IL-18 and TNF-a, while the ELISA technique was used to measure the level of MDA and SOD serum. T. ammi is a medicinal plant with anti-inflammatory and anti-nephropathy effects.

LncRNA FLG-AS1 Mitigates Diabetic Retinopathy by Regulating Retinal Epithelial Cell Inflammation, Oxidative Stress, and Apoptosis via miR-380-3p/SOCS6 Axis.

The objective of this study is to investigate lncRNA FLG-AS1-mediated miR-380-3p/SOCS6 axis in inflammation, oxidative stress, and apoptosis of retinal epithelial cells in diabetic retinopathy (DR). Fasting blood was collected from 60 DR patients and 60 healthy controls. The Pearson correlation was used to analyze the correlation between the expression levels of FLG-AS1 and miR-380-3p in DR patients. qRT-PCR and/or Western blotting were used to detect the expression of FLG-AS1, miR-380-3p, and SOCS6. After gain of function of FLG-AS1 or SOCS6 or loss of function of miR-380-3p, high glucose (HG)-treated human retinal pigment epithelial ARPE-19 cells were subjected to TUNEL assessment of apoptosis. ELISA was performed to detect the expression levels of IL-1β, IL-6, and TNF-α in cell culturesupernatant. DCFH-DA was used to detect the level of ROS in the cells. MDA and SOD assay kits were used to measure the activity of MDA and SOD in the cells. Dual-luciferase reporter assay was performed to verify the binding between miR-380-3p and FLG-AS1 or between miR-380-3p and SOCS6. Streptozotocin injections were used to induce diabetes in rats which were injected with FLG-AS1 overexpression lentiviral vectors in the eye. Twenty weeks later, retinal tissue was isolated and stained with hematoxylin-eosin or TUNEL. Compared to that in healthy controls, FLG-AS1 expression decreased 2.5-fold and miR-380-3p expression increased 2.6-fold in the serum of DR patients. The expression levels of FLG-AS1 and miR-380-3p were negatively correlated in DR patients (r = -0.3772, P = 0.003). Overexpression of FLG-AS1 reduced inflammation, oxidative stress, and apoptosis of HG-treated ARPE-19 cells and alleviated retinal injury in diabetic rats. FLG-AS1 promoted the expression of SOCS6 by targeting miR-380-3p. Inhibition of miR-380-3p or overexpression of SOCS6 reduced inflammation, oxidative stress, and apoptosis of HG-treated ARPE-19 cells. FLG-AS1 mitigates DR by regulating retinal epithelial cell inflammation, oxidative stress, and apoptosis via the miR-380-3p/SOCS6 axis.

Alpha-lipoic acid potentiates the anti-arrhythmic effects of ischemic postconditioning in the setting of cardiac ischemia/reperfusion injury in diabetic rats.

Prevention of lethal ventricular arrhythmias induced by myocardial ischemia/reperfusion (I/R) in diabetic patients is the major goal of cardioprotective strategies. Here, we aimed to examine the anti-arrhythmic effect of ischemic postconditioning (IPostC) and alpha-lipoic acid (ALA) in myocardial I/R injury of type-II diabetic rats, focusing on the involvement of connexin-43 and nitric oxide (NO) in this context. Diabetes (duration of 12weeks) was induced by high-fat diet and low dose of streptozotocin in thirty male Wistar rats (12weeks old, 200-250g). After mounting the hearts on the Langendorff apparatus, I/R was induced by the ligation of left anterior descending coronary artery for 35min, and reperfusion for 60min. ALA (100mg/kg/day) was administered orally in diabetic rats for five weeks before I/R. IPostC was applied immediately at early reperfusion. The arrhythmias were evaluated according to the Lambeth convention. Connexin-43 expression and NO levels were assessed by western blotting and Griess calorimetric method, respectively. IPostC could not significantly decrease the number, duration, and incidence of premature ventricular contraction, ventricular tachycardia, and ventricular fibrillation, also the severity of arrhythmias in diabetic hearts. However, IPostC in combination with ALA-preconditioning significantly decreased the above mentioned parameters compared with untreated or monotherapies-received diabetic rats (P < 0.05 to P < 0.001). Furthermore, this combination therapy significantly increased connexin-43 expression and NO levels, compared with untreated diabetic rats (P < 0.01). Preconditioning with ALA restored anti-arrhythmic effect of IPostC in diabetic hearts. Increased connexin-43 expression and NO levels may be the key players in this cardioprotection.

Inhibition on α-Glucosidase Activity and Non-Enzymatic Glycation by an Anti-Oxidative Proteoglycan from Ganoderma lucidum.

The prevention of postprandial hyperglycemia and diabetic complications is crucial for diabetes management. Inhibition of α-glucosidase to slow carbohydrate metabolism is a strategy to alleviate postprandial hyperglycemia. In addition, suppression of non-enzymatic glycation can diminish the advanced glycation end products and reduce the oxidative stress and inflammation, thereby preventing the diabetic complications. In this study, an anti-oxidative proteoglycan (named FYGL) extracted from Ganoderma lucidum was investigated in vitro for its inhibitory effect on α-glucosidase and non-enzymatic glycation using molecular kinetics, intrinsic fluorescence assay, and bovine serum albumin glycation models. The molecular kinetics and fluorescence assay revealed that FYGL decreases α-glucosidase activity by forming a FYGL–α-glucosidase complex. To evaluate the anti-glycation effect, fructose-glycated and methylglyoxal-glycated BSA models were analyzed by spectroscopic and SDS-PAGE methods. Results showed that FYGL inhibited the glycation at every stage and suppressed glycoxidation, possibly due to its anti-oxidative capacity and FYGL–BSA complex formation. Furthermore, we demonstrated in vivo that FYGL could alleviate postprandial hyperglycemia in db/db mice as well as AGE accumulation and vascular injury in diabetic rats. Overall, FYGL possesses anti-postprandial hyperglycemia and anti-glycation functions and would be potentially used in clinic for diabetes and related complication management.

Activation of NRF2/FPN1 pathway attenuates myocardial ischemia\u2013reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis

In patients with ischemic heart disease, myocardial ischemia–reperfusion injury (IRI) can aggravate their condition even worse, and diabetes increases their risk of myocardial IRI. Pathological pathways of common diseases and surgical operations like diabetes, obesity, coronary artery angioplasty, and heart transplantation entail disorders of iron metabolism. Ferroportin1 (FPN1) is the only mammalian protein associated with iron release and thus plays a vital role in iron homeostasis, while nuclear factor E2-related factor 2 (NRF2) controls the transcription of FPN1. Since the NRF2/FPN1 pathway may play a favorable role in the therapy of diabetic myocardial IRI, this work investigated the possible mechanism. In this study, we investigated the effects of ferroptosis in STZ-induced diabetic rats following myocardial IRI in vivo, and its alteration in glucose and hypoxia/reoxygenation-induced cardiomyocytes injury in vitro. Rats and H9c2 cardiomyocytes were randomly divided into 6 groups and treated with sulforaphane and erastin besides the establishment of diabetic myocardial IRI and hyperglycemic hypoxia-reoxygenation models. Cardiac functional and structural damage were detected by Evans blue/TTC double staining, echocardiography, HE staining, and serological indices. CCK-8 assay and ROS production were used to measure cardiomyocyte viability and oxidative stress level. Additionally, the changes in cell supernatant levels of Fe2+, SOD, MDA, and mRNA and protein expression of ferroptosis marker proteins confirmed the beneficial effects of the NRF2/FPN1 pathway on diabetic myocardial IRI related to iron metabolism and ferroptosis. Overall, these findings suggest that iron homeostasis-related ferroptosis plays an important role in aggravating myocardial IRI in diabetic rats, and NRF2/FPN1 pathway-mediated iron homeostasis and ferroptosis might be a promising therapeutic target against myocardial IRI in diabetes.

Curcumin nanoemulsion ameliorates brain injury in diabetic rats.

Diabetes mellitus has been implicated in the exacerbation of cerebral ischemic injuries. Among the most promising therapeutic approaches is the combination of nutraceuticals and nanotechnology. Curcumin has been termed "the magic molecule", and it was proven to exert several therapeutic actions. Therefore, the aim of the presented work was to investigate the therapeutic effects of curcumin nanoemulsion (NC) administered orally on the middle cerebral artery occlusion and reperfusion (MCAO/Re)-induced cerebral damage in rats with streptozotocin-induced diabetes. The cerebral injury was induced in rats by MCAO/Re 6 weeks after single intraperitoneal STZ injection (50mg/kg; i.p.). MCAO/Re diabetic rats were then treated with NC (50 and 100mg/kg; bw; p.o.) for two consecutive weeks. The results of the present study showed that oral treatment of MCAO/Re diabetic rats with NC was associated with a marked attenuation of the neurological deficit score as well as the brain imbalance of the redox homeostasis. NC treatment was also associated with decline in the brain expression of tumor necrosis factor, interleukin-1β, COX-2, cleaved caspase-3, and nuclear factor kappa B. In addition, the expression of glucose transporter 1 proteins upon treatment was restored. PRACTICAL APPLICATIONS: From all these results, it can be concluded that oral supplementation of curcumin nanoemulsion (NC) in diabetic rats reduced the brain injury via augmentation of the expression of glucose transporter 1, as well as its antioxidant and anti-inflammatory properties. Therefore, NC could be delineated as a promising treatment option for cerebral ischemia in diabetic patients.

Extraction of lycopene from tomato pomace and its protective effects on renal injury in diabetic rats

The aim of this study was to investigate the protective effects of lycopene from tomato pomace on renal injury in diabetic rats. Lycopene was extracted from tomato pomace. The rats were divided into control, model and 10, 20 and mg/kg lycopene groups. The diabetic nephropathy model was constructed in the latter four groups. Then, the latter three groups were treated with 10, 20 and mg/kg lycopene, respectively. After four weeks of treatment, compared with the model group, in 20 and 40 mg/kg lycopene groups the serum fasting plasma glucose level was decreased (P < 0.05), the fasting insulin level was increased (P < 0.05), the renal index and 24-h urinary protein level were decreased (P < 0.05), the blood urea nitrogen and serum creatinine levels were decreased (P < 0.05), the renal tissue superoxide dismutase and glutathione peroxidase levels were increased (P < 0.05), the renal tissue malondialdehyde level was decreased (P < 0.05), and the serum tumor necrosis factor α, interleukin 6 and hypersensitive C-reactive protein levels were decreased (P < 0.05). In conclusion, lycopene from tomato pomace can alleviate renal injury in diabetic rats. The mechanism may be related to the resistance of oxidative stress and inflammatory response.

Tripterygium glycoside ameliorates kidney injury in diabetic rats by regulating the PI3K/Akt signaling pathway

To discuss protective effect of Tripterygium Glycoside (TG) on renal injury in diabetic rats and preliminary exploration of its mechanism. The rats were divided into Normal, Model, Low, Middle and High groups. Measuring FBG, TG, TC, HDL-C, BUN and Scr concentration by ELISA assay; using coomassie brilliant blue method to measure 24 h Urine protein. Measuring Kidney index; using HE staining to observation renal histomorphological changes; The ultrastructural changes of renal tissue were observed by transmission electron microscope; TUNEL staining was used to detect the apoptosis of rat renal cells; using WB assay to evaluate PTEN, PI3K, Akt, Bcl-2, Bax and caspase-3 expression. Compared with Normal group, FBG, TG and TC concentrations significantly increased and HDL-C concentration significantly decreased (P < 0.001); BUN, Scr and 24 h Urine protein significantly up-regulated (P < 0.001); Kidney weight and KI significantly down-regulated; Kidney injury score and apoptosis cell number significantly increased (P < 0.001) with PTEN, Bcl-2 protein downregulation and PI3K, Akt, Bax and caspase-3 protein expression significantly up-regulation in Model group (P < 0.001). With TG supplement, the kidney injury significantly improved. TG improved diabetic induced kidney injury via PI3K/Akt pathway in vivo.