The Effects of Prolonged Treatment with Cemtirestat on Bone Parameters Reflecting Bone Quality in Non-Diabetic and Streptozotocin-Induced Diabetic Rats.

Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Experimental animals were assigned to four groups: non-diabetic rats, non-diabetic rats treated with cemtirestat, diabetic rats, and diabetic rats treated with cemtirestat. Higher levels of plasma glucose, triglycerides, cholesterol, glycated hemoglobin, magnesium, reduced femoral weight and length, bone mineral density and content, parameters characterizing trabecular bone mass and microarchitecture, cortical microarchitecture and geometry, and bone mechanical properties were determined in STZ-induced diabetic versus non-diabetic rats. Treatment with cemtirestat did not affect all aforementioned parameters in non-diabetic animals, suggesting that this drug is safe. In diabetic rats, cemtirestat supplementation reduced plasma triglyceride levels, increased the Haversian canal area and slightly, but insignificantly, improved bone mineral content. Nevertheless, the insufficient effect of cemtirestat treatment on diabetic bone disease does not support its use in the therapy of this complication of type 1 diabetes mellitus.

Heteroleptic oxidovanadium(IV)-malate complex improves glucose uptake in HepG2 and enhances insulin action in streptozotocin-induced diabetic rats.

Diabetes mellitus, a complex and heterogeneous disease associated with hyperglycemia, is a leading cause of mortality and reduces life expectancy. Vanadium complexes have been studied for the treatment of diabetes. The effect of complex [VO(bpy)(mal)]·H2O (complex A) was evaluated in a human hepatocarcinoma (HepG2) cell line and in streptozotocin (STZ)-induced diabetic male Wistar rats conditioned in seven groups with different treatments (n = 10 animals per group). Electron paramagnetic resonance and 51V NMR analyses of complex A in high-glucose Dulbecco's Modified Eagle Medium (DMEM) revealed the oxidation and hydrolysis of the oxidovanadium(IV) complex over a period of 24 h at 37 °C to give low-nuclearity vanadates "V1" (H2VO4-), "V2" (H2V2O72-), and "V4" (V4O124-). In HepG2 cells, complex A exhibited low cytotoxic effects at concentrations 2.5 to 7.5 µmol L-1 (IC50 10.53 µmol L-1) and increased glucose uptake (2-NBDG) up to 93%, an effect similar to insulin. In STZ-induced diabetic rats, complex A at 10 and 30 mg kg-1 administered by oral gavage for 12 days did not affect the animals, suggesting low toxicity or metabolic impairment during the experimental period. Compared to insulin treatment alone, complex A (30 mg kg-1) in association with insulin was found to improve glycemia (30.6 ± 6.3 mmol L-1 vs. 21.1 ± 8.6 mmol L-1, respectively; p = 0.002), resulting in approximately 30% additional reduction in glycemia. The insulin-enhancing effect of complex A was associated with low toxicity and was achieved via oral administration, suggesting the potential of complex A as a promising candidate for the adjuvant treatment of diabetes.

Structural characterization and hypoglycemic effect via stimulating glucagon-like peptide-1 secretion of two polysaccharides from Dendrobium officinale.

Two polysaccharides, named DOP-1 and DOP-2, with molecular weights of 6.8 kDa and 14.3 kDa, respectively, were isolated and purified from the stems of Dendrobium officinale. Monosaccharide composition, Fourier-transform infrared spectroscopy, methylation, and nuclear magnetic resonance analyses indicated that DOP-1 and DOP-2 may have a backbone consisted of →4)-ß-d-Glcp-(1→, →4)-ß-d-Manp-(1→, →4)-2-O-acetyl-ß-d-Manp-(1→ and →4)-3-O-acetyl-ß-d-Manp-(1→. In vivo assays showed that D. officinale polysaccharides (DOPs) exerted significant hypoglycemic effects accompanying increased serum insulin and glucagon-like peptide-1 (GLP-1) levels in streptozotocin-induced diabetic rats. Further in vitro experiments showed that DOP-induced GLP-1 secretion was inhibited by an intracellular calcium chelator, a Ca2+/calmodulin-dependent protein kinase (CaMK) II inhibitor, a specific calcium-sensing receptor antagonist, and a p38-mitogen-activated protein kinases (MAPK) inhibitor. These results indicated that DOPs may decrease fasting blood sugar levels by stimulating GLP-1 secretion and that intracellular DOP-induced GLP-1 secretion involved the Ca2+/calmodulin/CaMKII and MAPK pathways.

Antihyperglycemic, antihyperlipidemic and antioxidative evaluation of compounds from Senna sophera (L.) Roxb in streptozotocin-induced diabetic rats.

Senna sophera (L.) Roxb (Common name: Kasunda, Baner) (Leguminosae) is used as traditional medicine in Africa and Asia. The compounds were isolated from methanolic extract of leaves of Senna sophera (MFCS). Compound A was identified as Hexahydroxy diphenic acid and Compound B as Kaempferol. MFCS administration to diabetic rats exhibited significant reduction in the blood sugar level and showed gain in body weight. After the treatment of 100 mg/kg of MFCS, the blood sugar level was reduced to 52.33 ± 2.83 mg/dl in comparison to the blood sugar level of vehicle control 76.66 ± 3.17 mg/dl, whereas treatment with 50 mg/kg of MFCS reduced the blood sugar level slightly (72.33 ± 2.42 mg/dl). The daily continuous administration of MFCS for a period of 21 days normalised the serum lipid levels confirming the effect of MFCS on diabetic hyperlipidemia. Treatment with MFCS also reversed the activities of antioxidants, which could be a result of decreased lipid peroxidation.

Effect of treatment with vitamin D plus calcium on oxidative stress in streptozotocin-induced diabetic rats.

BACKGROUND: In diabetes mellitus, uncontrolled hyperglycemia has been reported to induce oxidative stress, which may lead to health complications. Vitamin D, however, acts as a non-enzymatic antioxidant to protect cells against oxidative stress and damage. OBJECTIVE: To investigate the antioxidative effect of vitamin D combined with calcium in streptozotocin (STZ)-induced diabetic rats. METHODS: Rats were divided into four groups (ten rats in each group). The first group (control) received a normal diet and water. The second group, including STZ-induced diabetic rats (diabetic controls), received a normal diet and water. The third group, also including STZ-induced diabetic rats, received vitamin D (2000 IU/day) with calcium (500 mg/kg/day) orally for 28 consecutive days. The fourth group consisted of STZ-induced diabetic rats that received insulin treatment for 28 consecutive days. Activities of superoxide dismutase (SOD), glutathione peroxidase (GPO) and catalase were measured in the liver tissues. The level of malonaldehyde (MDA) was measured in the plasma. RESULTS: Diabetic rats showed a significant decrease in the activities of SOD, GPO and catalase compared to normal rats. Oral administration of vitamin D with calcium to diabetic rats caused a significant increase in the activities of SOD, GPO and catalase compared with the untreated group. Furthermore, the plasma level of MDA was significantly elevated in diabetic rats compared to normal rats. Diabetic rats treated with vitamin D and calcium had a significantly reduced level of MDA, suggesting that vitamin D with calcium played a vital role in the protection of tissues from damage by free radicals. CONCLUSION: Oral supplementation with vitamin D and calcium may be a useful treatment for diabetic patients to reduce/prevent the pathological complications of diabetes.

In vitro and in vivo antidiabetic effect of extracts of Melia azedarach, Zanthoxylum alatum, and Tanacetum nubigenum.

BACKGROUND: To investigate the antidiabetic effect of Himalayan Medicinal plants from India viz. Melia azedarach (Family: Meliaceae), Zanthoxylum alatum (Family: Rutaceae), Tanacetum nubigenum (Family: Asteraceae) using in-vitro as well as in-vivo approaches. METHODS: Their effects were examined on stimulation of glucose uptake by C2C12 cultured cell line, inhibitory effect on human recombinant Protein tyrosine phosphatase-1B (PTP-1B) and followed by the hypoglycaemic activity of extracts in Streptozotocin (STZ) induced diabetic rats. RESULTS: All prepared extracts had been found to enrich with polyphenolic, flavonoids, terpenoids, anthraquinones and saponins type of compounds. n-Butanol fraction of Zanthoxylum alatum showed maximum PTP-1B inhibition (61.9%) whereas ethanol extract of Tanacetum nubigenum showed strong stimulation of glucose uptake (+61.2%) in C2Cl2 myotubes. In STZ induced Sprague-Dawley rats, significant decrease in blood glucose level was observed in ethanol extract of Melia azaderach treated group as 14.8% (p < 0.01) whereas in the ethanol extract of Tanacetum nubigenum treated group, it was observed as 15.5% (p < 0.01) compare to metformin which showed 26.8% (p < 0.01) lowering of blood glucose in the same time duration of 5 h study. CONCLUSION: This study demonstrated that these plants have a significant therapeutic value in type-2-diabetes mellitus and related complications thus supporting their traditional uses in Indian traditional system of medicine.

Biocompatible zinc oxide nanocrystals stabilized via hydroxyethyl cellulose for mitigation of diabetic complications.

The vascular complications of diabetes are the most serious manifestations of the disease. The hyperglycemia can directly promote an inflammatory state where the increase C-reactive (CRP) and cytokines, such as interleukins (IL-1 and IL-6), which contribute to the development of cardiovascular diseases. The current study was aimed to evaluate the role of environmentally-synthesized zinc oxide nanocrystals (ZnO-NPs) in augmentation of hyperglycemia and its complications, as well as the preservation of asymmetrical dimethylarginine (ADMA) level as a specific marker for endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. ZnO-NPs was chemically-synthesized using environmental benign biodegradable hydroxyl ethyl cellulose (HES) as both a stabilizing and directing agent in the presence of potassium hydroxide. HES is a biomaterial compound used in many biomedical applications due to its biodegradability and biocompatibility in nature. Particle size, morphological structure, purity, and crystallinity of the as-prepared ZnO-NPs were evaluated through different techniques, such as transmission electron microscopy (TEM), X-ray diffraction (XRD), and scanning electron microscopy connected to energy-dispersive X-ray spectra (SEM-EDS). Sixty male albino rats were used in this study and divided into four groups: control, ZnO-NPs, diabetic and treated groups; after the experimental period, CRP and interleukin-1 (IL-1α) were determined by ELISA. ADMA was estimated by RP-HPLC using a fluorescence detector. The results obtained indicate that CRP, IL-1α, and ADMA levels increased significantly concomitant with a reduction in NO level in the diabetic group, whereas ZnO-NPs supplementation significantly attenuated these parameters. Based on these encouraging results, the reported approach of environmental synthesis and application has the potential of leading to a new generation of nanometerials for treatment of diabetic complications with considerably enhanced selectively towards atherosclerosis.

METABOLIC EFFECTS OF TULBAGHIA VIOLACEA HARV. IN A DIABETIC MODEL.

BACKGROUND: Diabetes mellitus (DM) is a cluster of metabolic diseases with chronic hyperglycemia as a defining feature, associated with long-term organ damage and dysfunction. In this study we examined the effect of Tulbaghia violacea rhizome methanolic extract on blood glucose and lipids in normal and streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats (250-300g) were injected intraperitoneally (i.p.) with streptozotocin (60mg/kg body weight) to induce diabetes; or provided with distilled water for the control (CON) (3 ml/kg/b.w.) animals and treatment with TVL (60mg/kg.b.w). The rats were divided into 5 groups of 6 animals per group as follows: Non-diabetic control (NDC)-received distilled water (3ml/kg.b.w), Non-diabetic TVL (ND+TVL)-received TVL (60mh/kg b.w), Diabetic control (DC)-received distilled water (3ml/kg.b.w), Diabetic experimental (D+TVL)-received TVL (60mg/kg.b.w), Diabetic experimental (D+M)-received Metformin (250 mg/kg.b.w). All doses were administered daily via oral gavage. RESULTS: TVL-treated animals showed reduced blood glucose, increased plasma insulin, reduced plasma TG, TC, VLDL and increased HDL. Furthermore we found decreased thiobarbituric acid reactive substances (TBARS) and increased superoxide dismutase (SOD) activity and nitric oxide significantly. Regarding renal parameters we found increased blood urea nitrogen (BUN), and improved renal morphology in TVL-treated animals. CONCLUSION: Tulbaghia violacea has a hypoglycaemic effect which could due to its effects on multiple pathways of the hyperglycemic process. Further work is needed to identify the mechanism of its antidiabetic effect.

Protective Effect of Ethyl Acetate Fraction of Stereospermum Suaveolens Against Hepatic Oxidative Stress in STZ Diabetic Rats.

Stereospermum suaveolens is a folk remedy for the treatment of diabetes and liver disorders in southern parts of India. In the present study, the protective effect of the ethyl acetate fraction of ethanol extract from S. suaveolens against hepatic oxidative stress was evaluated in streptozotocin (STZ)-induced diabetic rats for 14 days. The ethyl acetate fraction was administered orally to the STZ diabetic rats at the doses of 200 and 400 mg/kg. Blood glucose level was measured according to glucose oxidase method. In order to determine hepatoprotective activity, changes in the levels of serum biomarker enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), and serum alkaline phosphatase (SALP) were assessed in the ethyl acetate fraction treated diabetic rats and were compared with the levels in diabetic control rats. In addition, the antioxidant activity of ethyl acetate fraction was evaluated using various hepatic parameters such as thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). It was found that administration of ethyl acetate fraction (200 and 400 mg/kg) produced a significant (P < 0.001) fall in fasting blood glucose level, TBARS, bilirubin, AST, ALT, and SALP, while elevating the GSH levels, and SOD and CAT activities in diabetic rats. Histopathologic studies also revealed the protective effect of ethyl acetate fraction on the liver tissues of diabetic rats. It was concluded from this study that the ethyl acetate fraction from ethanol extract of S. suaveolens modulates the activity of enzymatic and nonenzymatic antioxidants and enhances the defense against hepatic oxidative stress in STZ-induced diabetic rats.

Attenuation of Biochemical Parameters in Streptozotocin-induced Diabetic Rats by Oral Administration of Extracts and Fractions of Cephalotaxus sinensis.

Cephalotaxus sinensis (C. sinensis) large size, evergreen tree common in China and utilized for numerous effective pharmacological applications in Chinese traditional medicine. The hepato-renal effects of C. sinensis were evaluated in vivo using Streptozotocin (STZ)-induced diabetic rats as an tentative model. Animals were orally treated with 80% EtOH extract (aq.EE), H(2)O extract (WtE) and ethylacetate (EaF)/butanol fractions (BtF) of C. sinensis (200 mg/kg, b.w.) for 28 days whereas control received vehicle merely. The degree of fortification was measured by using biochemical parameters like serum transaminases (ALT and AST), alkaline phosphatase (ALP), creatinine, urea and urine sugar. Meanwhile, the histopathological studies were conducted out to support the above parameters. Administration of C. sinensis aq.EE/BtF (p<0.05) and EaF (p<0.01) patently prevented STZ-induced elevation levels of serum ALT, AST, ALP, creatinine, urea, urine sugar and increase body weight respectively, which were comparable with the standard drug tolbutamide, while WtE did not show any significant effect (p>0.05). Phytochemical studies revealed the presence of saponins, terpenes, sterols and flavonoids in C. sinensis which could be responsible for the possible hepato-renal protective action. The results sustain the fact that the extract/fractions of C. sinensis have an immense potential to be developed further into a phytomedicine.