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The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR. Article Highlights: We used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in diabetic retinopathy (DR) and the protective effect of sodium–glucose cotransporter 2 inhibitors (SGLT2i) against these alterations. SGLT2i had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. SGLT2i at this dose attenuated early pathogenic alterations, including microglia morphological changes, increased angiopoietin-2 expression, and decreased vessel density and hypoxia induced by diabetes. SGLT2i may break an early pathogenic vicious cycle and exert protective effects against DR. [ABSTRACT FROM AUTHOR]

Objective(s): To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism. Materials and Methods: STZ was used to induce diabetes in C57BL/6J mice. The mice were divided into normal control group (NC), diabetes group (DM), and diabetes+3-MA intervention group (DM+3-MA). Blood glucose, water consumption, and body weight were recorded weekly. At the end of the 6th week of drug treatment, 24-hour urine was collected. Blood and kidneys were collected for PAS staining to evaluate the degree of renal injury. Sirius red staining was used to assess collagen deposition. Blood urea nitrogen (BUN), serum creatinine, and 24-hour urine albumin were used to evaluate renal function. Western blot was used to detect fibrosis-related protein, inflammatory mediators, high mobility group box 1 (HMGB1)/NF-κB signal pathway molecule, vascular endothelial growth factor (VEGF), and podocin, and immunohistochemistry (IHC) was used to detect the expression and localization of autophagy-related protein and fibronectin. Results: Compared with the kidney of normal control mice, the kidney of diabetes control mice was more pale and hypertrophic. Hyperglycemia induces renal autophagy and activates the HMGB1/ NF-κB signal pathway, leading to the increase of inflammatory mediators, extracellular matrix (ECM) deposition, and proteinuria in the kidney. In diabetic mice treated with 3-MA, blood glucose decreased, autophagy and HMGB1/NF-κB signaling pathways in the kidneys were inhibited, and proteinuria, renal hypertrophy, inflammation, and fibrosis were improved. Conclusion: 3-MA can attenuate renal injury in STZ-induced diabetic mice through inhibition of autophagy and HMGB1/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD. [ABSTRACT FROM AUTHOR]

Background: Phenolic compounds (PC) are found in various foods that are part of the human diet, such as mushrooms. The identification of PC is crucial due to their bioactive properties and their role in disease prevention. This study aimed to assess the antioxidant and antidiabetic properties of the phenolic component extract (PCE) derived from the Pleurotus ostreatus mushroom. The extract was separated using high-performance liquid chromatography (HLPC). The PCE was then tested on diabetic rats fed a high-fat diet (HFD). Also, this study was an attempt to treat infertility caused by type 2 diabetes in male rats. Methods: Streptozotocin (STZ) was administered to Wistar rats after a 4-week HFD as a model of type 2 diabetes (D2). Animals were given phenols orally on a high-fat diet for four weeks after being diagnosed with diabetes. Results: PCE constituents were 48.02% carbohydrates, 21.15% protein, 6.16% fiber, 2.06% fat, and 6.93% ash. The evaluation of the PCE was carried out by assessing its retention rates and subsequently comparing the UV data to standards. Total phenols and flavonoids in the crude extract were 23.04 mg/g gallic acid equivalent and 8.14 mg/g quercetin equivalent, respectively. Catechin was found as the significant PC (121.53 µg/mL), while gallic acid was the second PC (11.64 µg/ml) in the PCE of mushrooms. PCE showed high radical scavenging activity on DPPH. With dosage and incubation duration in dark-dependent conditions, it was discovered to be 93.23% at a 500 µg/ml concentration after 120 min in the dark. PCE reduces blood glucose levels while elevating insulin levels and antioxidant activity indicators. Our results show that phenols and their bioactive components can change glucose metabolism in STZ-induced diabetic HFD rats (D2). Conclusions: This study supports PCE's therapeutic potential in treating hyperglycemia, increasing insulin secretion, and addressing diabetes-induced infertility. [ABSTRACT FROM AUTHOR]

Background: Phellinus fastuosus is a wood-eating medicinal fungus from Western Ghats of India. Therefore, we investigated hypoglycemic and hepatoprotective effects of P. fastuosus aqueous extract on streptozotocin-induced diabetic and carbon tetrachloride (CCl4) induced hepatotoxicity in rats, respectively. Result: As compared to the diabetic control group, a 400 mg/kg dose had significant hypoglycemic effects, including a reduction in blood glucose (24.44%) and gain in body weight. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity reduced by 31.81% and 32.84%, respectively, were also noted, along with decreases in triglycerides (24.32%) and cholesterol (25.89%) levels. The albumin, bilirubin and creatinine levels were also significantly reduced after administration of P. fastuosus extract in diabetic rats. Administration of P. fastuosus extract showed a substantial decrease in the activity of ALT, AST, alkaline phosphatase (ALP), catalase (CAT) and superoxide dismutase (SOD) in addition a decrease in the level of lipid peroxidation (LPO) as compared to CCl4-intoxicated rats. The cumulative effect of CCl4 increased the erythrocyte membrane peroxidation, whereas P. fastuosus extract reduced the cholesterol and increased phospholipid, thus preventing the alteration of membrane fluidity as compared to CCl4-intoxicated rats. FTIR and HR-LC-MS-based metabolic profiling revealed the presence of various functional groups and bioactive metabolites. Conclusion: The extract showed the hypoglycemic and hepatoprotective effects due to the presence of various bioactive metabolites. Exploration of therapeutic potential of P. fastuosus using bioassay-guided fractionation is needed. [ABSTRACT FROM AUTHOR]

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE−/− mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE−/− mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the leading cause of dementia worldwide, remains a challenge due to its complex origin and degenerative character. The need for accurate biomarkers and treatment targets hinders early identification and intervention. To fill this gap, we used a novel longitudinal proteome methodology to examine the temporal development of molecular alterations in the cortex of an intracerebroventricular streptozotocin (ICV-STZ)-induced AD mouse model for disease initiation and progression at one, three-, and six-weeks post-treatment. Week 1 revealed metabolic protein downregulation, such as Aldoa and Pgk1. Week 3 showed increased Synapsin-1, and week 6 showed cytoskeletal protein alterations like Vimentin. The biological pathways, upstream regulators, and functional effects of proteome alterations were dissected using advanced bioinformatics methods, including Ingenuity Pathway Analysis (IPA) and machine learning algorithms. We identified Mitochondrial Dysfunction, Synaptic Vesicle Pathway, and Neuroinflammation Signaling as disease-causing pathways. Huntington's Disease Signaling and Synaptogenesis Signaling were stimulated while Glutamate Receptor and Calcium Signaling were repressed. IPA also found molecular connections between PPARGC1B and AGT, which are involved in myelination and possible neoplastic processes, and MTOR and AR, which imply mechanistic involvements beyond neurodegeneration. These results help us comprehend AD's molecular foundation and demonstrate the promise of focused proteomic techniques to uncover new biomarkers and therapeutic targets for AD, enabling personalized medicine. [ABSTRACT FROM AUTHOR]

Mangifera indica (Anacardiaceae family) is renowned for its diverse pharmacological properties, encompassing antidiabetic, antioxidant, and anti-inflammatory effects. The present study delves into the insulin-releasing and glucose-lowering potential of the ethanolic extract of Mangifera indica (EEMI) leaves in streptozotocin-induced type 2 diabetic (STZ-T2D) rats, concurrently investigating its phytoconstituents. EEMI's effects on insulin secretion were measured using BRIN BD11 β-cells and isolated mouse islets. Its enzymatic inhibitory properties on carbohydrate digestion, and absorption, and free radicals were investigated using in vitro methods. In vivo parameters including the lipid profile and liver glycogen content were assessed in STZ-T2D rats. EEMI exhibited a dose-dependent increase in insulin secretion from clonal pancreatic BRIN BD11 β-cells and isolated mouse islets. EEMI inhibited starch digestion, glucose diffusion over time, and DPPH activity in vitro. In acute in vivo studies, EEMI improved food intake and oral glucose tolerance. Moreover, following 28 days of treatment with EEMI, a remarkable amelioration in body weight, fasting blood glucose, plasma insulin, liver glycogen content, total cholesterol, triglyceride, LDL, VLDL, and HDL levels was observed. Further phytochemical analysis with EEMI identified the presence of alkaloids, tannins, saponins, steroids, and flavonoids. The synergistic effects of EEMI, potentially attributable to naturally occurring phytoconstituents, hold promise for the development of enriched antidiabetic therapies, offering a promising avenue for the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the neuroprotective effect of Indole-3-propionic acid (IPA) against streptozotocin (STZ) induced diabetic peripheral neuropathy (DPN) in rats and in high glucose (HG) induced neurotoxicity in neuro2a (N2A) cells. Diabetes was induced in male SD rats STZ (55 mg/kg, i.p.) and IPA (10 and 20 mg/kg, p.o.) was administered for two weeks, starting from sixth week after diabetes induction. Neurobehavioral, functional assessments were made, and various molecular studies were performed to evaluate the effect of IPA on HG induced ER stress and mitochondrial dysfunction in sciatic nerves, DRGs and in N2A cells. Diabetic rats and high glucose exposed N2A cells showed marked increase in oxidative damage accompanied by ER stress and mitochondrial dysfunction along with increased apoptotic markers. IPA treatment for two weeks markedly alleviated these changes and attenuated pain behaviour. IPA exhibited neuroprotective activity against hyperglycaemic insults. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles (moMSCORS) in a murine wound closure model, this study evaluates their potential for preventing type 1 diabetes (T1D) in C57BL/6 mice. T1D was induced in C57BL/6 mice by repeated low doses of streptozotocin. moMSCORS were injected intravenously on weekly basis. moMSCORS reduced T1D incidence, the insulitis stage, and preserved insulin production in treated animals. moMSCORS primarily exerted immunomodulatory effects by inhibiting CD4+ T cell proliferation and activation. Ex vivo analysis indicated that moMSCORS modified the cellular immune profile within pancreatic lymph nodes and pancreatic infiltrates by reducing the numbers of M1 pro-inflammatory macrophages and T helper 17 cells and upscaling the immunosuppressive T regulatory cells. The proportion of pathogenic insulin-specific CD4+ T cells was down-scaled in the lymph nodes, likely via soluble factors. The moMSCORS detected in the pancreatic infiltrates of treated mice presumably exerted the observed suppressive effect on CD4+ through direct contact. moMSCORS alleviated T1D symptoms in the mouse, qualifying as a candidate for therapeutic products by multiple advantages: non-invasive sampling by epilation, easy access, permanent availability, scalability, and benefits of auto-transplantation. [ABSTRACT FROM AUTHOR]

Worldwide spread in the incidence of diabetes justified the need of extensive research in an appropriate model system to develop an effective treatment strategy for diabetology. In recent years, because of animal ethical issues and limitations, the silkworm (Bombyx mori) has emerged as a perfect invertebrate model for various biomedical experiments. However, there are several issues related to induce hyperglycaemia in the mammalian system that have not been studied in the silkworms. In the present study, we investigated the consequences of induced hyperglycaemia by oral and intravascular administration of streptozotocin (STZ) and glucose in the silkworms. Interestingly, results confirmed the competence of STZ to induce hyperglycaemia when administered through intravascular route, but suppress the glucose concentration if administrated orally in the silkworms. Comparatively, the severity of induced hyperglycaemia in the silkworms remained nearly the same in response to the oral and intravascular administration of glucose. Furthermore, prolonged administration of STZ has recorded negative effect on the growth rate of the silkworms, whereas a drastic decline in the same was reported in the silkworms administered with glucose. Notably, these results confirm that the response shown by the silkworms to STZ is very similar to that of mammals, making it an excellent model to study diabetic complications and consequences associated with STZ in diabetology. [ABSTRACT FROM AUTHOR]

Background: Peripheral insulin resistance and compromised insulin secretion from pancreatic β-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κβ/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic β-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic β-cell functioning. Methods: AGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κβ/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II). Results: AGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic β-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic β-cells. Conclusion: The current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic β-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in β-cell mass by mitigating the apoptosis of pancreatic β-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM). [ABSTRACT FROM AUTHOR]

Scutellariabarbata D. Don (S. barbata), a medicinal herb commonly used in traditional Chinese and Korean medicine, consists of bioactive neoclerodanes and flavonoids. However, its anti-hyperglycemic activity has not been reported. In this work, we used bioassay-guided fractionation to find effective anti-hyperglycemic fractions of S. barbata. The chemical components of these fractions were also determined structurally; they are scutellarin (1), luteolin (2), naringenin (3), tricin (4), baicalein (5), baicalin (6), apigenin (7), and wogonin (8). The most potent fraction SB6 consisting of flavonoids 5, 6, 7, and 8 showed 89% inhibition of α-glucosidase in the in vitro experiment. In further in vivo experiments on streptozotocin (STZ)-induced diabetic mice, SB6 exhibited significant anti-hyperglycemic activity comparable to metformin after 28 days of treatment. This fraction, however, did not show efficiency in reducing the weight gain of the treated mice. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS. Methods: We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE−/−) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay. Results: miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs. Conclusion: These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1. [ABSTRACT FROM AUTHOR]

The elemental composition of chemical elements can vary between healthy and diseased tissues, providing essential insights into metabolic processes in physiological and diseased states. This study aimed to evaluate the calcium (Ca) and phosphorus (P) levels in the bones of rats with/without streptozotocin-induced diabetes and/or exposure to infrasound. X-ray fluorescence spectroscopy was used to determine the concentrations of Ca and P in Wistar rat tibiae samples. The results showed a significant decrease in bone P concentration in streptozotocin-induced diabetic rats compared to untreated animals. Similarly, the Ca/P ratio was higher in the streptozotocin-induced diabetic group. No significant differences were observed in bone Ca concentration between the studied groups or between animals exposed and not exposed to infrasound. Moreover, streptozotocin-induced diabetic rats had lower bone P concentration but unaltered bone Ca concentration compared to untreated rats. Infrasound exposure did not impact bone Ca or P levels. The reduced bone P concentration may be associated with an increased risk of bone fractures in diabetes. [ABSTRACT FROM AUTHOR]

Long-term diabetes often leads to chronic wounds refractory to treatment. Cell-based therapies are actively investigated to enhance cutaneous healing. Various cell types are available to produce biological dressings, such as adipose-derived stem/stromal cells (ASCs), an attractive cell source considering their abundancy, accessibility, and therapeutic secretome. In this study, we produced human ASC-based dressings under a serum-free culture system using the self-assembly approach of tissue engineering. The dressings were applied every 4 days to full-thickness 8-mm splinted skin wounds created on the back of polygenic diabetic NONcNZO10/LtJ mice and streptozotocin-induced diabetic K14-H2B-GFP mice. Global wound closure kinetics evaluated macroscopically showed accelerated wound closure in both murine models, especially for NONcNZO10/LtJ; the treated group reaching 98.7% ± 2.3% global closure compared to 76.4% ± 11.8% for the untreated group on day 20 (p = 0.0002). Histological analyses revealed that treated wounds exhibited healed skin of better quality with a well-differentiated epidermis and a more organized, homogeneous, and 1.6-fold thicker granulation tissue. Neovascularization, assessed by CD31 labeling, was 2.5-fold higher for the NONcNZO10/LtJ treated wounds. We thus describe the beneficial impact on wound healing of biologically active ASC-based dressings produced under an entirely serum-free production system facilitating clinical translation. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a growing metabolic disease that is characterized by high blood sugar levels with life-threatening results. Diabetic wounds are a major problem because they do not resolve in few days. Major problems affecting wound healing are infection, age, stress, etc. at the wound site, and other associated disease conditions. Lycopene is a red pigment obtained from various fruits such as tomatoes, watermelon, and guava. It is a powerful antioxidant that scavenges reactive oxygen species and potential as nutraceuticals. It has reported antidiabetic, antioxidant, anti-obesity, anti-inflammatory, antihyperglycemic, and antiaging activities based on the literature. Objective: The objective of the current study is to find the wound-healing potential of lycopene emulgel (LE) and report the properties of the compound. Methods: Wound healing activity was assessed in Streptozotocin induced diabetic rats and control rats. Streptozotocin injection (55 mg/kg) was used to induce marked hyperglycaemia, compared with controls. The formulation was applied topically and was evaluated for efficacy. Results: Treatment of rats with lycopene emulgel (LE) topical application exhibited a significant reduction of wound closure of 95.3 and 88.9% and epithelisation within 21 days. Conclusion: The formulation was found to be novel, safe, and effective in the functional recovery of wounds. [ABSTRACT FROM AUTHOR]

Background: The in vivo assessment of a novel compound is a pivotal step in the development of a new drug. In this study, we selected 1-(2-bromophenyl)-1,11-dihydro-3H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H)-dione (2-BDBPQD), identified as an exemplary α-glucosidase inhibitor in preliminary in vitro assays, for further evaluation in an in vivo anti-diabetic context. Methods: The in vivo anti-diabetic effect of 2-BDBPQD was assessed using a streptozotocin (STZ)-induced diabetic Wistar rat model. Recognizing the relevance of lipid factors in diabetes, we also investigated the impact of this compound on the lipid profile of diabetic Wistar rats. In silico studies, encompassing docking studies and pharmacokinetic predictions of 2-BDBPQD, were conducted. Results: The results obtained indicated a significant reduction in blood glucose levels with 2-BDBPQD treatment compared to acarbose. However, no significant effects on the lipid profile were observed. In silico studies revealed that 2-BDBPQD interacted with key residues in the α-glucosidase active site and exhibited favorable pharmacokinetic properties. Conclusion: In summary, the study demonstrated the in vivo anti-hyperglycemic activity of 2-BDBPQD. Nevertheless, further in vivo evaluations are recommended to comprehensively assess its potential as a new drug for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Background: The discovery of novel diagnostic methods and therapies for Alzheimer's disease (AD) faces significant challenges. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate Apelin-13's mechanism of action in an in vivo model of AD induced by streptozocin (STZ). Methods: We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests, primarily, behavioral assessment, histological analysis, and biochemical assays, in order to evaluate synaptic plasticity and oxidative stress signaling pathways. Results: Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated by the enhancement of synaptic plasticity and the attenuation of oxidative stress signaling pathways. Conclusions: The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions. [ABSTRACT FROM AUTHOR]

Background: Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear. Methods: Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R. Results: Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation. Conclusions: These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes. [ABSTRACT FROM AUTHOR]

The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-β deposition, glycogen synthase kinase 3 beta (GSK3β), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3β/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 μg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3β/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms. [ABSTRACT FROM AUTHOR]

The present research studied the cytotoxicity, antioxidant, and antidiabetic activities of biogenically synthesized silver nanoparticles (AgNPs) using Ziziphora clinopodioides (Z. clinopodioides) as a green mediator. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and ultraviolet–visible spectroscopy (UV–Vis) were employed to determine AgNPs. In the in vivo experiment, the model rats were categorized into different groups receiving 50, 100, 200, and 400 μg/kg of AgNPs and diabetic, positive, and normal groups (n = 10) using a random division. A single dose of streptozotocin (STZ) at 60 mg/kg was administered to induce diabetes and hepatotoxicity in rats. The administration of AgNPs was performed via intragastric administration for 25 days. On the final day, the levels of glucose and biochemical enzymes, namely aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine transaminase (ALT), and gamma‐glutamyltransferase (GGT), were assessed in the serum. Following tissue processing, liver sections with a thickness of 5 μm were prepared. Later, the total volume of different liver components, such as hepatocytes, sinusoids, portal vein, central vein, hepatic arteries, and bile ducts, was measured. The portal vein and bile duct volumes did not vary significantly in groups treated by AgNPs. However, the volume of the central vein and hepatic arteries exhibited noticeable variations in groups treated by AgNPs. After administration of streptozotocin, the volume of hepatocytes and sinusoids increased significantly. However, treatment with a high dose of AgNPs significantly decreased the volume of hepatocytes and sinusoids. In diabetic rats, administering AgNPs reduced the fasting blood glucose levels compared to the model group. In addition, AgNPs decreased the elevated levels of AST and ALP enzymes in a manner that depended on the dosage of AgNPs used. This research demonstrates the hepatoprotective and antidiabetic properties of AgNPs, suggesting their potential implications as hepatoprotective and antidiabetic supplements to prevent diabetes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is causing serious health problems in the chronic period. Silibinin is a flavonoid obtained from the milk thistle (Silybum marianum), which is among the herbal ethnopharmacological administrations. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia‐reducing effect. However, behavioral parameters have not been evaluated together with insulin levels and liver function tests. Our aim in this study was to examine the effects of silibinin on insulin secretion, anxiety‐like behaviors, and learning in a streptozotocin (STZ)‐induced rat diabetes model. Wistar albino rats weighing 200–250 g were divided into 4 groups. Control: Saline solution, Diabetes: STZ 45 mg/kg, S 100: STZ 45 mg/kg + Silibinin 100 mg/kg, S 200: STZ 45 mg/kg + Silibinin 200 mg/kg. Administrations were continued for 21 days. On the 21st day, open field and elevated plus maze as unconditional anxiety tests; Barnes maze for learning and memory; and rotarod test for locomotor activity were conducted. Following behavioral tests, blood samples were taken under anesthesia. Blood glucose levels and ALT values were measured. Insulin levels were measured with an ELISA plate reader. Silibinin shortened the time to find the correct hole. Silibinin prevented the decrease in insulin due to STZ, exhibited a hyperglycemia‐reducing effect and decreased the elevation of ALT. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-β-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD. [ABSTRACT FROM AUTHOR]

Background and objective: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. Methods: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. Results: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). Conclusion: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways. [ABSTRACT FROM AUTHOR]

It is known that many diabetic patients experience testicular atrophy. This study sought to investigate the effect of 4-hexylresorcinol (4HR) on testicular function in rats with streptozotocin (STZ)-induced diabetes, focusing on testicular weight, sperm motility, histological alterations, and serum testosterone levels to understand the efficacy of 4HR on testes. Our findings reveal that 4HR treatment significantly improves testicular health in diabetic rats. Notably, the STZ group exhibited a testicular weight of 1.22 ± 0.48 g, whereas the STZ/4HR group showed a significantly enhanced weight of 1.91 ± 0.26 g (p < 0.001), aligning closely with the control group's weight of 1.99 ± 0.17 g and the 4HR group's weight of 2.05 ± 0.24 g, indicating no significant difference between control and 4HR groups (p > 0.05). Furthermore, the STZ/4HR group demonstrated significantly improved sperm motility compared to the STZ group, with apoptotic indicators notably reduced in the STZ/4HR group relative to the STZ group (p < 0.05). These results underscore the therapeutic potential of 4HR for maintaining testicular function under diabetic conditions. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) in human patients disrupts glucose metabolism post-pregnancy, affecting fetal development. Although obesity and genetic factors increase GDM risk, a lack of suitable models impedes a comprehensive understanding of its pathology. To address this, we administered streptozotocin (STZ, 75 mg/kg) to C57BL/6N mice for two days before pregnancy, establishing a convenient GDM model. Pregnant mice exposed to STZ (STZ-pregnant) were compared with STZ-injected virgin mice (STZ-virgin), citrate buffer-injected virgin mice (CB-virgin), and pregnant mice injected with citrate buffer (CB-pregnant). STZ-pregnant non-obese mice exhibited elevated blood glucose levels on gestational day 15.5 and impaired glucose tolerance. They also showed fewer normal fetuses compared to CB-pregnant mice. Additionally, STZ-pregnant mice had the highest plasma C-peptide levels, with decreased pancreatic islets or increased alpha cells compared to CB-pregnant mice. Kidneys isolated from STZ-pregnant mice did not display histological alterations or changes in gene expression for the principal glucose transporters (GLUT2 and SGLT2) and renal injury-associated markers. Notably, STZ-pregnant mice displayed decreased gene expression of insulin-receiving molecules (ISNR and IGFR1), indicating heightened insulin resistance. Liver histology in STZ-pregnant mice remained unchanged except for a pregnancy-related increase in lipid droplets within hepatocytes. Furthermore, the duodenum of STZ-pregnant mice exhibited increased gene expression of ligand-degradable IGFR2 and decreased expression of GLUT5 and GLUT12 (fructose and glucose transporters, respectively) compared to STZ-virgin mice. Thus, STZ-pregnant mice displayed GDM-like symptoms, including fetal abnormalities, while organs adapted to impaired glucose metabolism by altering glucose transport and insulin reception without histopathological changes. STZ-pregnant mice offer a novel model for studying mild onset non-obese GDM and species-specific differences in GDM features between humans and animals. [ABSTRACT FROM AUTHOR]

Evidence suggests that insulin resistance plays an important role in developing diabetes complications. The association between insulin resistance and pain perception is less well understood. This study aimed to investigate the effects of peripheral insulin deficiency on pain pathways in the brain. Diabetes was induced in 60 male rats with streptozotocin (STZ). Insulin was injected into the left ventricle of the brain by intracerebroventricular (ICV) injection, then pain was induced by subcutaneous injection of 2.5% formalin. Samples were collected at 4 weeks after STZ injection. Dopamine (DA), serotonin, reactive oxygen species (ROS), and mitochondrial glutathione (mGSH) were measured by ELISA, and gene factors were assessed by RT‐qPCR. In diabetic rats, the levels of DA, serotonin, and mGSH decreased in the nuclei of the thalamus, raphe magnus, and periaqueductal gray, and the levels of ROS increased. In addition, the levels of expression of the neuron‐specific enolase and receptor for advanced glycation end genes increased, but the expression of glial fibrillary acidic protein expression was reduced. These results support the findings that insulin has an analgesic effect in non‐diabetic rats, as demonstrated by the formalin test. ICV injection of insulin reduces pain sensation, but this was not observed in diabetic rats, which may be due to cell damage ameliorated by insulin. [ABSTRACT FROM AUTHOR]

A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute to a variety of essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models. Both CRV431 and NV556 inhibit several cyclophilin isoforms, among which cyclophilin D (CypD) has not been previously investigated in this context. It is unknown whether it is necessary to simultaneously inhibit multiple cyclophilin family members to achieve therapeutic benefits or if loss-of-function of one is sufficient. Furthermore, narrowing down the isoform most responsible for a particular aspect of NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow for more precise future therapies. Features of human diabetes-linked NAFLD/NASH can be reliably replicated in mice by administering a single high dose of streptozotocin to disrupt pancreatic beta cells, in conjunction with a high sugar, high fat, high cholesterol western diet over the course of 30 weeks. Here we show that while both wild-type (WT) and Ppif-/- CypD KO mice develop multipe severe NASH disease features under this model, the formation of HCC nodules was significantly blunted only in the CypD KO mice. Furthermore, of differentially expressed transcripts in a qPCR panel of select HCC-related genes, nearly all were downregulated in the CypD KO background. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Type 1 diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to insulin insufficiency as a consequence of the pancreatic β-cells' auto-immune attack. A potential novel remedy, counting on using mesenchymal stem cell (MSC)-derived exosomes loaded with an antioxidant known for its insulin-mimetic effect like selenium could be useful to address this condition and its related complications. The results indicated a hypoglycemic and antiapoptotic superiority for nano selenium-loaded exosomes rather than elemental selenium. Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterized by hyperglycemia due to insulin insufficiency as a consequence of the pancreatic β-cells' auto-immune attack. Nowadays, the application of mesenchymal stem cell-derived exosomes (MSCs-Exs) as the main cell-free therapy for diabetes treatment is becoming more and more extensive. In non-autologous therapy, researchers are moving towards a new strategy based on loading MSC-Exs with certain drugs, aimed at maintaining and maximizing the function of exosomes at the function site and enhancing their efficiency and safety. This study aims to explore and compare the therapeutic potentialities of mesenchymal stem cell-derived exosomes (MSCs-Exs) loaded with either selenium (Se) or nano selenium (NSe), a natural antioxidant micronutrient, in the management of T1DM in rats. In our 4-week experiment, six rat groups were included, namely, control, Ex+Se, Ex+NSe, STZ-diabetic (D), D+ Ex+Se, and D+Ex+NSe groups. Both diabetic-treated groups showed marked pancreatic regenerative antioxidant, immunomodulatory, anti-inflammatory, and anti-apoptotic capacities, with the D+Ex+NSe injection showing superiority in managing diabetes hazards, as evidenced by various biochemical and histological assessments. [ABSTRACT FROM AUTHOR]

A diabetic‐induced ulcer is a complication of diabetes in which the formation of an ulcer increases and also causes a delay in ulcer healing. Diabetes adds a bonus to various factors like starvation and stress, imbalanced acid‐pepsin secretions, impaired mucosal resistance, acid‐back diffusion, and neuronal dysfunction. Feeding a high‐fat diet for 15 days after induction of STZ in rats develops diabetes mellitus simultaneously with growth, resulting in an acceleration of ulcers for any of the above reasons. The OGTT investigation included both normal and diabetic rats, and the researchers establish a consistently low dosage of conventional oral hypoglycemic agents for the treatment. Clinical studies in the literature highlight that effectively treating patients with diabetes complications has been demonstrated through glycemic control. Hence, effective palliative hypoglycemic agents are employed. Long‐term usage has revealed that they exert a drastic negative effect. Hence, herbal drug combinations with these standard drugs have proved to be effective in minimizing the side effects. QE, which has hypoglycemic, dyslipidemia, and antioxidant properties, has been effective when administered with Glipizide (5 mg kg−1). The monotherapy of this Glipizide and QE has not shown a beneficial effect in protecting the stomach from ulcers. The combination (G + QE) showed effective control of glucose without any hypoglycemia. QE as a single adjunct with Glipizide has proven promising in preventing and treating diabetic ulcers. [ABSTRACT FROM AUTHOR]

Aerva lanata is known as Pashanabheda, a traditional plant used as an anti-calculus, hepatoprotective, anthelmintic, anti-diarrhoeal, and anti-diabetic. In the current investigation, the methanolic extract of Aerva lanata was assessed for its anti-diabetic effect in a streptozotocin-nicotinamide and dexamethasone-induced rodent model. The extract significantly lowered the blood sugar level in streptozotocin-nicotinamide-induced diabetic and glucose-loaded rats. The study showed a substantial decrease in serum total cholesterol, triglycerides, and low and very low-density lipoproteins while increasing the high-density lipoproteins significantly. Histopathology of the pancreas showed mild degenerative changes and revitalization of beta cells. Insulin and fasting blood sugar levels were significantly lowered in diabetic animals, induced by dexamethasone. The extract also effectively prevented dexamethasone-induced insulin resistance and demonstrated increased insulin sensitivity after 12 days of treatment. The extract also resulted in efficient inhibition of carbohydrase enzymes, a-glucosidase and a-amylase, in vitro. The above outcomes suggest that the flowers and stems of Aerva lanata have a potential anti-diabetic effect. [ABSTRACT FROM AUTHOR]

Coleus atropurpureus Benth leaves are traditionally used in Central Sulawesi, Indonesia to treat diabetes mellitus. This study aims to determine the secondary metabolite levels of the ethanol extract of C. atropurpureus leaves, its antioxidant activity, and its effect on blood glucose levels in Streptozotocin-induced diabetic rats. Extract phytochemical screening was carried out qualitatively according to standard methods. Quantitative analysis of flavonoids, saponins, tannins, and alkaloids by UV-Vis Spectrophotometry. The DPPH method was used to determine antioxidant activity. Diabetic rats were treated with ethanol extract of C. atropurpureus leaves at doses of 150, 200, and 250 mg/kg BW for 28 days, then their blood sugar levels were calculated. The ethanol extract of C. atropurpureus leaves showed antioxidant activity (IC50) 56.96 µg/mL. The 250 mg/kg BW dose group significantly reduced blood glucose levels. It can be concluded that the ethanol extract of C. atropurpureus leaves has the potential as a source of antidiabetic. [ABSTRACT FROM AUTHOR]

Diabetes is a worldwide leading cause of mortality and morbidity, and type 1 diabetes (T1D) is the most common chronic autoimmune disorder in children and young adults. There is currently no definitive treatment for T1D. Stem cell administration appeared as an experimental treatment showing an improvement in the clinical outcome and restoration of tissue architecture in many disorders. Mesenchymal stem cells (MSCs) showed their capacity to generate insulin-producing cells as a promising potential treatment for diabetic patients. The present work aimed to study the effect of MSCs on the ultrastructure and laboratory findings of streptozotocin (STZ)-induced T1D in rats. Sixty male albino rats were divided into three groups: group I (control), group II (STZ-induced diabetic), and group III (STZ-induced diabetic-treated with MSCs). Ultrastructure study, as well as glucose and insulin measurements, was done for the three groups. The diabetic group showed significantly higher glucose and lower insulin levels compared to the other two groups, while the diabetic group treated with MSCs showed a non-significant difference compared to the control group. On the ultrastructure level, the diabetic group showed nuclear degeneration, loss of cytoplasmic organelles, loss of cell membranes, pyknotic nuclei, and apoptosis. All these findings were mostly reversed by the use of MSCs in the diabetic-treated group. We conclude that the use of MSCs reversed the laboratory and ultrastructure effect of STZ-induced T1D in rats. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a prominent cause of dementia, resulting in neurodegeneration and memory impairment. This condition imposes a considerable public health burden on both patients and their families due to the patients' functional impairments as well as the psychological and financial constraints. It has been well demonstrated that its aetiology involves proteinopathy, mitochondriopathies, and enhanced reactive oxygen species (ROS) generation, which are some of the key features of AD brains that further result in oxidative stress, excitotoxicity, autophagy, and mitochondrial dysfunction. Objective: The current investigation was created with the aim of elucidating the neurological defence mechanism of trans,trans-Farnesol (TF) against intracerebroventricular-streptozotocin (ICV-STZ)-induced Alzheimer-like symptoms and related pathologies in rodents. Materials and methods: The current investigation involved male SD rats receiving TF (25–100 mg/kg, per oral) consecutively for 21 days in ICV-STZ-treated animals. An in silico study was carried out to explore the possible interaction between TF and NADH dehydrogenase and succinate dehydrogenase. Further, various behavioural (Morris water maze and novel object recognition test), biochemical (oxidants and anti-oxidant markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), pro-inflammatory (tumor necrosis factor-alpha; TNF-α) levels, and histopathological studies were evaluated in specific brain regions. Results: Rats administered ICV-STZ followed by treatment with TF (25, 50, and 100 mg/kg) for 21 days had significantly better mental performance (reduced escape latency to access platform, extended time spent in target quadrant, and improved differential index) in the Morris water maze test and new object recognition test models when compared to control (ICV-STZ)-treated groups. Further, TF treatment significantly restored redox proportion, anti-oxidant levels, regained mitochondrial capacities, attenuated altered AChE action, levels of TNF-α, and histopathological alterations in certain brain regions in comparison with control. In in silico analysis, TF caused greater interaction with NADH dehydrogenase and succinate dehydrogenase. Conclusion: The current work demonstrates the neuroprotective ability of TF in an experimental model with AD-like pathologies. The study further suggests that the neuroprotective impacts of TF may be related to its effects on TNF-α levels, oxidative stress pathways, and mitochondrial complex capabilities. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. Methods: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. Results: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. Conclusion: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2′MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2′-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2′-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2′-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2′-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2′-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2β2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2′-MeO6MF. [ABSTRACT FROM AUTHOR]

The production of nanoparticles enhances the bioactivity of biological molecules for drug delivery to diseased sites. This study explains how silver nanoparticle (AgNP) coating enhanced the protection effects of vanillic acid in male diabetic rats with streptozotocin- (STZ-) induced diabetes. Twenty-four rats were divided into four groups (n = 6) for this investigation. The first group (G1) is untreated, whereas diabetes was induced in the other three groups through STZ injection. Diabetic rats that were not getting therapy were included in the second group (G2, STZ-positive), whereas the other diabetic rats were divided into the third group (G3, vanillic acid-treated) and the fourth group (G4, vanillic acid-coated AgNPs treated). The treatment lasted four weeks. In G2, the induction of diabetes significantly (at P = 0.05) increased in serum glucose, glycated proteins, renal indices, interleukin-6 (IL-6), K+, immunoglobulins, and lipid peroxidation, while decreased Ca++, Na+, and other antioxidants in the kidney tissue homogenate. In addition, pathological altered signs were present in the pancreas and kidneys of diabetic rats. The renal and pancreatic tissues were effectively enhanced by vanillic acid or vanillic acid-coated AgNPs, bringing them very close to their prediabetic conditions. Vanillic acid-coated AgNPs offered a stronger defense against STZ-induced diabetes and lessened the effects of hyperglycemia compared to ordinary vanillic acid. Additionally, using vanillic acid coated with silver nanoparticles greatly increased the antioxidant and antidiabetic activity and reduced inflammation when compared to using vanillic acid alone. [ABSTRACT FROM AUTHOR]

Background: Streptozotocin (STZ) is a glucose analogue commonly used for inducing diabetes in experimental animals. This study is intended to investigate the ability of captopril (Cap) pretreatment to augment STZ-induced diabetogenic effect in an experimental rat model. If this hypothesis were proven, Cap administration to rats could reduce the dosage of STZ by augmenting its effect and resulting in a subsequent reduction in STZ cost. Forty-two adult male Wistar rats were randomly divided into seven groups: a control group that fed a normal diet, whereas the other six experimental groups were fed a high-fat diet (HFD). The six groups were then divided into STZ-30, STZ-30-Cap, STZ-40, STZ-40-Cap, STZ-50, and STZ-50-Cap. All Cap-received groups were supplemented with 50 mg/kg Cap orally one hour just before intraperitoneal (I.P.) injection of STZ. 30-STZ, 40-STZ, and 50-STZ-treated groups were injected once with STZ I.P. at doses of 30, 40, and 50 mg/kg, respectively. An intraperitoneal glucose tolerance test (IPGTT) was done. Pancreatic tissue was obtained to measure Tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1β), and nitric oxide (NO) by enzyme-linked immunosorbent assay (ELISA) and glucose transporter 2 (GLUT2) gene expression by reverse transcription polymerase chain reaction (RT-PCR). Pancreatic sections were examined by hematoxylin and eosin (H&E) stain, and immunohistochemical staining by anti-insulin and anti-TNF-α antibodies. Results: Results indicated that administration of Cap before STZ in different doses significantly augmented the hyperglycemic state that was evident by intraperitoneal glucose tolerance test, and markedly increased pancreatic pro-inflammatory markers. Histological analysis of islets of Langerhans indicated degeneration with extensive vacuolations associated with a significant decrease in mean area % of insulin immunoreactivity and an increase in optical density of TNF-α immunoreactivity. Conclusion: These findings pointed to the ability of captopril pretreatment to augment the hyperglycemic state and the diabetogenic response that was induced secondary to STZ injection in an experimental rat model. [ABSTRACT FROM AUTHOR]

SznF, a member of the emerging family of heme‐oxygenase‐like (HO‐like) di‐iron oxidases and oxygenases, employs two distinct domains to catalyze the conversion of Nω‐methyl‐L‐arginine (L‐NMA) into N‐nitroso‐containing product, which can subsequently be transformed into streptozotocin. Using unrestricted density functional theory (UDFT) with the hybrid functional B3LYP, we have mechanistically investigated the two sequential hydroxylations of L‐NMA catalyzed by SznF's binuclear iron central domain. Mechanism B primarily involves the O−O bond dissociation, forming Fe(IV)=O, induced by the H+/e− introduction to the FeA side of μ‐1,2‐peroxo‐Fe2(III/III), the substrate hydrogen abstraction by Fe(IV)=O, and the hydroxyl rebound to the substrate N radical. The stochastic addition of H+/e− to the FeB side (mechanism C) can transition to mechanism B, thereby preventing enzyme deactivation. Two other competing mechanisms, involving the direct O−O bond dissociation (mechanism A) and the addition of H2O as a co‐substrate (mechanism D), have been ruled out. [ABSTRACT FROM AUTHOR]

Background: The current investigation aimed to develop, optimise, and assess a mupirocin-loaded nanosponge-based topical delivery system for diabetic foot ulcer and to achieve prolonged drug release while improving drug deposition within the skin. The nanosponges carrying mupirocin were formulated using the emulsion solvent diffusion method. A 32 factorial design was utilised to investigate effect of two factors, specifically the concentration of ethyl cellulose and the stirring rate, on the physical attributes of the nanosponges. The optimised nanosponge formulation batch (F9) was subsequently incorporated into a Carbopol gel base, ensuring the desired physical attributes were achieved in the gel formulation containing nanosponges. The research included in vitro drug release evaluation, ex vivo drug deposition analysis, assessment of the antimicrobial action of the nanosponge formulation, and in vivo diabetic wound healing. Results: Drug polymer compatibility analysis was conducted using FT-IR spectroscopy revealed no interactions among mupirocin and ethyl cellulose molecules. Further FT-IR spectroscopy, DSC spectroscopy, and XRD spectroscopy analysis of optimised formulation batch revealed that the drug was successfully entrapped in nanosponges. Scanning electron microscopy confirmed the spherical and porous nature of the prepared nanosponges. The drug release pattern across the cellulose dialysis membrane followed a diffusion-controlled release pattern, and the drug deposition analysis exhibited substantial retention of mupirocin in the skin from the nanosponges formulation for up to 24 h. Furthermore, the optimised nanosponges gel formulation demonstrated stability and non-irritant properties, as indicated by the HET-CAM test. In vivo evaluation of wound healing activity in a Streptozotocin-induced diabetes mellitus with excision wound model revealed significant actions pertaining to wound healing and closure after 16 days of treatment. Conclusion: The mupirocin-loaded nanosponge gel contributed to remarkable and swift recovery and closure of wounds in diabetic rats. The nanosponges, acting as carriers for mupirocin, facilitated the effective delivery of the drug to the wound area, while the gel fostered an optimally humid environment conducive to wound care during the final stages of wound healing and sealing. [ABSTRACT FROM AUTHOR]

Purpose: Dapagliflozin exerts cardioprotective effects in Type 2 Diabetes Mellitus (T2DM). However, whether these effects prevent electrocardiographic changes associated with T2DM altogether remain unknown. Our aim was to investigate the prophylactic effect of dapagliflozin pretreatment on the rat ECG using a high-fat, high-fructose (HFHf) diet and a low dose streptozotocin (STZ) model of T2DM. Methods: Twenty-five (25) rats were randomized into five (5) groups: normal control receiving a normal diet while the other groups received an 8-week HFHf and 40mg/kg STZ on day 42, and either: saline for the diabetic control (1 mg/kg/d), low dose (1.0 mg/kg/d) and high dose dapagliflozin (1.6 mg/kg/d), or metformin (250 mg/kg/d). Oral glucose tolerance (OGT), electrocardiograms (ECGs), paracardial adipose mass, and left ventricular fibrosis were determined. Data were analyzed using GraphPad version 9.0.0.121, with the level of significance at p < 0.05. Results: Compared to the diabetic control group, a high dose of dapagliflozin preserved the OGT (p = 0.0001), QRS-duration (p = 0.0263), QT-interval (p = 0.0399), and QTc intervals (p = 0.0463). Furthermore, the high dose dapagliflozin group had the lowest paracardial adipose mass (p = 0.0104) and fibrotic area (p = 0.0001). In contrast, while metformin showed favorable effects on OGT (p = 0.0025), paracardial adiposity (p = 0.0153) and ventricular fibrosis (p = 0.0291), it did not demonstrate significant antiarrhythmic effects. Conclusion: Pretreatment with higher doses of Dapagliflozin exhibits prophylactic cardioprotective characteristics against diabetic cardiomyopathy that include antifibrotic and antiarrhythmic qualities. This suggests that higher doses of dapagliflozin could be a more effective initial therapeutic option in T2DM. [ABSTRACT FROM AUTHOR]

Background and Objectives: Diabetes mellitus (DM), is a metabolic disorder coupled with osteoporosis and elevated risk of bone fracture. This work aimed to clarify the impact of diabetes mellitus on bone remodeling changes and to study the role of vitamin D supplementation and mesenchymal stem cells (BM-MSCs) in decreasing bone remodeling changes in type II DM. Material and Methods: 30 adult male albino rats were classified into the control group (n-6) and the main experimental group (n=24). All rats in experimental group were given high fat diet and a single injection of streptozotocin (STZ) (45 mg/kg) intraperitoneally (IP) then after 8 weeks they were divided into; Type II DM group; continued without treatment, Type II DM +vitamin D group; received vitamin D orally daily, Type II DM +BM-MSCs group; received a once intravenous injection of 3 × 106 BM-MSCs and Combined treated group; treated with combined BM-MSCs and vitamin D. At the end of the experiment, Blood samples were drawn to measure glucose level, reactive Oxygen species (ROS), lipid profile (FFA), and tumor necrosis factor (TNF-α.). Femur bone was dissected for biochemical, histological, immunohistochemical, morphometric, and statistical analysis. Results: Mean serum levels of glucose, triglycerides, total cholesterol (TCH), ROS & TNF-α were significantly increased and associated with a significant decrease of HDL & FFA levels in Type II DM, Type II DM +vitamin D and Type II DM +BM-MSCs groups. In addition, the levels of Wnt/b-catenin and BCL2 were significantly decreased, while sclerostin and BAX, and the area percentage of VEGF were increased, in Type II DM, Type II DM +vitamin D and Type II DM +BMMSCs groups. Vitamin D and BM-MSCs encountered significant amelioration in biochemical markers and histological & immunohistochemical changes induced by STZ with a more obvious improvement in the combined treated group. Conclusion: Combined treatment of vitamin D and BM-MSCs significantly improved diabetic bone turnover compared to both vit. D, and MSCs injection alone by alleviating the antioxidative and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic retinopathy is a neurodegenerative, microvascular, and sight-threatening impact of chronic uncontrolled diabetes. Avocado/soybean (ASB), a relatively new nutraceutical mixture, has acquired a significant role as a natural substitutional therapy for numerous diseases. Glibenclamide (Gli), a potent sulfonylurea, was confirmed as a diabetic therapy. Aim of the Study: To explore the protective effects of ASB versus glibenclamide on the diabetic rats' retina induced by streptozotocin (STZ). Materials and Methods: Forty rats were categorized into four groups: Normal control, Diabetic Control, Diabetes+Avocado soybean, and Diabetes+Glibenclamide. Retinal specimens were processed for histological, immunohistochemical, ultrastructural studies. Morphometrical and statistical studies were also performed. Results: Diabetic retinal specimens demonstrated evident disorganization of the retinal layers, degenerated retinal pigment epithelium, photoreceptors, and outer nuclear layers with appearance of empty spaces and multiple vacuolations. Most of ganglion cells were lost, others appeared with pycnotic nuclei. Together with a highly significant decrease (P< 0.001) of the total thickness, and the thickness of the outer and inner nuclear layers of the rats' retina, and the number of the ganglion cells. Immune expression of TNF-α, VEGF, caspase-3, and vimentin illustrated a highly significant elevation (P< 0.001). Ultrastructural findings of retinal pigmented cell layer illustrated; swollen degenerated mitochondria with cytoplasmic vacuolation. Degenerated photoreceptors, ganglion cells have indented irregular nucleus, destructed nuclear membrane, and vacuolated cytoplasm. ASB amends the diabetic retinopathy changes, structurally and immunohistochemically, more than glibenclamide Conclusion: ASB has a more, retinal-protective efficacy on DR, than glibenclamide. [ABSTRACT FROM AUTHOR]

Depression and diabetes are closely linked; however, the pathogenesis of depression associated with diabetes is unclear, and there are no clinically effective antidepressant drugs for diabetic patients with depression. Bavachin is an important active ingredient in Fructus Psoraleae. In this study, we evaluated the anti-neuroinflammatory and antidepressant effects associated with diabetes and the molecular mechanisms of bavachin in a streptozotocin-induced diabetes mouse model. We found that bavachin clearly decreased streptozotocin (STZ)-induced depressive-like behaviors in mice. It was further found that bavachin significantly inhibited microglia activation and the phosphorylation level of PKCδ and inhibited the activation of the NF-κB pathway in vivo and in vitro. Knockdown of PKCδ with siRNA-PKCδ partially reversed the inhibitory effect of bavachin on the NF-κB pathway and the level of pro-inflammatory factors. We further found that PKCδ directly bound to bavachin based on molecular docking and pull-down assays. We also found that bavachin improved neuroinflammation-induced neuronal survival and functional impairment and that this effect may be related to activation of the ERK and Akt pathways mediated by the BDNF pathway. Taken together, these data suggested that bavachin, by targeting inhibition PKCδ to inhibit the NF-κB pathway, further reduced the inflammatory response and oxidative stress and subsequently improved diabetic neuronal survival and function and finally ameliorated diabetes-induced depressive-like behaviors in mice. For the first time, we found that bavachin is a potential agent for the treatment of diabetes-associated neuroinflammation and depression and that PKCδ is a potential target for the treatment of diabetes-associated neuroinflammation, including depression. [Display omitted] • Bavachin clearly decreased STZ-induced depressive-like behaviors in mice. • Bavachin clearly decreased STZ-induced neuroinflammation in mice. • Bavachin significantly inhibited the activation of PKCδ and NF-κB pathway. • Bavachin directly bound and inhibited the activation of PKCδ. • PKCδ played an important role in the inhibitory effect of bavachin on the activation of the NF-κB pathway. [ABSTRACT FROM AUTHOR]

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 μg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM. [ABSTRACT FROM AUTHOR]

The chronic metabolic disease known as diabetes mellitus causes hyperglycemia in the body. Antioxidant and antidiabetic qualities are well-known benefits of Hibiscus rosa sinensis (HRS). In this work, diabetic Wistar albino rats were used to assess the antidiabetic properties of HRS flower extract. A total of 18 animals were taken and divided into three groups (n = 6) - (Group 1): Normal control group, (Group 2): Diabetic control group, (Group 3): Diabetic group treated with a 125 mg/kg dose of HRS flower extract. Group 2 animals showed a progressive decrease in body weight, while Group 1 animals showed a considerable gain in body weight. After overcoming the weight loss, Group 3 animals also showed an increase in body weight that was similar to Group 1. Group 2 animals had blood glucose levels higher than 400 mg/dL, but Group 1 animals had blood glucose levels below 200 mg/dL throughout the experiment. Group 3 animals first had glucose levels higher than 350 mg/dL and then lower than 200 mg/dL, comparable to Group 1 animals. Upon histological examination, the pancreatic islets of Group 2 animals showed vacuolation, necrosis, and degeneration. The animals in Group 3 displayed regenerated islets of Langerhans and enhanced pancreatic anatomy. The animals in Group 3 also returned to normal in terms of body weight and blood glucose levels, similar to those in Group 1. These findings show that Hibiscus rosa sinensis has potential as an alternative diabetic treatment; further research is needed to fully understand its modes of action and long-term effects. [ABSTRACT FROM AUTHOR]

Introduction: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. Method: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aβ)-40, Aβ42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. Results: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aβ levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. Conclusion: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis. Plain Language Summary: This work is mainly focused on the investigation of the antioxidant activity of S-nitrosoglutathione (GSNO) in intracerebroventricular infusion of streptozotocin (ICV-STZ)-induced Alzheimer's disease (AD) in rats. GSNO is an endogenous nitric oxide donor and has potent antioxidant activities. Our study revealed for the first time that GSNO may have antioxidant activities in AD by improving the endogenous antioxidant defense system. Further, GSNO treatment improved spatial retention and contextual fear memory in rats. Also, GSNO treatment decreased the AD neuropathological parameters (neuronal damage, amyloid beta-Aβ40, Aβ42) and improved the neuroprotective parameters (GSH, brain-derived neurotrophic factor, and nuclear factor erythroid 2-related factor-2) levels in AD brain tissues. These findings indicate that GSNO activates the neuronal antioxidant defense system and normalizes oxidative stress in the AD brain. [ABSTRACT FROM AUTHOR]

Results from studies of the antidiabetic and antihyperglycemic activity of a low-molecular-weight NGF mimetic, compound GR-2 [bis-(N-monosuccinyl-L-glutamyl-L-lysine)hexamethylenediamide], on a streptozotocin-induced diabetes model in Wistar rats are presented. GK-2 administered perorally at a dose of 5 mg/kg for 28 d significantly reduced the glycemia level in diabetic rats and increased the overall plasma antioxidant capacity. The glycemia level and plasma antioxidant capacity were in an inverse exponential relationship and were closely correlated to each other (correlation coefficient 0.899). [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disease characterized by persistent hyperglycemia, revealing a decrease in insulin efficiency. The sustained glucotoxic pancreatic microenvironment increases reactive oxygen species generation, resulting in chronic oxidative stress responsible for massive DNA damage. This triggers PARP-1 activation with both NAD+ and ATP depletion, affecting drastically pancreatic beta cells' energy storage and leading to their dysfunction and death. The aim of the present study is to highlight the main histological changes observed in pancreatic islets pre-treated with a unique NADH intraperitoneal injection in a streptozotocin-(STZ)-induced diabetes model. In order to adjust NADH doses, a preliminary study with three different doses, 500 mg/kg, 300 mg/kg, and 150 mg/kg, respectively, was conducted. Subsequently, and on the basis of the results of the aforementioned study, Wistar rats were randomly divided into four groups: non-diabetic control group, diabetics (STZ 45 mg/kg), NADH-treated group (150 mg/kg) 15 min before STZ administration, and NADH-treated group (150 mg/kg) 15 min after STZ administration. The effect of NADH was assessed by blood glucose level, TUNEL staining, histo-morphological analysis, and immunohistochemistry. The optimum protective dose of NADH was 150 mg/kg. NADH effectively decreased hyperglycemia and reduced diabetes induced by STZ. Histologically, NADH pre-treatment revealed a decrease in beta cell death favoring apoptosis over necrosis and therefore preventing inflammation with further beta cell destruction. Our data clearly demonstrate that NADH prior or post-treatment could effectively prevent the deleterious loss of beta cell mass in STZ-induced diabetes in rats and preserve the normal pancreatic islet's function. [ABSTRACT FROM AUTHOR]