Dose Of Streptozotocin Research Articles

A Mouse Model of Hepatocellular Carcinoma Induced by Streptozotocin and High-Fat Diet.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the second most common cause of cancer-related death. HCC is associated to chronic diseases such as viral hepatitis, alcoholic, and non-alcoholic fatty liver disease (NAFLD), diabetes mellitus, and obesity, among others. Although pre-clinical models have been investigated to mimic the transition from NAFLD to HCC, they do not accurately reproduce the phenotypic evolution from simple steatosis to steatohepatitis, fibrosis/cirrhosis, and HCC. Hence, these models have failed to demonstrate the influence of diabetes on hepatic carcinogenesis. Here, we report a novel mouse model of HCC triggered by fast-developing diabetes and NAFLD. The first step consists in a single intraperitoneal injection of a low dose of streptozotocin into neonatal C57BL/6J mice to induce type 2 diabetes. In a second step, mice are fed with high-fat diet to accelerate the development of simple steatosis. Continuous high-fat diet exacerbates hepatic fat deposition with increased lobular inflammation (by activation of foam cell-like macrophages) and fibrosis (by activating hepatic stellate cells), two representative pathological traits of steatohepatitis/fibrosis. After 20weeks, all mice developed multiple HCCs. This model of hepatic carcinogenesis triggered by diabetes mellitus and NAFLD offers the advantage of being rapid and accurately recapitulates the pathogenesis of human HCC without the need of administering hepatic carcinogens.

Effect of aqueous-alcoholic extract of Ducrosia Anethifolia Boiss on the fetal liver of diabetic rats

Objective: Moshgak (Ducrosia anethifolia) is a wild plant with medicinal value. The present study aimed to evaluate the effect of Moshgak on the liver tissue of the diabetic rat fetus. Materials and Methods: In this animal study, the aqueous-alcoholic extract of Moshgak was prepared in the standard method. Forty rats were divided randomly into five groups, including control, sham, and three diabetic groups. The rats were diabetic with intraperitoneal injection of a single dose of streptozotocin (80 mg) and 2 diabetic groups were treated with Moshgak extract (280 and 560 mg/kg/bw) for 19 days. The rats were anesthetized and their blood was taken to measure the blood glucose, insulin, and malondialdehyde. Then, their fetuses were removed. The fetal liver sections were obtained by using the stereological methods. The micrometry of the liver tissue was performed and data were analyzed. Results: The finding showed a statistically significant increase (P < 0.01) in the total volume of liver, connective tissue, sinusoid, and hepatocytes in diabetic rats compared to control rats, while these parameters decreased significantly in treated groups with Moshgak. Hepatic cell count hepatic decreased in the treated groups. Furthermore, the changes in blood glucose, malondialdehyde, and insulin in diabetic rats were improved significantly by Moshgak treatment. The dilation of sinusoids, hepatocyte vacuolation, and mild lymphocytosis was observed in all diabetic groups except the treatment group with Moshgak 560 mg/kg/bw. Conclusions: According to obtained results, Moshgak extract was able to compensate partially the changes induced by diabetes in the fetal liver tissue. Therefore, due to the side effects of diabetes during pregnancy, further research on anti-diabetic properties of Moshgak is suggested.

Melatonin supplementation counteracts fiber loss in knee ligaments of diabetes-induced rats.

Diabetes mellitus (DM) is a prevalent metabolic disease. The clinical impact of sustained hyperglycemia on ligament healing has not been well characterized. Diabetes is a known cause of macro-, microvascular, and diabetic ulcer healing difficulties among tissues. Therefore, we aimed to investigate the healing potential occurring in injured and healthy ligaments among diabetic and healthy individuals using a rat model. We hypothesize that DM may contribute to altering the knee medial collateral ligament (MCL), thus its morphology, biochemical fitness, and functionality. The study cohort consisted of 40 rats. The animals were randomized into four equal groups. Groups I and II (20 rats) received saline subcutaneously and served as controls. Groups III and IV (20 rats) were injected with a single dose of streptozotocin (STZ). All animals underwent surgery to cut the left tibial collateral ligament in the hind limb and suture it. The access site was sutured to create inflammation and study the regenerative capacities of animals with normal carbohydrate metabolism and pharmacologically induced diabetes. Each animal then underwent sham surgery to access and suture the right tibial collateral ligament in the hind limb without ligament intervention. After the animals had undergone surgeries, groups II and IV were given melatonin supplementation for 4weeks. Rats with DM presented with more fibrosis and calcification of the MCL and decreased healing potential. Treatment with melatonin in diabetic rats mitigated alterations and improved the antioxidant status of ligaments from the diabetic group.

Atorvastatin Accelerates Alveolar Bone Loss in Type 1 Diabetic Rats Submitted to Periodontitis.

Periodontal bone loss is potentiated by diabetes. Despite the beneficial anti-inflammatory and antiresorptive effects of Atorvastatin (ATV) on periodontitis, it has been reported to increase the risk of diabetes, which may modify the course of periodontal disease. Therefore, this study aimed to evaluate the effect of ATV on alveolar bone in rats with periodontitis and diabetes. For this, 72 Wistar rats were divided into groups: Naïve (N) not submitted to any procedure; Experimental periodontitis (EP) group submitted to ligature-induced periodontitis; diabetes mellitus (DM), submitted to EP and receiving single dose of streptozotocin (60 mg/kg, i.p.) after 12 hours of fasting; and ATV DM, submitted to EP and DM and receiving orally 27 mg/kg of ATV, 30 minutes before ligature placement, and continued daily until the 11th day. Animals from EP and DM received saline solution 0.9% as placebo. Glycemic levels measured in all animals and then were euthanized. Maxillae were collected for macroscopic, micro-tomographic, and microscopic analyses. DM caused intense bone loss (60%), characterized by a reduction in trabecular thickness and bone volume. DM reduced osteoblasts, increasing osteoclast counts, and induced an inflammatory infiltrate in the periodontium. ATV was found ineffective in protecting bone in diabetic rats, exacerbating bone loss by 21%. Additionally, ATV significantly increased blood glucose levels. In summary, ATV did not prevent alveolar bone loss or modulate inflammation in DM animals undergoing EP. ATV also increased blood glucose levels in these animals. Therefore, the systemic use of ATV in uncontrolled diabetic conditions should be carefully evaluated.

Agmatine ameliorates diabetes type 2-induced nephropathy in rats

Objective: To assess the nephroprotective potential of agmatine in a rat model of streptozotocin-induced diabetic nephropathy. Methods: A single dose of streptozotocin (40 mg/kg) coupled with a fructose diet induced diabetes in Wistar rats. Agmatine (40 and 80 mg/kg) was administered to rats for 12 weeks. The body weight and fasting blood glucose were measured weekly. Insulin level, urine output, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C were also determined at the end of the experiment. Furthermore, superoxide dismutase, glutathione, interleukin-1β, interleukin-6, and tumor necrosis factor-alpha were evaluated in kidney tissue. Histopathological study was also performed using hematoxylin and eosin staining. Results: Agmatine at both doses significantly increased final body weight, and lowered fasting blood glucose, urine output, insulin, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C levels compared with the diabetic group (P < 0.05). Inflammatory markers and antioxidant effect were significantly improved in agmatine-treated rats. Moreover, the histopathological changes in renal structure were ameliorated by agmatine treatment. Conclusions: Agmatine alleviates diabetic nephropathy by improving renal functions and reducing inflammation and oxidative stress. The molecular mechanisms of its nephroprotective actions need to be investigated in future study.

The Effect of Probiotic Supplementation on the Levels of Biomarkers in Diabetic Animal Model: A Research Protocol

Introduction: Type 2 Diabetes Mellitus (T2DM) is characterised by hyperglycaemia, insulin secretion defects, or resistance. Most T2DM drugs help to improve glycaemic status, but the response varies among individuals. The modern lifestyle with unhealthy eating habits leads to gut dysbiosis. Altered gut microbiota can disrupt the host’s metabolic and signaling pathways, intestinal barrier integrity, and function. Probiotics could restore a healthy microbiota in the intestine, thus improving glycaemic status. Need of the study: Probiotics may assist in re-establishing a healthy microbiota composition in the intestine. Limited studies have evaluated the supplementation of probiotics for effectively managing T2DM. Aim: To investigate the effects of probiotics on biomarker levels in type 2 diabetic male Wistar rats. Materials and Methods: This interventional case-control study will be conducted at the Centre for Toxicology and Developmental Research (CEFTE) at Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India. The study will involve 46 male Wistar rats divided into five groups. Diabetes will be induced by feeding the animals a High-Fat Diet (HFD) and administering a low dose of Streptozotocin (STZ) injection. Groups 1 and 2 will be on basal and HFDs, serving as negative and positive controls, respectively. Groups 3, 4 and 5 will be the intervention groups. The study duration will be four weeks and three days for diabetes induction and six weeks for intervention. Blood samples will be collected periodically to assess biomarkers, and at the end of the study, internal organs will be harvested for histopathological examination. Institutional Ethics Committee (IEC) approval has been obtained. Categorical variables will be analysed using Chi-square or Fisher’s exact test, while continuous variables will be analysed using repeated measures Analysis of Variance (ANOVA). A p-value of ≤0.05 will be considered statistically significant, and statistical analysis will be performed using Statistical Package for Social Sciences (SPSS) version 16.0.

Особливості ультраструктурних змін у нейросенсорних елементах сітківки щурів при моделюванні діабетичної ретинопатії на тлі осьової міопії

The formation and development of diabetic retinopathy in conditions of myopization of the eyeball is accompanied by the features of the clinical picture of retinopathy. With myopia, the incidence of especially proliferative retinopathy, as well as the rate of progression of these diabetic changes in the retina, can be reduced. The aim of our work was a comparative study of the ultrastructure of the neurosensory elements of the retina in rats in the simulation of streptozotocin-induced diabetes and deprivation axial myopia. Experiments were performed on rats aged from 2 to 10 weeks, which were divided into 4 groups. The 1st control group included intact animals, the 2nd - with myopia, the 3rd - with diabetes; the 4th - with myopia and diabetes. Two-week-old rats were modeled with a high degree of axial myopia by blepharorrhaphy of both eyes and exposure to low light for another 2 weeks. In rats with axial myopia and intact rats, streptozotocin-induced diabetes was modeled by repeated intraperitoneal administration of subdiabetic doses of streptozotocin (15.0 mg/kg body weight) for 5 days. After 2 months, all animals were removed from the experiment under anesthesia and their eyes were enucleated. The tissue samples were photographed in a PEM-100-01 electron microscope and the ultrastructure of the neurosensory elements of the retina was studied. The obtained results of the study indicate that ultrastructural retinal neurosensory elements differed in different groups. When modeling diabetes against the background of axial myopia, some areas with signs of hydropic dystrophy with large fields of organelle destruction were observed in the cells of the inner layers of the retina, mainly in the inner nuclear layer, which is inherent in diabetes, but there were also areas whose ultrastructure was close to normal. This indicates that the process of myopization of the eyeball of rats with the lengthening of the anterior-posterior axis can mitigate the severity of ultrastructural changes of the retina in the simulation of diabetic retinopathy.

Empagliflozin alleviates diabetes-induced cognitive impairments by lowering nicotinamide adenine dinucleotide phosphate oxidase-4 expression and potentiating the antioxidant defense system in brain tissue of diabetic rats

BackgroundDiabetes-induced cognitive impairment is a major challenge in patients with uncontrolled diabetes mellitus. It has a complicated pathophysiology, but the role of oxidative stress is central. Therefore, the use of antidiabetic drugs with extra-glycemic effects that reduce oxidative damage may be a promising treatment option. MethodsMale Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated (n = 8 per group). Type 1 diabetes was induced by a single intraperitoneal dose of streptozotocin (STZ) (40 mg/kg). Two treatment groups received empagliflozin for 5 weeks (20 mg/kg/po). Cognitive ability was evaluated using open field, Elevated Plus Maze (EPM) and the Morris Water Maze (MWM) tests at study completion. Blood and brain tissue samples were collected - and analysis for malondialdehyde (MDA) and glutathione (GLT) content and catalase (CAT) and superoxide dismutase (SOD) enzyme activity were performed. Additionally, expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox-4) enzyme in brain tissue was analyzed using RT-PCR. ResultsSTZ increased blood glucose and induced diabetes with oxidative stress by lowering the antioxidant system potency and increasing Nox-4 expression after 5-weeks in brain tissue accompanied by reduction in cognitive performance. Also, diabetes induced anxiety-like behavior and impaired spatial memory in MWM, EPM and open field tests. However, empagliflozin reversed these changes, improving SOD and CAT activity, GLT content and reducing Nox-4 expression and MDA concentration in brain tissue while improving cognitive ability. It reduced anxiety and depression-related activities. It also improved spatial memory in MWM test. ConclusionUncontrolled diabetes negatively impacts mental function and impairs learning and cognitive performance via oxidative stress induction, the Nox-4 enzyme playing a central role. Empagliflozin reverses these effects, improving cognitive ability via promoting the anti-oxidative system and damping Nox-4 free radical generator enzyme expression. Therefore, empagliflozin is a promising treatment, providing both antidiabetic and extra-glycemic benefits for improving brain function in the diabetic milieu.

Aerobic exercise training improves memory function through modulation of brain-derived neurotrophic factor and synaptic proteins in the hippocampus and prefrontal cortex of type 2 diabetic rats.

Defective insulin signaling in the brain may disrupt hippocampal neuroplasticity resulting in learning and memory impairments. Thus, this study investigated the effect of aerobic exercise training on cognitive function and synaptic protein markers in diabetic rats. Twenty male Wistar rats (200-250g), were fed on high-fat diet and received a low dose of streptozotocin (35mg/kg, i.p) to induce type 2 diabetes. Then diabetic animals were randomly divided into sedentary and training groups. The exercise training program was treadmill running at 27m/min for 60min/day for 8 weeks. One day after the last training session, Morris Water Maze (MWM) task was performed to evaluate spatial learning and memory. Then, the hippocamp and prefrontal cortex tissues were instantly dissected for immunoblotting assay of BDNF, GSK-3β, p-GSK-3β, P38, p-P38, ERK1/2, p-ERK1/2, heat shock protein-27 (HSP27), SNAP-25, synaptophysin, and PSD-95. Independent t-test analysis and two-way ANOVA was used to determine the differences under significance level of 0.05 using the 26th version of IBM SPSS statistical software. The results showed that aerobic exercise improved memory as assessed in the MWM task. Moreover, aerobic exercise up-regulated HSP27 and BDNF protein levels in the prefrontal cortex, and hippocampus coincided with robust elevations in SNAP25 and PSD-95 levels. Moreover, exercise reduced phosphorylated P38, while increased p-ERK1/2 and p-GSK-3β (p). Our findings suggest that aerobic exercise may debilitate the harmful effects of diabetes on the cognitive function possibly through enhancing synaptic protein markers.

Dapagliflozin Ameliorates Neural Damage in the Heart and Kidney of Diabetic Mice.

(1) Background: Measures for the control of diabetes mellitus (DM) and, especially, for the control of its complications represent a main objective of the research carried out on this disease, since both mortality and morbidity relating to DM represent real problems for the health system worldwide. The aim of our study was to evaluate nervous tissue from the heart and kidneys of mice with diabetes induced by streptozotocin (STZ) in the presence or absence of dapagliflozin (DAPA) treatment. (2) Methods: For this purpose, we used 24 C 57Bl/6 male mice, aged between 8 and 10 weeks. The mice were divided into three groups: sham (DM-), control (DM+), and treated (DM+). Diabetes mellitus was induced by injecting a single intraperitoneal dose of STZ. The duration of diabetes in the mice included in our study was 12 weeks after STZ administration; then, the heart and kidneys were sampled, and nervous tissue (using the primary antibody PGP 9.5) from the whole heart, from the atrioventricular node, and from the kidneys was analyzed. (3) Results: The density of nerve tissue registered a significant decrease in animals from the control group (DM+), to a value of 0.0122 ± 0.005 mm2 nerve tissue/mm2 cardiac tissue, compared with the sham group (DM-), wherein the value was 0.022 ± 0.006 mm2 nervous tissue/mm2 cardiac tissue (p = 0.004). Treatment with dapagliflozin reduced the nerve tissue damage in the treated (DM+DAPA) group of animals, resulting in a nerve tissue density of 0.019 ± 0.004 mm2 nerve tissue/mm2 cardiac tissue; a statistically significant difference was noted between the control (DM+) and treated (DM+DAPA) groups (p = 0.046). The same trends of improvement in nerve fiber damage in DM after treatment with DAPA were observed both in the atrioventricular node and in the kidneys. (4) Conclusions. These data suggest that dapagliflozin, when used in streptozotocin-induced diabetes in mice, reduces the alteration of the nervous system in the kidneys and in the heart, thus highlighting better preservation of cardiac and renal homeostasis, independent of any reduction in the effects of hyperglycemia produced in this disease.

Restoring glucose balance: Conditional HMGB1 knockdown mitigates hyperglycemia in a Streptozotocin induced mouse model

Diabetes mellitus (DM) poses a significant global health burden, with hyperglycemia being a primary contributor to complications and high morbidity associated with this disorder. Existing glucose management strategies have shown suboptimal effectiveness, necessitating alternative approaches. In this study, we explored the role of high mobility group box 1 (HMGB1) in hyperglycemia, a protein implicated in initiating inflammation and strongly correlated with DM onset and progression. We hypothesized that HMGB1 knockdown will mitigate hyperglycemia severity and enhance glucose tolerance. To test this hypothesis, we utilized a novel inducible HMGB1 knockout (iHMGB1 KO) mouse model exhibiting systemic HMGB1 knockdown. Hyperglycemic phenotype was induced using low dose streptozotocin (STZ) injections, followed by longitudinal glucose measurements and oral glucose tolerance tests to evaluate the effect of HMGB1 knockdown on glucose metabolism. Our findings showed a substantial reduction in glucose levels and enhanced glucose tolerance in HMGB1 knockdown mice. Additionally, we performed RNA sequencing analyses, which identified potential alternations in genes and molecular pathways within the liver and skeletal muscle tissue that may account for the in vivo phenotypic changes observed in hyperglycemic mice following HMGB1 knockdown. In conclusion, our present study delivers the first direct evidence of a causal relationship between systemic HMGB1 knockdown and hyperglycemia in vivo, an association that had remained unexamined prior to this research. This discovery positions HMGB1 knockdown as a potentially efficacious therapeutic target for addressing hyperglycemia and, by extension, the DM epidemic. Furthermore, we have revealed potential underlying mechanisms, establishing the essential groundwork for subsequent in-depth mechanistic investigations focused on further elucidating and harnessing the promising therapeutic potential of HMGB1 in DM management.

Hypoglycemic effects of Stachys affinis Bunge in streptozotocin-induced diabetic mice

BACKGROUND: Stachys affinis Bunge (S. affinis) tubers are rich in carbohydrate with a large amount of stachyose which had been proven to have antidiabetic potential. OBJECTIVE: The present study aims to evaluate hypoglycemic effects of tuber extract of Stachys affinis in streptozotocin-induced diabetic mice. METHODS: The stachyose content of the extract was determined by UPLC. Diabetes was induced by the administration of single dose of streptozotocin (170 mg/kg). The hypoglycemic effects of the extract were evaluated by comparing fasting blood glucose level, glucose tolerance, insulin sensitivity between groups treated with the S. affinis tuber extract (at doses of 750 mg/kg and 1500 mg/kg) and diabetic control group over 28 days of treatment. RESULTS: The daily treatment with the extract at doses of 750 mg/kg and 1500 mg/kg significantly reduced fasting blood glucose level from 278.12 mg/dL to 127.50 mg/dL, and 238.97 mg/dL to 177.12 mg/dL (p < 0.01), respectively. Besides, the treatment also improved the sensitivity of diabetic treated mice to insulin (P < 0.05). CONCLUSION: The study revealed that the S. affinis tuber extract demonstrated significant hypoglycemic effects.

Protective role of eugenol against diabetes-induced oxidative stress, DNA damage, and apoptosis in rat testes.

Diabetes mellitus, a metabolic disorder alters gonadal development and spermatogenesis,reactive oxygenspecies production, DNA damage, and apoptosis, which subsequently lead to male subfertility. Eugenol is an antioxidant, traditionally used as medication for digestive disorders and antioxidant therapy, decrease transport of glucose from GIT to systemic circulation. This experiment was aimed to decipher cellular and molecular insights of eugenol in protecting diabetic germ cells in rats. Rats were assigned randomly into five groups: control, eugenol control (Eugenol 400; EUG), diabetic (DIA), diabetic + eugenol 100 (DIA + EUG 100), and diabetic + eugenol 400 (DIA + EUG 400). EUG 400 and DIA + EUG 400 groups received 400 mg/kg eugenol orally. DIA + EUG 100 group received 100 mg/kg eugenol. Treatment was conducted for 4 weeks. Type 1 diabetes was induced by injecting a single i.p. dose of streptozotocin (55 mg/kg). Morphometric, biochemical, sperm parameters, oxidative stress, hormonal levels, histopathology, and fibrosis in the testis and epididymis, were evaluated. DNA damage was evaluated using halo and comet assays; DNA fragmentation and apoptosis using TUNEL assay. Eugenol treatment significantly normalized biochemical parameters, reduced MDA while increased albumin and GSH levels in diabetes. Eugenol significantly increased sperm numbers, motility and attenuated abnormal sperm head morphology in diabetes. Moreover, eugenol significantly reversed diabetes-induced cellular damages, altered spermatogenesis, and collagen deposition in testis and epididymis. It also significantly attenuated diabetes-associated DNA breaks and apoptosis. These findings suggest that 4 weeks treatment with 400 mg/kg of eugenol could be beneficial for diabetic patients to prevent subfertility.

Investigating Alzheimer’s Disease‐Related Pathology in a Chronic Hyperglycemic Mouse Model

AbstractBackgroundDiabetes is a major risk factor for Alzheimer’s disease (AD). Hyperglycemia is the primary characteristic of diabetes. Hyperglycemia was induced in both young and aged mice. Following an incubation period, a hyperglycemic rescue was introduced to lower hyperglycemia, and to determine if hyperglycemia itself, or neuroinflammation as a result of hyperglycemia, increased AD pathology (i.e., hyperphosphorylated tau and reactive gliosis).MethodYoung (7‐month‐old; N = 24) and aged (18 month old; N = 24) C57BL/6J (wildtype) mice were injected with a low and staggered dose of streptozotocin (STZ) to induce sustained hyperglycemia. After a 9‐week incubation period of hyperglycemia (e.g., +250mg/dl), a group of mice were treated with Phloridzin (PZ) ‐ a drug that reduces hyperglycemia by preventing renal and intestine glucose uptake ‐ for two consecutive weeks to determine if hyperglycemia itself or the subsequent neuroinflammation, is what increase the risk for AD.ResultSTZ increased hyperglycemia levels; PZ lowered hyperglycemia levels. Both young and aged STZ, PZ, and STZ+PZ mice showed significantly differences in P‐S396‐tau/total, P‐T181‐tau/total, proinflammatory cytokines, and increases reactive microglia and astrocytes compared to controls.ConclusionPZ did not rescue hyperglycemic‐induced AD pathology.

SGLT2 and DPP4 inhibitors improve Alzheimer’s disease‐like pathology and cognitive function through distinct mechanisms in T2D‐AD mouse model

AbstractBackgroundThere are common mechanisms between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D), such as insulin resistance. As insulin signaling has important roles in regulation of neuronal functions in the brain, the hypotheses and theories regarding the pathogenesis of AD implicate brain insulin resistance as a key factor. Also, recent studies demonstrated that sodium‐glucose cotransporter 2 inhibitor (SGLT2‐i) and dipeptidyl peptidase‐4 inhibitor (DPP4‐i) which are T2D drugs have been shown to exert beneficial effects on insulin sensitivity and neuroprotection beyond glucose‐lowering actions. However, in relation to the two drugs, the brain metabolic dysfunction and its mechanisms impaired by insulin resistance have never been investigated.MethodWe developed T2D‐AD mice model using 60% high‐fat diet for 12 weeks and a single dose of streptozotocin (100 mg/kg/i.p) at week 4 of the diet. Subsequently treated with SGLT2‐i (empagliflozin, 25 mg/kg/day/po) and DPP4‐i (sitagliptin, 100 mg/kg/day/po) for 7 weeks. After behavior tests, expression properties of brain insulin signaling, AD related proteins and drugs action‐associated proteins were examined by using western blotting and immunohistochemistry.ResultT2D‐AD mice not only increased blood glucose and body weight, but also had insulin resistance through insulin tolerance test and glucose tolerance test. SGLT2‐i and DPP4‐i were effective in ameliorating insulin sensitivity and reducing body weight gain. In addition, as a result of evaluating hippocampus‐dependent spatial learning and preference memory through behavioral tests, SGLT2‐i and DPP4‐i were found to improve learning, memory, and cognitive functions. Interestingly, SGLT2‐i and DPP4‐i reduced AD‐associated hyperphosphorylated tau (pTau) and amyloid β (Aβ) accumulation in different ways, respectively, along with enhancing brain insulin signaling. SGLT2‐i reduced pTau accumulation through ACE2/Ang(1‐7)/MasR, and DPP4‐i showed an effect of reducing Aβ accumulation by increasing IDE.ConclusionThese findings suggested that SGLT2‐i and DPP4‐i prevented AD‐like pathology and cognitive decline by affecting brain insulin signaling through different mechanisms.

Combination Therapy with Enalapril and Paricalcitol Ameliorates Streptozotocin Diabetes-Induced Testicular Dysfunction in Rats via Mitigation of Inflammation, Apoptosis, and Oxidative Stress.

As the impacts of diabetes-induced reproductive damage are now evident in young people, we are now in urgent need to devise new ways to protect and enhance the reproductive health of diabetic people. The present study aimed to evaluate the protective effects of enalapril (an ACE inhibitor) and paricalcitol (a vitamin D analog), individually or in combination, on streptozotocin (STZ)-diabetes-induced testicular dysfunction in rats and to identify the possible mechanisms for this protection. This study was carried out on 50 male Sprague-Dawley rats; 10 normal rats were allocated as a non-diabetic control group. A total of 40 rats developed diabetes after receiving a single dose of STZ; then, the diabetic rats were divided into four groups of equivalent numbers assigned as diabetic control, enalapril-treated, paricalcitol-treated, and combined enalapril-and-paricalcitol-treated groups. The effects of mono and combined therapy with paricalcitol and enalapril on testicular functions, sperm activity, glycemic state oxidative stress, and inflammatory parameters, as well as histopathological examinations, were assessed in comparison with the normal and diabetic control rats. As a result of diabetes induction, epididymal sperm count, sperm motility, serum levels of testosterone, follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH), and the antioxidant enzyme activities, were significantly decreased, while abnormal sperm (%), insulin resistance, nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly increased, along with severe distortion of the testicular structure. Interestingly, treatment with paricalcitol and enalapril, either alone or in combination, significantly improved the sperm parameters, increased antioxidant enzyme activities in addition to serum levels of testosterone, FSH, and LH, reduced insulin resistance, IL-6, and TNF-α levels, and finally ameliorated the diabetes-induced testicular oxidative stress and histopathological damage, with somewhat superior effect for paricalcitol monotherapy and combined therapy with both drugs compared to monotherapy with enalapril alone. Monotherapy with paricalcitol and its combination therapy with enalapril has a somewhat superior effect in improving diabetes-induced testicular dysfunction (most probably as a result of their hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties) compared with monotherapy with enalapril alone in male rats, recommending a synergistic impact of both drugs.

PTPN2 Regulates Metabolic Flux to Affect β-Cell Susceptibility to Inflammatory Stress.

Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation and models of T1D, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, low and high dose streptozotocin (STZ) treated Ptpn2 βKO mice displayed hyperglycemia and accelerated death, respectively. Furthermore, cytokine treated Ptpn2 KO islets resulted in impaired glucose-stimulated insulin secretion, mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to maladaptive metabolic fitness. Consistent with the phenotype, proteomic analysis identified an important metabolic enzyme ATP-citrate lyase (ACLY) as a novel PTPN2 substrate.

Alzheimer's disease-related brain insulin resistance and the prospective therapeutic impact of metformin.

Besides COVID-19, two of the most critical outbreaks of our day are insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). Each disease's pathophysiology is well established. Furthermore, a substantial overlap between them has coexisted. Uncertainty remains on whether T2DM and AD are parallel illnesses with the same origin or separate illnesses linked through violent pathways. The current study was aimed at testing whether the insulin resistance in the brain results in AD symptoms or not. Insulin resistance was induced in the brains of rats using a single intracerebroventricular streptozotocin (STZ) dose. We then measured glucose, insulin receptor substrate 2 (IRS-2), amyloid β (Aβ) deposition, and tau phosphorylation in the brain to look for signs of insulin resistance and AD. The results of this study indicated that a single dose of STZ was able to induce insulin resistance in the brain and significantly decline IRS-2. This resistance was accompanied by obvious memory loss, Aβ deposition, and tau phosphorylation, further visible diminishing in neurotransmitters such as dopamine and acetylcholine. Furthermore, oxidative stress was increased due to the antioxidant system being compromised. Interestingly, the pancreas injury and peripheral insulin resistance coexisted with brain insulin resistance. Indeed, the antidiabetic metformin was able to enhance all these drastic effects. In conclusion, brain insulin resistance could lead to AD and vice versa. These are highly linked syndromes that could influence peripheral organs. Further studies are required to stabilize this putative pathobiology relationship between them.

The anti-fibrotic effect of atrial natriuretic peptide depends on myocardial accumulation of the peptide in rat heart

Abstract Background The atrial natriuretic peptide (ANP) has an anti-fibrotic function for the heart. However, during heart failure (HF), which is characterized by marked myocardial fibrosis, ANP has a time-limited effect due to the rapid peptide degradation. Angiotensin-receptor-neprilysin inhibitors are a new class of drug that inhibits ANP degradation and improves cardiac performance, raising the question of the impact of increased ANP bioavailability on this pharmacological effect. Purpose We aim to assess the impact of intracardiac accumulation of ANP on cardiac function and myocardial fibrosis. An original strategy consisted of using a mutated ANP, MANP, also known as fsANP (frameshift), which is highly resistant to enzymatic degradation. Methods Type 2 diabetes was induced in adult male rats by a high fat diet coupled to low dose streptozotocin injections (25 mg/kg). MANP and ANP were administered each at a dose of 2 pmol/kg/min by subcutaneous osmotic minipumps. Sacubitril was given orally at a dose of 18 mg/kg. The protocol duration was 42 days. Cardiac fibrosis and cultured cardiac fibroblasts (CFs) were evaluated in the presence or absence of ANP, MANP, and angiotensin-receptor-neprilysin inhibitors; sacubitril. In addition to classical immunohistological and biochemical approaches, cGMP production was measured by real-time imaging in live cultured CFs (n=477). Results: MANP and sacubitril preserved cardiac performance more efficiently than ANP (p<0.05). Moreover, MANP, as well as sacubitril attenuated myocardial, epicardial, and perivascular fibrosis were more efficient than ANP (p<0.05). There was an increase in the bioavailability of MANP compared to ANP in cardiac tissue (p<0.05). Furthermore, a high-level expression of protein kinase G, and inhibition of the SMADs signaling pathway were identified in CFs. Moreover, cGMP bio-sensing in CFs, showed that similarly to ANP, MANP enhances cGMP production and activates PKG signaling, resulting in similar SMADs pathway inhibition (p<0.05). These results indicate similar biological efficiency as ANP and MANP. Conclusion MANP and sacubitril are more efficient than ANP to improve cardiac function and to reduce myocardial fibrosis in HF. Both molecules increase ANP bioavailability. This study proves that tissue accumulation of ANP is an important therapeutic target during HF.

Structural changes in testes of Streptozotocin induced diabetic rats and possible protective effect of royal jelly: light and electron microscopic study

ABSTRACT Diabetes mellitus (DM) is one of the most common metabolic diseases causing damage in many organs in the body including the testes. Royal Jelly (RJ) is one of the honey bee products that has antioxidant, anti-inflammatory and antidiabetic properties. This study was performed to evaluate the changes in the microscopic structure of the testes in Streptozotocin (STZ)-induced diabetic rats, and the possible protective role of RJ. 60 adult male albino rats were divided into three groups. Group I Control group, Group II STZ group, and Group III STZ+RJ group. Group II received a single dose of STZ (50 mg/kg) by intraperitoneal injection. Group III received a single dose of STZ as in the second group then received RJ orally by intragastric tube in dose of (100 mg/kg/day) for 4 weeks after confirmation of diabetes. Light and electron microscopic studies were performed. Group II revealed marked structural changes affecting seminiferous tubules with sever reduction in germinal epithelium and loss of mature spermatozoa in their lumina. The interstitial tissue revealed degenerated Leydig cells and congested blood vessels. Mallory trichrome stained section of group II revealed marked increase in the amount of collagen fibers. Group III revealed highly preserved testicular architecture almost near to that appeared in the control group except few tubules that were damaged. In conclusion, RJ protected the testicular structure from the damaging effect of diabetic oxidative stress through its antioxidant effect thus preserving male fertility.