Streptozotocin Group Research Articles

Glabridin from licorice alleviates vascular inflammation and promotes vascular remodeling of the left anterior descending coronary artery in diabetic rat heart

IntroductionThe aim of this study was to investigate the effects of glabridin on vascular inflammation and vascular remodeling of the left anterior descending artery (LAD) in diabetic rat heart.Material and methodsEighty male Wistar rats were divided into five groups: (1) control rats; (2) glabridin control rats that received diet supplemented with glabridin (CGB); (3) diabetic rats (STZ); (4) diabetic rats that received a supplemented with glabridin (STZ + GB) 40 mg/kg BW; and (5) diabetic rats treated with glyburide (STZ + GR) 4 mg/kg BW. Diabetic animals were rendered diabetic by injection of a single dose (60 mg/kg BW) of streptozotocin (STZ). After 8 weeks, the biochemical markers of oxidative stress were assessed. The three-dimensional morphology of LAD was examined by vascular corrosion casting. Enzyme-linked immunosorbent assay was applied to determine the expression of TNF-α and IL-1β proteins. Western blot and immunofluorescence analysis were used to detect the expression of VEGF and TGF-β1 secretions.ResultsThe lumen diameter of the LAD was notably smaller and stenotic. LAD analysis revealed arterial notch and evolved irregular caliber. Moreover, neovascularization appeared and was extensive. The Trolox equivalent antioxidant capacities and Trolox equivalent antioxidant capacity levels of heart tissue were significantly decreased and levels of malondialdehyde were found to be elevated in STZ rats whereas they were improved in the STZ + GB group. Increased expression levels of VEGF, TGF-β1, TNF-α, and IL-1β proteins in heart tissues were observed in the STZ group. The inflammation cytokine levels were decreased in the STZ + GB group.ConclusionsThese results revealed that glabridin was able to reduce LAD and heart tissue damage. Glabridin can be an antioxidant and can reduce the pathology of the LAD in terms of reducing inflammation and restoring condition of the LAD. It would be beneficial in examining the role of glabridin as a therapeutic aim in diabetes treatment research in coronary artery disease.

Assessment of β-Aescin Effect in Streptozotocin Induced Diabetic Model: Diabetic Hepatotoxicity Study

Objective - Diabetic hepatotoxicity involves complex events which include kupffer cell activation, formation of reactive oxygen species, cytokines release (TNF-α, IL-1β), and finally leads to hepatocyte death. “β- Aescin showed anti-inflammatory, anti-oxidant, gastroprotective and anti-oedema properties. The present study investigated the protective effect of β- Aescin in streptozotocin induced diabetic hepatotoxicity.
 Method - Female mice were divided into six groups, the first group served as the control, the second to sixth group received single i.p. dose of 90 mg/kg of STZ, the second group served as the untreated diabetic group, the third, fourth and fifth group received β- aescin intra-peritoneally at the dose of 0.9 mg/kg, 1.8 mg/kg and 3.6 mg/kg body weight respectively. The last sixth group was treated with 10 mg/kg glibenclamide i.p. for 14 days. A significant decrease in the blood glucose level was showed in β-aescin group as compared to the control group.
 Result - A significant increase of blood glucose level was observed in high and mid dose of β- aescin (3.6 mg/kg and 1.8 mg/kg respectively), standard drug (glibenclamide 10 mg/kg) groups as compared to control group. ROS generation was evaluated by using DCF-DA estimation method for the acute toxicity in liver tissue. Streptozotocin group showed more ROS generation in comparison to β- aescin group (3.6 mg/kg). Serum biochemical markers showed a significant decrease in β- aescin treated diabetic mice compared to untreated diabetic mice. Histopathological evaluation showed severe changes in untreated diabetic liver tissue marked by large number of inflammatory cells such as lymphocytes along with hepatic sinusoidal inflammation and hepatocyte necrosis whereas treated diabetic mice with β- aescin showed reduction in hepatotoxicity marked by regeneration changes of hepatocytes and mildly hepatocyte degeneration.
 Conclusion - In the study, β- aescin showed beneficial effects on the efficient properties of the liver and microscopic improvements in diabetic hepatotoxicity.

Use of Intranasal Insulin as Neuroprotection From Hyperglycemia in Rat Model of Extremely Preterm Infants

Background: Hyperglycemia is common in extremely preterm infants (EPI) and is a risk factor for increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive deficits are common in this population. In a rat model of insulinopenic hyperglycemia, abnormal neurochemistry in the hippocampus was found, with lactate, glutamate (Glu):glutamine (Gln) ratio lower and Phosphorylated Creatinine (PCr):Creatinine (Cr) higher. Intranasal insulin has been shown to improve cognitive function in animal models of Alzheimer’s disease and type 2 diabetes mellitus, as well as in adult human studies of Alzheimer’s disease. No study has previous investigated the use of intranasal insulin on preventing the long-term effects of hyperglycemia in the EPI population. Objective: To determine whether administration of intranasal insulin during early postnatal days would negate the effects of hyperglycemia on the developing hippocampus in neonatal rat model of streptozotocin (STZ)-induced hyperglycemia. Design/Methods: STZ (80mg/kg IP) was injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. STZ pups were randomized to intranasal insulin, 3U twice daily from P3-P6 (STZ + INS) or left untreated (STZ). Neurochemical profile (consisting of 20 metabolites, PCr:Cr and Glu:Gln ratios) of the hippocampus was evaluated using ultra-high-field (9.4 T) magnetic resonance spectroscopy (MRS) on P7 (acute effects) and P56 (long-term effects) compared with the control group (CON)(N=6/group). Results: Mean glucose values from P3-P6 were higher in STZ groups (STZ = 279.0 +/- 132.2 mg/dL, STZ+INS = 274.4 +/- 89.5 mg/dL, CONT = 128.4 +/- 15.1 mg/dL). The neurochemical profile was different at both P7 and P56. On P7, compared with the control, the taurine (Tau) was higher in the STZ groups (p = 0.007. At P56, PCr:Cr was higher in the STZ group compared to CONT and STZ+INS groups (p = 0.04). No difference noted between the STZ+INS and CONT groups. No other metabolites were altered. Conclusion: Neonatal hyperglycemia alters the acute and long-term neurochemical profile in the hippocampus of developing rats. The increase in PCr:Cr ratio in the STZ group indicates lower demand for ATP and PCr, secondary to decreased neuronal activity, which has been demonstrated in previous studies. PCr:Cr ratio of the STZ+INS group was no different than control, indicating that intranasal insulin reverses the negative effect on neuronal activity caused by neonatal hyperglycemia.

Investigation of extracellular matrix genes associated with Alzheimer’s disease in the hippocampus of experimental diabetic model rats

Both type 2 diabetes (T2D) and Alzheimer’s disease affect large number of people all over the world, especially in developed countries, and involve common molecular mechanisms in degenerative processes. Our study is to investigate the expression levels of the ADAMTS4, TIMP3, RELN, and BCAN genes which encode extracellular matrix molecules and are thought to be related to the pathophysiology of Alzheimer’s disease in rats that we used to develop a T2D model by injection of a streptozotocin (STZ) and feeding with high-fat diet (HFD). In total, 40 rats were divided into four groups: HFD + STZ (10), HFD (10), STZ (10), and the control (10). The weight and blood glucose levels of all rats were recorded, and the insulin tolerance test was performed. At the end of the experimental period, the hippocampus of the rats was isolated and a part of this was used for gene expression analysis through real-time PCR, whereas other parts were used for histological analyses. Our results show that plaque-like structures were found in the histological examination of the experimental T2D model. In molecular studies, the expression levels of the ADAMTS4, TIMP3, RELN, and BCAN genes were decreased in the HFD +STZ and STZ groups compared with the control, whereas the same expression levels, except that of inhibitor TIMP3, were found to increase in the HFD group. These genes encoding proteases that regulate neuronal activity have decreased levels in the T2D model. There may be potential in the adoption of new treatment approaches for Alzheimer’s and T2D.

Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis.

Simple SummaryThe aim of the present study was to discover novel early molecular biomarkers of liver neoplasms which arise in non-alcoholic steatohepatitis (NASH) Stelic Animal Model (STAM) mice. Significant increase of lipid deposits, hepatocyte ballooning, fibrosis, and incidences and multiplicities of hepatocellular adenomas and carcinomas were detected in the livers of 18-week-old STAM mice. From the results of proteome analysis of STAM mice hepatocellular carcinomas, significant elevation of a novel protein, cache domain-containing 1 (CACHD1) was found. Furthermore, we observed CACHD1-positive foci in STAM mice livers, which number, area, and cell proliferation index within the foci were significantly elevated. Results of immunohistochemical and in vitro functional analysis indicated that CACHD1 may become a useful early biomarker and potential molecular target in NASH-associated hepatocarcinogenesis, which is involved in control of cell proliferation, autophagy and apoptosis.In the present study, potential molecular biomarkers of NASH hepatocarcinogenesis were investigated using the STAM mice NASH model, characterized by impaired insulin secretion and development of insulin resistance. In this model, 2-days-old C57BL/6N mice were subjected to a single subcutaneous (s.c.) injection of 200 μg streptozotocin (STZ) to induce diabetes mellitus (DM). Four weeks later, mice were administered high-fat diet (HFD) HFD-60 for 14 weeks (STAM group), or fed control diet (STZ group). Eighteen-week-old mice were euthanized to allow macroscopic, microscopic, histopathological, immunohistochemical and proteome analyses. The administration of HFD to STZ-treated mice induced significant fat accumulation and fibrosis development in the liver, which progressed to NASH, and rise of hepatocellular adenomas (HCAs) and carcinomas (HCCs). In 18-week-old animals, a significant increase in the incidence and multiplicity of HCAs and HCCs was found. On the basis of results of proteome analysis of STAM mice HCCs, a novel highly elevated protein in HCCs, cache domain-containing 1 (CACHD1), was chosen as a potential NASH-HCC biomarker candidate. Immunohistochemical assessment demonstrated that STAM mice liver basophilic, eosinophilic and mixed-type altered foci, HCAs and HCCs were strongly positive for CACHD1. The number and area of CACHD1-positive foci, and cell proliferation index in the area of foci in mice of the STAM group were significantly increased compared to that of STZ group. In vitro siRNA knockdown of CACHD1 in human Huh7 and HepG2 liver cancer cell lines resulted in significant inhibition of cell survival and proliferation. Analysis of the proteome of knockdown cells indicated that apoptosis and autophagy processes could be activated. From these results, CACHD1 is an early NASH-associated biomarker of liver preneoplastic and neoplastic lesions, and a potential target protein in DM/NASH-associated hepatocarcinogenesis.

The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

Recently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

Resveratrol inhibits macrophage infiltration of pancreatic islets in streptozotocin-induced type 1 diabetic mice via attenuation of the CXCL16/NF-κΒ p65 signaling pathway

Aim:Despite CXC chemokine ligand 16 (CXCL16) contributes to the pathogenesis of many inflammatory disorders, the mechanism by which CXCL16 is involved in T1DM remains unclear. In this study, we examined the role of the CXCL16/NF-κΒ p65 signaling pathway in the progression of this disease and the possible protective effect of resveratrol (RES) on streptozotocin (STZ)–induced T1DM. Main methodsMice were classified into four groups of 10 animals each. The control group received citrate buffer. The RES group received 50 mg/kg i.p. RES for 12 days beginning on day 4 of citrate buffer. The STZ group received 55 mg/kg i.p. STZ once a day for 5 consecutive days. The fourth group injected with RES (50 mg/kg) for 12 days starting on day 4 of STZ injection. Biochemical, physical and oxidative stress parameters were measured in all groups. Moreover, expression of CXCL16 and CD45 was measured in pancreatic islets and spleen. Additionally, NF-κΒ p65 was investigated in isolated islets. Key findingsOur results showed a significant elevation of CXCL16, NF-κΒ p65 and CD45 in islets of diabetic (DM) mice. Intriguingly, RES significantly restored distorted biochemical, physical and oxidative stress parameters after STZ treatment as well as inhibited the expression of CXCL16/NF-κΒ p65 in pancreatic islets. Moreover, RES normalized CXCL16 and CD45 expression in islets and spleen. SignificanceThis study demonstrates first evidence that CXCL16/NF-κΒ p65 signaling pathway is associated with macrophage infiltration to pancreatic islet in T1DM and that RES successfully improved T1DM may be at least via inhibiting this pathway.

Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin

Adiponectin (APN) plays a major role in the regulation of insulin sensitivity and glucose homeostasis. Insulin and APN have a positive effect on memory. In this study, we examined whether the inhibition of AMPK could block the memory improving effect of APN or affect the IRS1 expression.Animal model of AD was developed by intracerebroventricular (icv) injection of 3 mg/kg streptozotocin (STZ), in 12 weeks old Wistar rats, on days 1 and 3 after cannulation. Dorsomorphin (DM) and APN (600 nM) were injected 30 and 20 min before the acquisition phase, respectively. DM was applied in 3 different doses (0.2, 2 and 20 μM). All behavioral tests were performed on days 15 and 16; the Preference Index (PI) was calculated for novel object recognition (NOR) test, while the step through latency (STL) and total time in dark compartment (TDC) were recorded and analyzed for the passive avoidance task. Relative expression of insulin receptor substrate-1 (IRS-1) protein in the hippocampus was measured by western blotting.In early retrieval test, STZ + APN treatment increased STL (P < 0.0001) and decreased TDC (P < 0.05) in comparison to STZ group, while STZ + APN + DM (2μM) caused a decrease in STL (P < 0.05) and increase in TDC (0.2μM and 2μM DM; P < 0.05). Icv injection of DM (0.2μM and 2μM) before APN decreased the PI significantly (P < 0.05) in comparison to STZ + APN group. APN treatment raised the IRS-1 expression and DM reversed this increment, significantly (P < 0.0001).It is concluded that the memory improving effect of APN is mediated, at least in part, by the AMPK pathway. APN is also able to boost insulin signaling by overexpression of IRS-1 in the hippocampus.

Effects Of STZ Neonatal Administration on Maternal Glucose Tolerance in Different Reproductive States

Background: Rodent models of diabetes during pregnancy have the potential to yield useful insights into maternal and offspring outcomes as well as their underlying mechanisms. Maternal mild hyperglycemia, which better resembles human gestational diabetes, can be induced by administering streptozotocin (STZ) in the neonatal period. Although STZ neonatal injection is a well-established experimental model to induce mild hyperglycemia, there are no studies focusing on the stability of this phenotype across different reproductive states. Objective: The aim of the present study was to compare the effects of STZ neonatal administration on maternal glucose tolerance in cycling, pregnant and lactating rats. Methods: Newborn female rats from the same litter were assigned either to Control (n=11) or STZ condition (STZ 100 mg/kg in 100 microliters citrate buffer subcutaneous; n=11). One Control and one STZ treated female from each litter were used in this study. Oral glucose tolerance tests (OGTT) were performed in adulthood prior to mating (postnatal day 75), on pregnancy day 17, and 10 days after their litter was weaned. Glycemic changes during the OGTT were evaluated by estimation of the total area under the curve (AUC). Results: In both Control and STZ groups the glycemic curve changed across reproductive states probably reflecting metabolic adaptations to these states. Neonatal STZ treatment resulted in a higher AUC relative to controls at all three timepoints but the size of this increase varied with reproductive states. Conclusion: The degree of glucose intolerance demonstrated in female rats that received STZ as newborns varies across reproductive state.

Impairment of renal steroidogenesis at the onset of diabetes

Accumulating evidence indicates the association between changes in circulating sex steroid hormone levels and the development of diabetic nephropathy. However, the renal synthesis of steroid hormones during diabetes is essentially unknown. Male Wistar rats were injected with streptozotocin (STZ) or vehicle. After one week, no changes in functional or structural parameters related to kidney damage were observed in STZ group; however, a higher renal expression of proinflammatory cytokines and HSP70 was found. Expression of Steroidogenic Acute Regulatory protein (StAR) and P450scc (CYP11A1) was decreased in STZ kidneys. Incubation of isolated mitochondria with 22R-hydroxycholesterol revealed a marked inhibition in CYP11A1 function at the medullary level in STZ group. The inhibition of these first steps of renal steroidogenesis in early STZ-induced diabetes led to a decreased local synthesis of pregnenolone and progesterone. These findings stimulate investigation of the probable role of nephrosteroids in kidney damage associated with diabetes.

Insulin enhances neointimal hyperplasia following arterial injury through the PI3K/Akt pathway in type 1 diabetic rats.

Although insulin is known to affect neointimal hyperplasia via distinct signaling pathways, how neointimal hyperplasia is affected in insulin‑deficient type1 diabetes remains unknown. The aim of the current study was to investigate two major signaling branches of insulin action regulating neointimal hyperplasia following arterial injury in type 1 diabetes with or without exogenous insulin administration. Rats were treated with vehicle (control group), streptozotocin(STZ) alone (STZ group; uncontrolled type1 diabetes) or STZ followed by insulin (STZ+I group; controlled type1 diabetes). Subsequently, a type 1 diabetic rat model of carotid artery balloon injury was established. Following this, the intima‑to‑media area ratios were examined for evidence of neointimal hyperplasia in the carotid arteries of the rats by performing hematoxylin‑eosin staining. Furthermore, the protein expression of extracellular signal‑regulated kinase (ERK), phosphorylated(p‑) ERK, protein kinaseB(Akt) and p‑Akt in the carotid arteries of the rats was determined via immunoblotting. Moreover, an invitro model of type1 diabetes was induced by incubation of primary vascular smooth muscle cells (VSMCs) with glucose and/or insulin. Cellular proliferation and signaling protein expression levels in VSMCs were determined by measuring the incorporation of tritiated thymidine and performing immunoblotting, respectively. The results demonstrated that compared with that in control rats, neointimal hyperplasia and expression of p‑Akt in uncontrolled type 1 diabetic rats were significantly decreased. This decrease was recovered in controlled type1 diabetes with insulin therapy. Furthermore, the difference in the expression of p‑ERK between groups was not significant. Additionally, the results of the cell experiments were consistent with those from the animal studies. In conclusion, the preferential signaling along the phosphatidylinositol3‑kinase/Akt pathway of insulin action in response to insulin restoration may contribute to neointimal hyperplasia. The present study provides a novel approach for the further treatment of neointimal hyperplasia in type1 diabetes.

Attenuating properties of Rubus fruticosus L. on oxidative damage and inflammatory response following streptozotocin-induced diabetes in the male Wistar rats.

Diabetes mellitus is a prevalent metabolic disorder that entails numerous complications in various organs. In current era, different types of diseases are being treated by the applications of herbs. The present study is aimed at investigating the anti-inflammatory and antioxidant effects of the Rubus fruticosus hydroethanolic extracts (RFHE) in the streptozotocin (STZ)-induced diabetic rats. At this experimental research, male Wistar rats with the weight of 220 ± 20g, were categorized randomly into five groups of vehicles as control, STZ (60mg kg- 1 of body weight, intraperitoneally (i.p.)) and RFHE (50, 100 and 200mg kg- 1, i.p.). In the last stage (end of week 4) of the experiment, after being euthanized, the blood samples of the rats were collected for measuring malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS) as well as inflammatory markers like tumor necrosis factor (TNF)-α, interleukin (IL)-6 and C-reactive protein (CRP). Data from this study was revealed that diabetes causes oxidative damage and consequently the serum level of inflammatory markers rises. RFHE was shown to be significantly correlated with lowering the level of MDA, TNF-α, IL-6 and CRP of diabetic rats. Moreover, RFHE significantly elevated the GSH and TAS serum levels in diabetic rats when compared with STZ group. RFHE might have anti-diabetic properties; this outcome may be mediated by high antioxidant and anti-inflammatory effects.

IGF-1R/β-catenin signaling axis is implicated in streptozotocin exacerbating bone impairment in ovariectomized rats

Objective The aim of this study was to investigate the role of the insulin-like growth factor-1 receptor (IGF-1R)/β-catenin signaling axis in bone impairment induced by hyperglycemia in ovariectomized rats. Methods Rats were divided into four groups. The sham group received sham operation and a single intraperitoneal administration of vehicle. The ovariectomy (OVX) group was subjected to bilateral OVX and vehicle injection. The streptozotocin (STZ) group received sham operation and a single STZ injection to induce hyperglycemia. The OVX + STZ group received bilateral OVX and a single STZ injection. Dual-energy X-ray absorptiometry measurement, bone biomechanics test, micro-computed tomography scan, and hematoxylin–eosin staining were performed to evaluate bone alteration in this model. The expression of relevant signals including IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin were examined by quantitative real-time polymerase chain reaction and western blot. Results The OVX, STZ, and OVX + STZ groups induced bone loss, attenuated bone strength, and impaired microarchitecture compared with the sham group, respectively. Compared with OVX, more serious bone damage was found in the OVX + STZ group, which showed enhanced phosphorylation of IGF-1R, GSK-3β, and β-catenin. Conclusion OVX plus STZ induced more serious bone impairment than OVX alone, which involves the IGF-1R/β-catenin signaling axis in the pathogenesis. This may provide a potential target for treatment of postmenopausal diabetic osteoporosis.

Effects of Regular Exercise on Diabetes-Induced Memory Deficits and Biochemical Parameters in Male Rats.

The main objective of current work was to determine the effects of treadmill-running and swimming exercise on passive avoidance learning (PAL) and blood biochemical parameters in rats with streptozotocin (STZ)-induced diabetes. Male Wistar rats were divided into the following 6 groups (N = 6-8 per group): CON, healthy rats without exercise (N = 8); STZ, diabetic rats without exercise (N = 8); CON-SE, healthy rats subjected to swimming exercise (2months; N = 6); STZ-SE, diabetic rats subjected to swimming exercise (2months; N = 7); CON-TE, healthy rats subjected to treadmill exercise (2months; N = 8); STZ-TE, diabetic rats subjected to treadmill exercise (2months; N = 8). Diabetes was induced by a single intraperitoneal injection of 50mg/kg STZ. Our results showed that STZ decreased the step-through latency in the retention test (STLr) and increased the time spent in the dark compartment (TDC) when compared with the CON group. However, treadmill-running and swimming exercise in STZ-treated rats increased the STLr and decreased the TDC when compared with STZ-treated rats without exercise in PAL. Blood low-density lipoprotein (LDL) and triglyceride (TG) levels in the STZ group were significantly higher than those in the CON group, whereas plasma total antioxidant capacity (TAC) and levels of catalase (CAT) and glutathione peroxidase (GPx) were lower in the STZ group compared with the CON group. The levels of LDL and TG decreased and the levels of TAC, CAT, and GPx increased in the exercise groups in comparison with the STZ group. The present results indicate that regular exercise enhances learning and memory in diabetic rats and that these effects may occur through activation of the antioxidant system.

Beneficial actions of a long-acting apelin analogue in diabetes are related to positive effects on islet cell turnover and transdifferentiation.

The current study has tested the hypothesis that the positive effects of apelin receptor activation in diabetes are linked to benefits on islet cell apoptosis, proliferation and transdifferentiation using Ins1Cre/+ ;Rosa26-eYFP transgenic mice and induction of diabetes-like syndromes by streptozotocin (STZ) or high-fat feeding. Groups (n = 6-8) of streptozotocin (STZ)-induced diabetic and high-fat diet (HFD)-fed mice received once-daily injection (25 nmol/kg) of the long-acting acylated apelin-13 analogue, pGlu(Lys8 Glu-PAL)apelin-13 amide, for 10 or 12 days, respectively. pGlu(Lys8 Glu-PAL)apelin-13 amide treatment partly reversed body weight loss induced by STZ and normalized circulating insulin. There was no effect of pGlu(Lys8 Glu-PAL)apelin-13 amide on these variables in HFD-fed mice, but an increase in pancreatic insulin content was observed. pGlu(Lys8 Glu-PAL)apelin-13 amide also fully, or partially, reversed the detrimental effects of STZ and HFD on plasma and pancreatic glucagon concentrations. In HFD-fed mice, the apelin analogue decreased dietary-induced elevations of islet, β- and α-cell areas, whilst reducing α-cell area in STZ-induced diabetic mice. In terms of islet cell lineage, pGlu(Lys8 Glu-PAL)apelin-13 amide effectively reduced β- to α-cell transdifferentiation and helped maintain β-cell identity, which was linked to elevated Pdx-1 expression. These islet effects were coupled with decreased β-cell apoptosis and α-cell proliferation in both models, and there was an accompanying increase of β-cell proliferation in STZ-induced diabetic mice. Taken together these data demonstrate, for the first time, that pancreatic islet benefits of sustained APJ receptor activation in diabetes are linked to favourable islet cell transition events, leading to maintenance of β-cell mass.

Effects of a Nutritional Formulation Containing Caprylic and Capric Acid, Phosphatidylserine, and Docosahexaenoic Acid in Streptozotocin-Lesioned Rats.

Background:It has been studied that nutrition can influence Alzheimer’s disease (AD) onset and progression. Some studies on rodents using intraventricular streptozotocin (STZ) injection showed that this toxin changes cerebral glucose metabolism and insulin signaling pathways.Objective:The aim of the present study was to evaluate whether a nutritional formulation could reduce cognitive impairment in STZ-induced animals.Methods:The rats were randomly divided into two groups: sham and STZ. The STZ group received a single bilateral STZ-ICV injection (1 mg/kg). The sham group received a bilateral ICV injection of 0.9% saline solution. The animals were treated with AZ1 formulation (Instanth® NEO, Prodiet Medical Nutrition) (1 g/kg, PO) or its vehicle (saline solution) for 30 days, once a day starting one day after the stereotaxic surgery (n = 6–10). The rats were evaluated using the open field test to evaluate locomotor activity at day 27 after surgery. Cognitive performance was evaluated at day 28 using the object recognition test and the spatial version of the Y-maze test. At day 30, the rats were anesthetized with chloral hydrate (400 mg/kg, i.p) and euthanized in order to evaluate IBA1 in the hippocampus. The differences were analyzed using one-way ANOVA with Bonferroni’s or Kruskal Wallis with Dunn’s post-hoc test.Results/Conclusion:STZ-lesioned rats present memory impairment besides the increased microglial activation. The treatment with AZ1 formulation reversed the memory impairment observed in the object recognition test and Y-maze and also reduced IBA1 in CA1 and DG.

Supplementation with Fermented Rice Bran Attenuates Muscle Atrophy in a Diabetic Rat Model.

Fermented rice bran (FRB), a prospective supplement, has been proven to ameliorate certain medical conditions. However, its nutraceutical effect on muscle atrophy has never been investigated. The present study aimed to evaluate the effect of FRB on muscle atrophy in a streptozotocin (STZ)-induced diabetic rat model. Three groups of Sprague-Dawley rats, namely the control, STZ, and FRB groups, were treated as follows. The diabetic groups (STZ and FRB) were injected intraperitoneally with STZ (40 mg/kg BW), whereas the control group was injected with the vehicle. The STZ and control groups were fed the AIN93M diet, and the FRB group was fed 10% of FRB based on the AIN93M diet. The diabetic groups had reduced muscle size compared to the control group; however, these changes were alleviated in the FRB group. Moreover, the FRB group had a significantly lower expression of FBXO32/Atrogin-1 and TRIM63/MuRF1 (p < 0.05) due to blocked NF-κB activation. In conclusion, the anti-inflammatory effect of FRB may be beneficial for ameliorating muscle atrophy in diabetic conditions.

Gait analysis correlates mechanical hyperalgesia in a model of streptozotocin-induced diabetic neuropathy: A CatWalk dynamic motor function study

Peripheral neuropathy is a complication of diabetes commonly associated with pain and decline in motor compound action potential, leading to alterations in plantar pressure during gait. We identified motor impairments in streptozotocin (STZ)-induced diabetic neuropathic rats and correlated with mechanical withdrawal thresholds, establishing this correlation as a complementary method to investigate the development of chronic hyperalgesia in diabetic neuropathy. MethodsUNICAMP’s Ethics Committee (protocol number 3902-1) approved all experiments. Male Lewis rats (200-250 g) received a STZ-low-dose (25 mg/kg/day) (STZ group) or 0.1 M sodium citrate buffer (SCB, control group) once a day, during five consecutive days. Diabetic rats (250 mg/dL blood glucose) were submitted to electronic von Frey and CatWalk tests at 0, 7, 14, 21, and 28 days after treatment. ResultsSTZ, but not SCB, induced diabetes. After the 14th day (STZ)-induced diabetic rats showed mechanical hyperalgesia and a reduction in the hind limbs footprint intensities. At the 28th day, rats presented alterations in spatial parameters (Maximum Contact Area; Stride Length; Print Area), which showed a strong correlation with mechanical withdrawal thresholds (r2 = 0.97; 0.99, and 0.93, respectively). ConclusionsCorrelation between gait parameters and mechanical withdrawal thresholds enables a better experimental approach to evaluate the development of chronic hyperalgesia in the STZ-induced diabetes model. It allows a concise crosstalk of motor and sensorial functions, which are usually analyzed individually. CatWalk gait parameters can be used as a complementary tool to investigate the development of hyperalgesia in STZ-induced diabetic neuropathic rats.

Effect of Alpina oxyphylla extract on streptozotocin-induced kidney injure via regulating TGF-\u03b21 and MyD88

BackgroundAbnormal renal metabolism is closely related to the development of chronic kidney disease. It is well known that renal inflammation plays an important role in the occurrence and development of tubulointerstitial damage in the renal tubules. The purpose of the experiment was to observe the bioactivity of Alpina oxyphylla extract (AOE) on renal injury in diabetic nephropathy (DN) rats induced by streptozotocin (STZ).MethodsThirty male Wistar rats were randomly divided into five group (n = 6): (1) intact control (non-diabetic, ND); (2) intact diabetic (STZ), (3) diabetic rats treated with gliclazide 5 mg/kg (STZ-gli), (4) diabetic rats treated with AOE 400 mg/kg (AOE 400), (5) diabetic rats treated with AOE 800 mg/kg (AOE 800). The diabetic nephropathy rat model was established by single intraperitoneal injected 50 mg/kg STZ. Fasting blood glucose (FBG) and body weight was observed at 1、3、6 weeks. After 6 weeks, the renal function parameters of five groups and 24 h urinary protein were detected. Expression of transforming growth factor-beta1 (TGF-β1) and myeloid differentiation factor 88 (MyD88) were assessed by Western Blot.ResultsThe STZ group showed hyperglycemia, proteinuria, renal function damage, and the levels of 24 h urinary protein, fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (Scr), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and interleukin-6 (IL-6) in the STZ group increased significantly compared with the ND group. The expression of TGF-β1 in STZ group was increase (p < 0.01), and the expression of MyD88 was significantly lower than in ND group (p < 0.05). The treatment of DN rats with AOE attenuated DN-associated in the serum biochemical index and the expression of TGF-β1.ConclusionsAOE can effectively protect kidney tissues of diabetic nephropathy, and probably through regulating level of TGF-β1/MyD88.

Protective Effects of Co-administration of Zinc and Selenium Against Streptozotocin-Induced Alzheimer's Disease: Behavioral, Mitochondrial Oxidative Stress, and GPR39 Expression Alterations in Rats.

Changes in the concentrations of trace metals such as zinc (Zn) and selenium (Se) can pathologically lead to neurodegenerative conditions such as the Alzheimer's disease (AD). Previous studies have shown that mitochondrial dysfunction plays an important role in the pathogenesis of AD. Several male Wistar rats were randomly divided into five groups: sham group, AD group that received 3mg/kg of streptozotocin (STZ) intracerebroventricularly, AD + Zn group that received 10mg/kg of Zn intraperitoneally (i.p.) for 1week, AD + Se group that received 0.1mg/kg of Se i.p. for 1week, and AD + Zn + Se group that received 10mg/kg of Zn i.p. plus 0.1mg/kg of Se i.p. for 1week. At end of the study, behavioral tests and mitochondrial oxidative stress and GPR39 gene expression evaluations were carried out. Co-administration of Zn and Se significantly decreased the potential collapse of mitochondrial membrane, reactive oxygen species levels, and lipid peroxidation levels while significantly increased cognitive performance, superoxide dismutase (SOD), glutathione peroxidase, and catalase activity in the brain mitochondria compared with the STZ group. In addition, no significant changes were observed in GPR39 expression in the co-treated group. Findings of the current study showed that ZnR/GPR39 receptor, mitochondrial dysfunction, and oxidative stress play important roles in the pathogenesis of AD. Co-treatment of Zn and Se improved the cognitive performance, mitochondrial dysfunction, and oxidative stress caused by STZ-induced AD. Therefore, therapeutic approaches to improve mitochondrial function could be effective in preventing the initiation and progression of AD.