STZ-induced Hyperglycemic Mice Research Articles

Anti-hyperglycemic effect of herbal formula of Moringa oleifera, Vernonia amygdalina and Centella asiatica extracts in streptozotocin-induced hyperglycemic mice

IntroductionMoringa oleifera, Vernonia amygdalina, and Centella asiatica are herbs used in traditional Chinese medicine and are commonly used in Southeast Asian countries to treat a variety of diseases. The experimental evidence showed that M. oleifera leaves, V. amygdalina leaves, and C. asiatica had the effect of supporting their treatment of diabetes. This study investigated the anti-hyperglycemic effect of a novel herbal formula from M. oleifera leaf, V. amygdalina leaf, and C. asiatica aerial part extracts. MethodsThe extract was examined for anti-hyperglycemic capacity in oral glucose tolerance test in normal mice. To confirm their role in a higher model, the extract was studied in the streptozotocin (STZ)-induced hyperglycemic model. Plasma glucose concentration, body weight, organ weight, malondialdehyde, glutathione in liver and kidneys, and pancreatic histology were also evaluated. Besides, in vitro properties of the extract were tested including α-amylase and α-glucosidase inhibitory, and antioxidant activities. ResultsAfter 7-day of treatment, the extract showed strong anti-hyperglycemic activity in the STZ-induced hyperglycemic mice, plasma glucose levels were reduced by 48.75 % and 54.13 % in the group administered with 200 mg/kg and 400 mg/kg of the extract, respectively, compared with the hyperglycemic control. The extract had the effect to protect the liver and kidneys against oxidation stress by enhancing glutathione levels in the liver and decreasing malondialdehyde levels in the liver and kidneys. The pancreatic β-cell protection was also observed by improving the size and number of pancreatic islets by the extract compared to the hyperglycemic control. The extract showed a significant α-amylase and α-glucosidase inhibitory activities, and antioxidant activity through DPPH and ABTS quenching and reducing power abilities. DiscussionThese results demonstrated remarkable potential of the combined extract of M. oleifera leaves, V. amygdalina leaves, and aerial part of C. asiatica in the management of diabetes.

Chitosan-based injectable hydrogels with dual glucose sensors for precise control of insulin release and diabetes mellitus therapy

Chitosan-based injectable hydrogels were designed and fabricated through the dynamic crosslinking of dual-reversible covalent bonds (imine and phenylboronate ester) for precise insulin release. The hydrogels contain dual glucose-sensors/responsive elements, featuring high sensitivity and rapid responsiveness to glucose level variation in cumulative and half-hourly pulsed insulin release. The hydrogels demonstrated improved cytocompatibility against HSF cells and histological long-term analysis of tissue after implantation. Evaluation of the glycemic control ability in STZ-induced hyperglycemic mice revealed that the hydrogel system showed excellent glycemic control ability in the glucose tolerance test and maintained blood glucose levels in a normal range for up to 11 days after a single administration. Thus, the hydrogel system showed applicable potential in insulin replacement therapy for diabetes mellitus.

Soy yoghurts produced with efficient GABA (γ-aminobutyric acid)-producing Lactiplantibacillus plantarum ameliorate hyperglycaemia and re-establish gut microbiota in streptozotocin (STZ)-induced diabetic mice.

Soy yogurt has been gaining popularity as a vegan food produced simply by soymilk fermentation with proper microbial manipulation. It is well known that soy containing rich isoflavones is beneficial for ameliorating hyperglycaemic disorders. Soy fermentation can improve the bioavailability of these precious nutrients. Lactiplantibacillus plantarum is one of the most abundant and frequently isolated species in soymilk manufacturing. Soy yogurts produced with efficient GABA (γ-aminobutyric acid)-producing L. plantarum and the deglycosylating activity of L. plantarum were functionally assessed in a STZ-induced hyperglycaemic mouse model. Hyperglycaemic mice were assigned into groups and treated with daily gavage of either dH2O, soymilk, soy yoghurts produced with high GABA-producing L. plantarum GA30 (LPGA30), low GABA-producing L. plantarum PV30 (LPPV30) or the soy yoghurts fortified with additional 30 mg g-1 GABA counterparts (GA + GABA and PV + GABA groups). Except the dH2O group, all soy yoghurt groups retained body weight with improved glucose homeostasis, glucose tolerance test results and renal tissue integrity, while the soymilk group shows partial benefits. Plasma GABA concentrations in the daily soy yoghurt-supplemented groups (LPGA30 and LPPV30) plateaued at 5 times higher than the average 0.5 μM in dH2O and soymilk groups, and their GABA-fortified soy yoghurt counterparts (GA + GABA and PV + GABA) groups were accountable for the restored plasma insulin levels. Gut microbiome analysis revealed dysbiosis in STZ-induced hyperglycemic mice of the dH2O group with breached out facultative anaerobic Proteobacteria over the normal phyla Firmicutes and Bacteroidetes. Restored gut microbiota with transitionally populated Actinobacteria was demonstrated in the LPGA30 group but not in the LPPV30 group. Soy yoghurts produced with efficient GABA-producing L. plantarum GA30 showed exceptional benefits in modulating gut microbiota with dominant genera of Enterococcus, Lactobacillus and Bifidobacterium, and the presence of some minor beneficial microbial communities including Akkermansia muciniphila, Butyricicoccus pullicaecorum, Corynebacterium spp. and Adlercreutzia spp. Efficient GABA-producing L. plantarum GA30 fermented soymilk to produce soy yoghurts that exhibit profound synergistic protections over rich soy isoflavones to restore pancreatic β-cell functions for insulin production in STZ-induced hyperglycaemic mice. Additionally, the probiotic role of GABA-producing L. plantarum in re-establishing healthy gut microbiota in hyperglycaemic mice implies a possible symbiotic relationship, awaiting further exploration.

In Vitro and In Vivo Assessments of Anti-Hyperglycemic Properties of Soybean Residue Fermented with Rhizopus oligosporus and Lactiplantibacillus plantarum

Soy isoflavones possess antioxidative, anti-inflammatory, anti-diabetic and phytoestrogenic properties. Soybean residue contains a fair amount of nutrients such as glycosylated isoflavones, minerals and dietary fibers, and is a substantial waste product produced from soymilk and tofu manufacturing. A solid-state fermentation of soybean residue by Rhizopus oligosporus or co-inoculated with Lactiplantibacillus plantarum improves the availability of isoflavones and GABA content which is attributed to ameliorated hyperglycemic symptoms in STZ-induced hyperglycemic mice. The effortless solid-state fermentation with present microbial manipulation supports an anti-hyperglycemia value-added application of soybean residue for functional food development. Background: Due to an awareness of the food crisis and with a rapidly rising prevalence of diabetes, recycling the substantial fibrous soybean residue disposed from soy industries has received consideration. Methods: Lactiplantibacillus plantarum was previously screened for active glutamate decarboxylase, and β-glucosidase activities were adopted for the fermenting of soybean residue using a traditional tempeh solid-state fermenting process with fungal Rhizopus oligosporus. Fermented soybean residue was chemically analyzed and functionally assessed in in vitro and in vivo hyperglycemic conditions. Results: A 48 h longer solid-state fermentation of the soybean residue co-inoculated with R. oligosporus and L. plantarum showed improved contents of isoflavone aglycones and GABA which were attributed to augmented antioxidative capacity, lowered ROS level, improved blood biochemistry, and better blood glucose homeostasis in STZ-induced hyperglycemic mice. Conclusion: The advantages of a food industrial effortless fermentation process, and a health nutritional endorsing anti-hyperglycemic value-added property offer a practical alternative in recycled soybean residue.

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by \u03b2-catenin signaling

Although hyperglycemia has been documented as an unfavorable element that can further induce liver ischemia–reperfusion injury (IRI), the related molecular mechanisms remain to be clearly elaborated. This study investigated the effective manner of endoplasmic reticulum (ER) stress signaling in hyperglycemia-exacerbated liver IRI. Here we demonstrated that in the liver tissues and Kupffer cells (KCs) of DM patients and STZ-induced hyperglycemic mice, the ER stress-ATF6-CHOP signaling pathway is activated. TLR4-mediated pro-inflammatory activation was greatly attenuated by the addition of 4-phenylbutyrate (PBA), one common ER stress inhibitor. The liver IRI in hyperglycemic mice was also significantly reduced after PBA treatment. In addition, deficiency of CHOP (CHOP−/−) obviously alleviates the hepatic IRI, and pro-inflammatory effects deteriorated by hyperglycemia. In hyperglycemic mice, β-catenin expression was suppressed while the ATF6-CHOP signal was activated. In the liver tissues of PBA-treated or CHOP−/− hyperglycemic mice, the expression of β-catenin was restored. Furthermore, CHOP deficiency can induce protection against hyperglycemia-related liver IRI, which was disrupted by the knockdown of β-catenin will cause this protection to disappear. High glucose (HG) treatment stimulated ATF6-CHOP signaling, reduced cellular β-catenin accumulation, and promoted the TLR4-related inflammation of BMDMs. But the above effects were partially rescued in BMDMs with CHOP deficiency or by PBA treatment. In BMDMs cultured in HG conditions, the anti-inflammatory functions of CHOP−/− were destroyed by the knockdown of β-catenin. Finally, chimeric mice carrying WT or CHOP−/− BMDMs by bone marrow transplantation were adopted to verify the above conclusion. The current study suggested that hyperglycemia could trigger ER stress-ATF6-CHOP axis, inhibit β-catenin activation, accelerate inflammation, and deteriorate liver IRI, thus providing the treatment potential for management of sterile liver inflammation in DM patients.

Catalpol Weakens Depressive-like Behavior in Mice with Streptozotocin-induced Hyperglycemia via PI3K/AKT/Nrf2/HO-1 Signaling Pathway

Depression has huge social risks of high incidence, disability, and suicide. Its prevalence and harm in people with hyperglycemia are 2–3 times higher than in normal people. However, antidepressants with precise curative effects and clear mechanisms for patients with hyperglycemia are currently lacking. Prescriptions containing Radix Rehmannia glutinosa Libosch., a traditional medicinal herb with a wide range of nutritional and medicinal values, are often used as antidepressants in Chinese clinical medicine. Catalpol is one of the main effective compounds of Radix R. glutinosa, with multiple biological activities such as hypoglycemia. Here, the antidepressant effect of catalpol on the pathological state of streptozotocin (STZ)-induced hyperglycemia and the underlying molecular mechanisms were analyzed. Results showed that administering catalpol orally to hyperglycemic mice for 21 consecutive days significantly reversed the abnormalities in tail suspension, forced swimming, and open field tests. Catalpol also reversed the abnormal phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) and the abnormal levels of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, heme oxygenase-1 (HO-1), and antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and malondialdehyde in the hippocampus and frontal cortex of STZ-induced hyperglycemic mice. Thus, catalpol attenuates depressive-like behavior in pathological hyperglycemic state, and the antidepressant mechanism could at least be partly attributed to the upregulation of the PI3K/AKT/Nrf2/HO-1 signaling pathway in both brain regions, thus restoring the balance between oxidative and antioxidant damage. These data expanded the scientific understanding of catalpol and provided preclinical experimental evidence for its application.

Hypoglycemic effects of Tibetan medicine Huidouba in STZ-induced diabetic mice and db/db mice

ObjectiveHuidouba (HDB) is a Chinese folk medicine used to treat diabetes in Sichuan Province, China. Therefore, we investigated the anti-diabetic effects of HDB and its underlying mechanisms. We hypothesized that HDB treatment could enhance glucose tolerance and insulin sensitivity, and thus prevent a hyperglycemia state. MethodsTo test the hypothesis, streptozotocin (STZ)-induced diabetic mice and db/db mice, widely used models of hyperglycemia and insulin-resistant diabetes, were either treated with HDB, metformin, or acarbose. Blood glucose, oral glucose tolerance test, insulin tolerance test, pancreatic histopathology and serum biochemistry were detected to assess the hypoglycemic effect of HDB. ResultsHDB treatments were found to show the effect in reducing glucose levels. HDB also resulted in a significant reduction in body weight and food intake in the STZ-induced diabetic mouse model. Furthermore, it significantly improved glucose and insulin tolerance in the two diabetic mouse models. Importantly, insulin, glucagon, pancreatic polypeptide, and somatostatin immunohistochemistry revealed that HDB treatment improved the function and the location of the cells in the islets compared with the other two treatments. HDB treatment resulted in significant restoration of islet function. Our results illustrated the underlying mechanism of HDB in the progression of diabetes, and HDB can be an effective agent for the treatment of diabetes. ConclusionThe results of this study suggested that HDB can reduce blood glucose levels in STZ-induced hyperglycemic mice and db/db mice.

Hyperglycemia induces RAGE-dependent hippocampal spatial memory impairments

Diabetes is a prevalent metabolic disorder that has long been associated with changes in different regions of the brain, including the hippocampus. Changes in hippocampal synaptic plasticity and subsequent impairment in cognitive functions such as learning and memory, are well documented in animal models of type 1 and type 2 diabetes. It is known that RAGE contributes to peripheral micro- and macro-vascular complications of diabetes. However, it is still unknown if RAGE plays a similar role in the development of CNS complications of diabetes. Therefore, we hypothesize that RAGE contributes to cognitive dysfunction, such as learning and memory impairments, in a mouse model of STZ-induced hyperglycemia. Control and STZ-induced hyperglycemic mice from WT and RAGE-KO groups were used for the behavioral experiments. While STZ-induced hyperglycemia decreased locomotor activity in the open field (OF) test, it did not affect the recognition memory in the novel object recognition (NOR) test in either genotype. Spatial memory, however, was impaired in STZ-induced hyperglycemic mice in WT but not in RAGE-KO group in both the Barnes maze (BM) and the Morris water maze (MWM) tests. Consistently, the RAGE antagonist FPS-ZM1 protected WT STZ-induced hyperglycemic mice from spatial memory impairment in the BM test. Our findings indicate that the parameters associated with locomotor activity and recognition memory were independent of RAGE in STZ-induced hyperglycemic mice. In contrast, the parameters associated with hippocampal-dependent spatial memory were dependent on RAGE expression.

MON-481 MA-[D-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Enhances the Effects of Insulin on Glycemic Control and Cognitive Function in Streptozotocin-Induced Hyperglycemic Swiss Webster Mice

Glucose dysregulation and disruption of insulin signaling in the brain have been suggested as a possible etiology of Alzheimer’s Disease. In the present study, we show that oral delivery of MA-[D-Leu-4]-OB3 to young male Swiss Webster (SW) mice rendered hyperglycemic by intraperitoneal injection of streptozotocin (STZ), prevented insulin-induced increase in body weight gain and enhanced the effects of insulin alone on fasting blood glucose to levels approaching those of normal SW mice of the same age and sex. Novel object testing indicated that insulin treatment improved working memory in STZ-induced hyperglycemic mice, and that MA-[D-Leu-4]-OB3 given in combination with insulin significantly accelerated the time course of this improvement. Although positive results in an animal model may not be recapitulated in human pathology, our data suggest that MA-[D-Leu-4]-OB3, when added to an insulin regimen, may have application to the treatment of Alzheimer’s Disease by improving insulin sensitivity and glycemic control, thus slowing or preventing the progression of memory disruption associated with this disease.

Glycolytic Activation Promotes PDGF-B Production in Adipose Tissue Macrophages during Obesity Development

The vascular network develops with remodeling in adipose tissue (AT) during obesity. We have found that PDGF-B detaches pericytes from the vasculature, which plays a crucial role in angiogenesis during obesity. The expression of PDGF-B was significantly elevated in obesity-associated infiltrated CD11c-positive (+) AT macrophages (ATMs). Interestingly, the expression was low in both CD11c+ ATMs and CD206+ ATMs of lean mice. Since glycolytic and oxidative metabolism are key metabolic programs that regulate ATMs’ polarity and function, we hypothesized that hyperglycemia and inflammation synergistically drive PDGF-B production by reprogramming metabolic pathways in ATMs. The expression of PDGF-B was increased in the AT of high-fat diet (HFD)-fed mice and STZ-induced hyperglycemic mice. In accordance, exposure to high glucose led to increase the expression of PDGF-B in association with that of Itgax (CD11c) in RAW264.7 macrophages. In peritoneal macrophages, LPS but not IL-4 provoked PDGF-B expression, which was completely blocked by pretreatment with 2-DG, a glycolysis inhibitor. Moreover, LPS effectively augmented high glucose-induced its expression, and that was abolished by MG132, an NFκB inhibitor. Since macrophages highly accumulated in obese AT, where pericytes were detached from vasculature, we examined directly whether PDGF-B from macrophage involves in AT expansion during obesity. To this end, we intraperitoneally injected liposome-encapsulated clodronate (CL) to mice twice a week for 6 weeks during HFD feeding. ATMs were effectively depleted by CL with reduced PDGF-B expression in AT of HFD-induced obese mice. Importantly, HFD-induced obesity was effectively prevented by CL. In conclusion, PDGF-B from ATMs has a crucial function in AT expansion during obesity. Hyperglycemia and chronic inflammation reprogram metabolic pathways toward glycolysis, and subsequent activation of NFκB plays a pivotal role in the production of PDGF-B in ATMs during obesity. Disclosure Y. Onogi: None. T. Wada: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. T. Matsuzawa: None. A. Okekawa: None. E. Watanabe: None. H. Tsuneki: None. T. Sasaoka: None.

Chlorogenic acid attenuates diabetic retinopathy by reducing VEGF expression and inhibiting VEGF-mediated retinal neoangiogenesis

Diabetic retinopathy (DR) is one of the most common and serious complications of diabetes mellitus (DM). This study aims to investigate the amelioration of chlorogenic acid (CGA) on proliferative DR (PDR) via focusing on inhibiting retinal neoangiogenesis. CGA reduced the increased cell proliferation, migration and tube formation induced by vascular endothelial growth factor (VEGF) in human retinal endothelial cells (HREC) and choroid-retinal endothelial RF/6A cells. CGA abrogated VEGF-induced the phosphorylation of VEGFR2 and its downstream mitogen-activated extracellular regulated kinase (MEK1/2), extracellular regulated protein kinase (ERK1/2) and p38 kinase. CGA reduced high glucose (HG)-induced the activation of microglia BV-2 cells. CGA also reduced HG-induced the increased VEGF expression and hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus in BV2 cells. Retinal immunofluorescence staining with cluster of differentiation 31 (CD31) and retinal histopathological observation both demonstrated that CGA (1, 10mg/kg) decreased the increased retinal vessels in streptozotocin (STZ)-induced hyperglycemic mice. CGA reduced the elevated serum VEGF level and microglia activation in STZ-induced hyperglycemic mice. In conclusion, CGA inhibits retinal neoangiogenesis during the process of DR by abrogating HG-induced HIF-1α-mediated paracrine VEGF expression in microglia cells and inhibiting VEGF-induced angiogenesis in retinal endothelial cells.

PENGARUH EKSTRAK ETANOL BUAH LABU SIAM (SECHIUM EDULE JACQ.SWARTZ.) TERHADAP KADAR INTERLEUKIN 6 DAN HISTOPATOLOGI PANKREAS MENCIT HIPERGLIKEMIA YANG DIINDUKSI STREPTOZOTOCIN (STZ)

Diabetes mellitus now becomes a global serious theat with continues encreasingly prevalence. Ethanol extract of squash fruit Chayotte (Sechium edule) is a plant that contains flavonoidsareanti-inflammatory. The objective of this study was to determine the effect of ethanol extract of Squash fruit Chayotte (Sechium edule) to Interleukin 6 level and increasedthe size ofthe diameter of the pancreas in STZ-induced hyperglycemic mice model. Goals : This research is experimental research uses Post test randomized controlled group design upon male mice, and divided into 4 groups; negative control group, positive control group is treated with streptozotocin at a dose of 60 mg/kg weight, and groups of therapy (dosage 100 gram/kg weight, 200 gram/kg weight). Methods : The measurement of the level interleleukin 6 (IL-6) used ELISA method and the description of histopatoligy pancreas. The data analysis of level IL-6 level uses One Way ANOVA (α = 0,005) and pancreas histology image used descriptive analysis. Result : The results showed a decrease in the levels of IL-6, although not significant if it’s compared to the positive control. The preparat histopathology pancreas observation increased diameter which showed widening of cell β of pancreas. Conclution : The conclusion of this research was that ethanol extract of squash fruit can reduce levels IL-6 and prevent the hiperglikemia mice pancreas damages

Daidzin decreases blood glucose and lipid in streptozotocin-induced diabetic mice

Purpose: To investigate the ameliorative effect of daidzin (DZ) on diabetes in streptozotocin (STZ)- induced diabetic Institute of Cancer Research (ICR) mice, with a view to determining its usefulness in the treatment of diabetes. Methods: The effect of DZ (100, 200 and 400 mg/kg) on blood glucose was investigated in both normal and STZ-induced diabetic mice with glibenclamide (3 mg/kg) and metformin (400 mg/kg) as positive control, respectively. Serum or hepatic levels of lipid, proinflammatory factors, malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Glucosidase activity assay and glucose uptake by C2C12 myotubes were performed in vitro and the expression of glucose transporter 4 (GLUT4) in C2C12 cells was determined by western blot. Results: DZ (200 and 400 mg/kg) did not decrease fasting blood glucose in normal mice but inhibited starch-induced postprandial glycemia. Oral administration of 400 mg/kg of DZ for 14 days significantly decreased mouse blood glucose (p < 0.01), as well as serum total cholesterol (TC, p < 0.01), triglycerides (TG, p < 0.01), low-density lipoprotein cholesterol (LDL-c, p < 0.01) levels in STZ-induced hyperglycemic mice and improved oral glucose tolerance. The serum and hepatic activity of SOD was enhanced (p < 0.01 and p < 0.001, respectively) while MDA level decreased (p < 0.001). Blood concentrations of interleukin-6 (IL-6, p < 0.001), tumor necrosis factor α (TNF-α, p < 0.01), monocyte chemotactic protein 1 (MCP-1, p < 0.01) were also significantly reduced. In vitro glucosidase activity results showed that DZ inhibited α-glucosidase with IC50 values of 82, 98 and 389 μg/mL for α- glucosidase from S. cerevisiae , Rhizopus sp. and rat intestines, respectively. It also stimulated glucose uptake and GLUT4 membrane translocation in C2C12 myotubes at 20 μM (p < 0.05). Conclusion: Oral administration of DZ is effective in alleviating diabetic hyperglycemia, dyslipidemia and inflammation. Inhibition of α-glucosidase and stimulation of glucose consumption by muscles may account for its inhibitory effect on blood glucose. Keywords: Daidzin, Diabetes, Inflammation, Superoxide dismutase (SOD), Malondialdehyde (MDA), Glucosidase, C2C12 myotubes, Glucose transporter

Broad Infiltration of Macrophages Leads to a Proinflammatory State in Streptozotocin-Induced Hyperglycemic Mice.

Chronic diseases are often associated with altered inflammatory response, leading to increased host vulnerability to new inflammatory challenges. Employing streptozotocin (STZ)-induced diabetes as a model, we further investigate mechanisms leading to enhanced neutrophil (polymorphonuclear leukocytes [PMN]) responses under hyperglycemia and compare them with those under chronic colitis. We show that, different from colitis under which the PMN response is significantly potentiated, the existence of a proinflammatory state associated with broad increases in macrophages in various organs plays a dominant role in promoting the PMN inflammatory response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment not through inducing a high level of IL-17, which is the case in colitis, but through increasing F4/80+ macrophages in the peritoneal cavity, resulting in elevations of IL-6, IL-1β, TNF-α, and CXCL1 production. Insulin reversal of hyperglycemia, but not the neutralization of IL-17, reduces peritoneal macrophage numbers and ameliorates PMN infiltration during peritonitis. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and they are attributable to exacerbated nephropathy and colitis when inflammatory conditions are induced by doxorubicin and dextran sulfate sodium, respectively. Furthermore, analyses of monocyte production and macrophage proliferation in tissues suggest that significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages.

Curcumin, Hesperidin, and Rutin Selectively Interfere with Apoptosis Signaling and Attenuate Streptozotocin-Induced Oxidative Stress-Mediated Hyperglycemia.

Type I Diabetes is characterized by the presence of hyperglycemia due to insulin deficiency and consequent impaired hepatic glucose metabolism. During diabetes, the liver becomes the most important tissue for the regulation of serum glucose. However, elevated glucose causes continuous oxidative damage to the liver, reducing its capacity to ameliorate hyperglycemia, which contributes to macrovascular complications [1]. Numerous epidemiological studies have demonstrated that excess human consumption of diets rich in specific bioflavonoid phytochemicals attenuates the effects of diabetes. Thus, this study was designed to investigate whether a bioflavonoid mixture could : i) attenuate streptozotocin (STZ)-induced hyperglycemia, ii) potentiate antioxidant signaling in the liver, and iii) ameliorate the apoptotic signaling cascade in the liver of STZ-induced hyperglycemic mice. In order to examine our hypothesis, three well-investigated antioxidant phytochemicals, curcumin, hesperidin and rutin, were combined into a mixture (CHR) for this study. Diabetes was induced in 6-month-old female ICR mice by STZ (100 mg/kg, i.p.) administration, and CHR or vehicle control was orally administered (200 mg/kg per body weight of each ingredient) to the hyperglycemic mice (blood glucose levels > 250 mg/dl) for a period of 14 days. Administration of CHR to the hyperglycemic mice significantly reduced blood glucose levels, attenuated STZ-induced lipid peroxidation and total nitrate/nitrite levels, and significantly augmented the expression of superoxide dismutase and glutathione in the liver. STZ-induced hyperglycemia resulted in downregulation of antiapoptotic proteins Bcl-2 by 66% and Bcl-XL by 51%, and upregulation of the pro-apoptotic Bad (69%) with an increase in the ratio of cytosolic/mitochondrial cytochrome c by 81% in hepatic tissue. Administration of CHR significantly ameliorated apoptotic signaling in STZ-induced diabetic mice, significantly increasing Bad/Bcl-2 and Bad/Bcl-XL ratios to 410% and 244% respectively in the hyperglycemic group. This study demonstrated that a bioflavonoid mixture of curcumin, hesperidin and rutin (CHR) ameliorates hepatic oxidative stress caused by STZ-induced hyperglycemia, resulting in improved hepatic function and glucose regulation.

Effects of Grifola frondosa non-polar bioactive components on high-fat diet fed and streptozotocin-induced hyperglycemic mice

Context: Consumption of medicinal mushrooms for disease prevention and maintaining health has a very long history in Asia. Grifola frondosa (Fr) S.F. Gray (GF) (Meripilaceae) is a medicinal fungus popularly used for enhancing immune systems, lowering blood glucose, and improving spleen, stomach, and nerve functions.Objective: This study examines the hypoglycemic effects of GF in vitro and in vivo, and analyzes the chemical profiles of its bioactive components.Materials and methods: In vitro hypoglycemic effects of GF was evaluated enzymatically using α-amylase and α-glucosidase inhibition assays, whereas in vivo study was conducted on high-fat diet fed and streptozotocin (HFD + STZ)-induced hyperglycemic mice. GC-MS was used to determine the chemical profiles of bioactive components.Results: The non-polar fraction of GF exhibited a stronger anti-α-glucosidase activity (IC50: 0.0332 mg/ml) than acarbose, but its anti-α-amylase activity (IC50: 0.671 mg/ml) was weaker. Oral administration of GF at 600 mg/kg (GF600) significantly lowered the blood glucose, HbA1c, average blood glucose, and serum total cholesterol levels in hyperglycemic mice. Although GF was found to contain mainly oleic acid and linoleic acid, their levels in the fungus were low, suggesting that the effects of GF on HFD + STZ-induced hyperglycemic mice could be due to factors other than these fatty acids.Conclusion: These results conclude that GF possesses anti-α-glucosidase activity, and hypoglycemic effect in HFD + STZ-induced hyperglycemic mice.

Guizhi-Fuling-Wan, a Traditional Chinese Herbal Medicine, Ameliorates Memory Deficits and Neuronal Apoptosis in the Streptozotocin-Induced Hyperglycemic Rodents via the Decrease of Bax/Bcl2 Ratio and Caspase-3 Expression.

Brain neuronal apoptosis and cognitive impairment are associated with hyperglycemia and diabetes mellitus. The present study determined if the Chinese herbal medicine Guizhi-Fuling-Wan (GFW) would reduce memory loss and neuronal apoptosis in streptozotocin- (STZ-) induced hyperglycemic rodents. Two weeks after STZ induction, GFW was orally administered once daily for 7 days. GFW significantly improved spatial memory deficits in STZ-induced hyperglycemic mice. GFW decreased TUNEL-positive cells and caspase-3 positive cells in STZ-induced hyperglycemic rats. It also was found that GFW treatment reduced caspase-3 protein levels and increased levels of the antiapoptotic protein Bcl-2 that were indicative of neuroprotection. The protective therapeutic effects of GFW on neuronal apoptosis and cognition deficits caused by STZ-induced hyperglycemia may be due in part to inhibition of the cellular apoptosis pathway. GFW may have therapeutic effects in patients with diabetes-mellitus-induced neuropathology.

Effects of selected minerals on leptin secretion in streptozotocin-induced hyperglycemic mice.

The effects of lithium, magnesium, vanadate, and zinc on leptinemia and leptin secretion by adipose tissue were investigated in streptozotocin- (STZ) induced hyperglycemic mice. After the administration of studied minerals in drinking water for 4 weeks, fasting serum leptin concentrations were elevated, accompanied by normoglycemia in STZ-injected mice, regardless which mineral was provided (P < 0.05). However, the in vitro administration of lithium, magnesium, and vanadate did not significantly influence the leptin secretion of adipose tissue. A low zinc treatment (0.1 mM) augmented, whereas both a pharmacological treatment of zinc (1 mM) and zinc depletion (1 mM TPEN) attenuated, leptin secretion (P < 0.05). The present study shows that STZ-induced hyperglycemic mice have hypoleptinemia and reduced leptin secretion by adipose tissue. Moreover, these defects can be improved by a moderate zinc administration.

POSSIBLE PROTECTIVE EFFECT OF MELATONIN AND/OR DESFERRIOXAMINE AGAINST STREPTOZOTOCIN-INDUCED HYPERGLYCAEMIA IN MICE

There is a clear link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alteration of endogenous antioxidants. The present study is an attempt to evaluate the possible protective effect of melatonin (MLT) and/or desferrioxamine (DF) against streptozotocin (STZ)-induced hyperglycaemia in mice. Serum lipid profile, pancreatic tissue contents of glutathione (GSH) and malondialdehyde (MDA) were determined. MLT and/or DF were given p.o. in doses of 5 mg kg−1day−1and 250 mg kg−1day−1, respectively for 15 consecutive days prior to STZ treatment (60 mg kg−1day−1i.p.) for 3 consecutive days. Results revealed that STZ induced a marked increase in serum glucose, serum triglycerides (TG), cholesterol (CHO) andLDL-cholesterol . On the contrary HDL-cholesterol was markedly decreased in STZ-treated group. Moreover, STZ induced a significant decrease in the pancreatic content of GSH with concomitant increase in MDA content. Administration of MLT or (MLT+DF) prior to STZ treatment revealed a marked decrease in serum glucose level by 35.6 and 31.6%, respectively as compared to STZ-treated group. Furthermore, MLT pretreatment of STZ-induced hyperglycemic mice, has not only normalized GSH content of pancreatic tissues but also increased its level more than that of control animals by 110%. On the contrary, MDA content of pancreatic tissues was markedly decreased even lower than normal control group. MLT also, induced a marked protection in terms of decreasing serum CHO, LDL, TG by 21.8, 83.8 and 82.2%, respectively, while HDL was increase by 56% as compared to STZ treated group. DF was found to be less effective than MLT in the protection against STZ-induced hyperglycemia. In conclusion, these data suggest that MLT protects against the damaging consequences induced by hyperglycemia either systemically or in the pancreatic tissues.