Metformin-like effects of Quei Fu Di Huang Wan, a Chinese herbal mixture, on streptozotocin-induced diabetic rat.

Effect on plasma glucose concentration of Quei Fu Di Huang Wan (Quei Fu DHW), the herbal mixture widely used to treat diabetic disorder in Chinese traditional medicine, was investigated in diabetic rats deficient in insulin. Changes of plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats) receiving repeated oral administration of Quei Fu DHW were determined. Also, the mRNA level (by Northern blotting) and protein level (by Western blotting) of phosphoenolpyruvate carboxykinase (PEPCK) in liver from STZ-diabetic rats were measured to compare differences between groups receiving repeated oral administration of Quei Fu DHW, metformin, and two active herbs (Zou Guei or Fuzei) at effective dosages. In STZ-diabetic rats, acute oral administration of Quei Fu DHW decreased the plasma glucose level significantly in a dose-dependent manner from 5 mg/kg to 26.0 mg/kg. Similar treatment with Quei Fu DHW also brought on a plasma glucose-lowering effect in normal rats, although the effectiveness was not as significant as in STZ-diabetic rats. Repeated oral treatment of Quei Fu DHW at 26 mg/kg every 8 h, three times daily for 3 days, produced a plasma glucose-lowering activity similar to that of metformin-treatment in STZ-diabetic rats. Oral administration of Zou Guei (Cinnamomi Cortex) or Fuzei (Aconiti Tuber), the individual constituent of Quei Fu DHW, at the dose of 50 mg/kg into STZ-diabetic rats for 3 days normalized hyperglycemia. Similar to the repeated treatment with Quei Fu DHW, Fuzei at the effective dose reversed the elevated mRNA and protein levels of PEPCK in liver from STZ-diabetic rats. This is consistent with findings that metformin restored the increased gene expression of PEPCK in liver from STZ-diabetic rats. However, the gene expression of PEPCK in STZ-diabetic rats was not influenced by similar treatment with Zou Guei. The present study found that oral administration of Quei Fu DHW could decrease hepatic gluconeogenesis in a way similar to metformin in lowering plasma glucose in diabetic rats lacking insulin. Thus, this preparation may be a helpful adjuvant for the treatment of diabetic disorders in clinical practice.     

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds

Metformin was reported to increase plasma active glucagon-like peptide-1 (GLP-1) in humans. There are two possible mechanisms for this effect: (1) metformin inhibits dipeptidyl peptidase IV (DPPIV), an enzyme degrading GLP-1, and (2) metformin enhances GLP-1 secretion. To elucidate the mechanism(s), we examined (1) IC(50) of metformin for DPPIV inhibition, (2) plasma active GLP-1 changes after oral biguanide (metformin, phenformin, and buformin) treatment in fasting DPPIV-deficient F344/DuCrj rats, and (3) plasma intact GLP-1 excursions after oral administration of metformin and/or valine-pyrrolidide, a DPPIV inhibitor, in fasting DPPIV-positive F344/Jcl rats. Our in vitro assay showed that metformin at up to 30mM has no inhibitory activity towards porcine or rat DPPIV. Metformin treatment (30, 100, and 300mg/kg) increased plasma active GLP-1 levels dose-dependently in DPPIV-deficient F344/DuCrj rats (approximately 1.6-fold at 3 and 5h after administration of 300mg/kg). This treatment had no effect on blood glucose levels. Similarly, phenformin and buformin (30 and 100mg/kg) elevated plasma intact GLP-1 levels in F344/DuCrj rats. In DPPIV-positive F344/Jcl rats, coadministration of metformin (300mg/kg) and valine-pyrrolidide (30mg/kg) resulted in elevation of plasma active GLP-1, but neither metformin nor valine-pyrrolidide treatment alone had any effect. These findings suggest that metformin has no direct inhibitory effect on DPPIV activity and that metformin and the other biguanides enhance GLP-1 secretion, without altering glucose metabolism. Combination therapy with metformin and a DPPIV inhibitor should be useful for the treatment of diabetes.     

Beneficial Effect of Metformin on Nerve Regeneration and Functional Recovery After Sciatic Nerve Crush Injury in Diabetic Rats

Neuroprotective effects of metformin have been increasingly recognized in both diabetic and non-diabetic conditions. Thus far, no information has been available on the potential beneficial effects of metformin on peripheral nerve regeneration in diabetes mellitus. The present study was designed to investigate such a possibility. Diabetes was established by a single injection of streptozotocin at 50 mg/kg in rats. After sciatic nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with metformin (30, 200 and 500 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. It was found that metformin significantly enhanced axonal regeneration and functional recovery compared to saline after sciatic nerve injury in diabetic rats. In addition, metformin at 200 and 500 mg/kg showed better performance than that at 30 mg/kg. Taken together, metformin is capable of promoting nerve regeneration after sciatic nerve injuries in diabetes mellitus, highlighting its therapeutic values for peripheral nerve injury repair in diabetes mellitus.     

Assessment of genomic instability in normal and diabetic rats treated with metformin

To examine if a single or multiple oral administration of metformin, a member of the biguanide class of anti-diabetic agents, has any genotoxic and cytotoxic potential in normal and diabetic rats, a mammalian model, cytogenetic assays through several endpoints such as induction of micronuclei, chromosome aberrations, mitotic activity of bone marrow cells, sperm-head anomaly and assays of some oxidative stress markers have been conducted by the use of standard techniques. Diabetes was induced by streptozotocin injection. Metformin was administrated to both diabetic and non-diabetic rats in single doses of 100, 500 or 2500 mg/kg along with vehicle control groups for diabetic and non-diabetic rats. The animals were killed by cervical dislocation at 24 h after treatment, and then bone marrow cells were sampled. Also, a multiple dose study has done in which diabetic and non-diabetic animals were treated with 100 or 500 mg/kg of metformin daily for 4 or 8 weeks after which the animals were killed by cervical dislocation, and then bone marrow and sperm cells were collected. Concurrent control groups were also included in each experiment. The obtained results revealed that metformin was neither genotoxic nor cytotoxic for the rats in all groups at all tested doses. Moreover, metformin significantly reduced the diabetes-induced genomic instability and cell proliferation changes in somatic and germinal cells in a dose-dependent manner (2500, 500, >100 mg/kg). In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including, enhanced lipid peroxidation and reduction in the reduced glutathione level. Treatment with metformin ameliorated these biochemical markers. In conclusion, metformin is a non-genotoxic or cytotoxic compound and may protect from genomic instability induced by hyperglycemia. Apart from its well-known anti-diabetic effect, the antigenotoxic effect of metformin could be possibly ascribed to its radical scavenger effect that modulated the genomic instability responses and cell proliferation changes induced by hyperglycemia.     

二甲双胍对华法令诱导大鼠动脉钙化的影响及其机制初探

目的:研究二甲双胍(metformin,MET)对华法令(Warfarin,WFN)诱导大鼠动脉钙化的影响及其机制。方法:将28只SD大鼠随机分为正常对照组、8周(W)钙化组、8W钙化+8W MET 100 mg/kg治疗组、8W钙化+8W MET 200 mg/kg治疗组。采用Von Kossa染色法检测胸主动脉组织中钙结节;邻甲酚肽络合酮比色法测定颈总动脉组织中钙沉积含量;免疫组化染色检测血管壁中成骨基因Runx2及血管平滑肌标志物α-SMA的表达;Western Blot检测血管壁中Runx2及自噬标志物LC3II的表达。结果:WFN干预8 W后,大鼠动脉中钙沉积含量显著增加(P0.01),MET治疗组主动脉钙含量与钙化组相比均显著降低(P0.01)。Von Kossa染色可见钙化组(WFN组)动脉壁中层黑色连续钙盐沉积条带,而进行MET治疗后,黑色条带明显减少,对照组未见黑色条带。免疫组化显示钙化组血管壁Runx2表达阳性,棕褐色染色较深,而α-SMA表达则显著下降,基本未见棕褐色染色沉积;MET治疗后能够逆转上述趋势。Western Blot显示钙化组血管壁Runx2表达明显上升,MET治疗后Runx2表达被抑制。此外,钙化过程中伴随着自噬标志物LC3II表达轻度上升;随着MET浓度升高,血管壁中自噬水平呈剂量依赖性显著升高。结论:二甲双胍能够有效抑制大鼠动脉钙化,减轻血管平滑肌细胞由收缩表型向成骨样表型转换,其机制可能与诱导自噬有关。     

Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat

The effects of toremifene, a new triphenylethylene derivative, on the uterus and DMBA-induced mammary tumors in rats were compared to tamoxifen. The ability of toremifene to compete with [3H]estradiol for cytoplasmic estrogen receptor from rat uterus was similar to tamoxifen, the IC50 being 26 and 23 microM respectively. In immature intact rats the two compounds, administered orally for three consecutive days, had similar intrinsic partial estrogenic efficacy, at 50 mg/kg, about 40% of that of estradiol benzoate (EB). However, at doses less than or equal to 10 mg/kg, the estrogenic effect of toremifene was seen at doses about 40 times higher than that of tamoxifen. The two compounds, administered together with a standard dose of EB, expressed the same maximal antiestrogenic efficacy (about 65% inhibition) at 50 mg/kg. However, the minimal effective antiestrogenic dose of toremifene was about 10 times that of tamoxifen and the ratio between antiestrogenic/estrogenic properties was favourable to toremifene. The duration of the antiestrogenic (antiuterotrophic) effect of a single oral dose (10 mg/kg) of the two compounds proved similar: at least 4 days in intact rats and 3 days in ovariectomized rats. In DMBA-induced tumor bearing rats toremifene was administered p.o., 6 times/week for 4 weeks at 0.08, 0.4, 2, 10 and 50 mg/kg. It was effective at the doses of 2, 10 and 50 mg/kg, inducing 39, 35 and 46% tumor regressions. The activity of toremifene at the minimal effective dose of 2 mg/kg was then compared with that of tamoxifen given at the same dose level. The compounds had comparable activity (47 vs 44% tumor regressions).     

Interaction between diazepam and oral antidiabetic agents on serum glucose,insulin and chromium levels in rats

This study was undertaken to investigate the effect of diazepam in the presence and absence of glibenclamide, metformin or their combination on serum levels of glucose, insulin and chromium in rats. Results indicated that diazepam (10 mg/kg i.p.) induced marked hyperglycaemic effects in hyperglycaemic rats. This effect was associated with significant reductions in serum chromium levels and insignificant reduction in serum insulin levels. Diazepam-induced hyperglycaemia was counter-acted by concurrent administration of glibenclamide (5 mg/kg orally), metformin (500 mg/kg orally) or their combination. The effect of diazepam on serum chromium level was counteracted partially by administration of glibenclamide and augmented in the presence of metformin or its combination with glibenclamide. It is concluded that the diazepam-induced hyperglycaemia, as well as the hypoglycaemic effect of glibenclamide, might be related to changes in serum chromium levels.     

Lucrative antioxidant effect of metformin against cyclophosphamide induced nephrotoxicity

Cyclophosphamide is anticancer drug with a well-Known nephrotoxicity. This work was applied to study the lucrative antioxidant influence of metformin as co-therapy on the nephrotoxicity induced by cyclophosphamide in the treatment of different cancer diseases. Four groups of male Sprague Dawley rats were used; Control group (C) received single I.P. injection of 0.2 ml saline, Metformin (MET) group received daily gavage of 200 mg/kg metformin for two weeks, Cyclophosphamide (CP) group received single I.P. injection of 200 mg/kg CP, Protector group (CP.MET) received daily gavage of 200 mg/kg metformin for two weeks and single I.P. injection of 200 mg/kg CP at day 7. By day 14 rats were euthanized. Samples were collected from kidney tissues and blood for kidney function evaluation, histopathological and assessment of oxidative stress markers. The results disclosed that CP yields many functional and structural damage to the kidney, worsened oxidative stress markers and kidney function indicators. The protector group displayed better kidney tissue morphology, acceptable kidney function indicators as well as satisfactory oxidative stress markers.In assumption, metformin could be combined with CP owing to its lucrative effect counter to CP persuaded nephrotoxicity.     

The mechanism of hypoglycemic action of the semi-purified fractions of Averrhoa bilimbi in streptozotocin-diabetic rats.

In the present study, we have examined the possible mechanism of the hypoglycemic action of the semi-purified fractions of an ethanolic extract of Averrhoa bilimbi Linn (Oxalidaceae) leaves (ABe) in streptozotocin-diabetic male Sprague-Dawley (SD) rats. The ABe was partitioned with water and butanol to yield a butanol-soluble fraction (BuF) and a water-soluble fraction (AF). The AF was further partitioned with ethyl acetate and hexane to obtain ethyl acetate (EF) and hexane (HF) soluble fractions. The hypoglycemic property of each fraction was assessed by the oral glucose tolerance test (OGTT) at a dose of 125-mg/kg-body weight in streptozotocin (STZ)-diabetic rats (STZ 60 mg/kg i.p.). Fractions AF, BuF and the reference drug metformin (500 mg/kg body weight), produced significant blood glucose-lowering effect in the diabetic rats when compared to the vehicle (distilled water). In the long-term study, the diabetic rats were randomly divided into 4 groups and treated orally by gavage with vehicle, AF (125 mg/kg body weight), BuF (125 mg/kg body weight), and metformin (500 mg/kg body weight) respectively twice a day for 14 days. On day 7 and day 14, AF and BuF, like the reference drug, metformin, lowered the fasting blood glucose concentration significantly (P < 0.05) when compared with the vehicle. The serum insulin level was significantly increased in the AF-treated rats only on day 14 when compared to that in the vehicle-treated rats on day zero (P < 0.05). The serum insulin level in BuF-treated rats was also significantly higher (P < 0.05) on both day 7 and day 14 compared to that on day zero. Hepatic glucose-6-phosphatase activity was significantly lower (P<0.05) in AF- and metformin-treated groups, but not in BuF-treated groups, compared to that in vehicle-treated group. However, there was no change in hepatic glycogen content in AF-, BuF- and metformin-treated group compared to the vehicle-treated group. These results indicate that AF is more potent than BuF in the amelioration of hyperglycemia in STZ-diabetic rats and is a potential source for the isolation of new orally active agent(s) for anti-diabetic therapy.     

Myosin light chain mono- and di-phosphorylation differentially regulate adhesion and polarity in migrating cells

A high carbohydrate-high fat (HC-HF) diet-associated with hyperinsulinemia has been previously reported to induce accelerated growth of prostate cancer in a xenograft model. High energy supply and insulin/insulin growth factor-1 axis are two of the mechanisms proposed. We hypothesize that metformin may have a protective effect against prostate cancer progression by affecting metabolisms associated with high energy intake. In the present study, animals were randomized into five groups, receiving a HC-HF diet with 50, 100, or 250 mg/kg body weight (mg/kg) metformin in drinking water, a standard diet or HC-HF diet alone. Animals on the HC-HF diet developed obesity and insulin resistance. They had significantly higher body weight, fasting blood glucose at an upper level of normal range, higher insulin secretion and utilization, and fatty degeneration of the liver. Metformin at the doses employed significantly reduced food and water consumption; however, only a dose of 250 mg/kg showed a significant reduction in body weight gain and suppression of gluconeogenesis as well remarkably reduced insulin secretion. There was no observed metformin-related hepato-toxicity in any of the groups. In summary, metformin at various doses exhibits protective effects on the metabolic disorder caused by the HC-HF diet with the most effective protection at a dose of 250 mg/kg. These effects may explain its translational role relating to its anti-neoplastic potential.     

Metformin: an effective attenuator of risperidone-induced insulin resistance hyperglycemia and dyslipidemia in rats

The use of atypical antipsychotics in the clinical management of schizophrenia and schizoaffective disorders has been associated with the development of insulin resistance. The present study evaluates the possible individual ameliorating effect of single daily oral treatments with 20 mg/kg/day of metformin and 0.1 mg/kg of glibenclamide in two groups of Wistar rats pretreated with 0.2 mg/kg of risperidone for 60 days. Two additional groups of rats were only treated with 0.2 mg/kg of risperidone and 10 mL/kg of distilled water, respectively, also for 60 days. Results showed that oral pre-treatment with metformin significantly attenuated increases in the weight gain pattern, fasting glucose, fasting plasma insulin, serum triglyceride and total cholesterol levels that were elevated by risperidone treatment. Metformin also significantly reduced glycosylated hemoglobin concentration, fasting insulin-glucose ratio and fasting insulin resistance index. Conversely, oral pre-treatment with glibenclamide for 60 days did not significantly reduce any of the measured parameters except for glycosylated hemoglobin concentrations. Thus, results of this study showed that 20 mg/kg of metformin effectively ameliorated the development of risperidone-induced insulin resistance and dyslipidemia which was mediated via improvement in insulin resistance. This study provides insight into the therapeutic potential of metformin in preventing risperidone-induced insulin resistance diabetes mellitus and dyslipidaemia.     

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor‐alpha, prostaglandin E₂), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)‐2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose‐dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX‐2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long‐term CsA treatment to maintain their liver and kidney functions.     

Metformin (dimethyl-biguanide) induced DNA damage in mammalian cells

Metformin (dimethyl-biguanide) is an insulin-sensitizing agent that lowers fasting plasma-insulin concentration, wherefore it's wide use for patients with a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance. During pregnancy it is a further resource for reducing first-trimester pregnancy loss in women with the polycystic ovary syndrome. We tested metformin genotoxicity in cells of Chinese hamster ovary, CHO-K1 (chromosome aberrations; comet assays) and in mice (micronucleus assays). Concentrations of 114.4 μg/mL and 572 μg/mL were used in in vitro tests, and 95.4 mg/kg, 190.8 mg/kg and 333.9 mg/kg in assaying. Although the in vitro tests revealed no chromosome aberrations in metaphase cells, DNA damage was detected by comet assaying after 24 h of incubation at both concentrations. The frequency of DNA damage was higher at concentrations of 114.4 μg/mL. Furthermore, although mortality was not observed in in vitro tests, the highest dose of metformin suppressed bone marrow cells. However, no statistically significant differences were noted in micronuclei frequencies between treatments. In vitro results indicate that chronic metformin exposure may be potentially genotoxic. Thus, pregnant woman undergoing treatment with metformin should be properly evaluated beforehand, as regards vulnerability to DNA damage.     

丝胶对糖尿病肾病大鼠肾脏TGF-β_1/Smad3信号通路的作用

目的：观察彩色蚕茧提取物—丝胶对糖尿病肾病大鼠肾脏转化生长因子-β1（TGF-β1）和Smad3蛋白表达的影响。方法：60只雄性SD大鼠随机分为5组（n=12）：正常对照组、糖尿病肾病模型组、丝胶治疗组、二甲双胍组和丝胶预防组。模型组、丝胶治疗组、丝胶预防组和二甲双胍组大鼠均建立链脲佐菌素（STZ）致动物模型,以血糖≥16.7 mmol/L作为成模标准;待模型成功建立后,丝胶治疗组大鼠给予丝胶灌胃（2.4 g/（kg.d）,35 d）、二甲双胍组大鼠给予二甲双胍灌胃（55.33 mg/（kg.d）,35 d）,丝胶预防组大鼠于注射STZ前给予同等剂量丝胶灌胃35天。分别检测各组大鼠血糖和肾重/体重;免疫组化染色观察肾脏TGF-β1蛋白的表达;Western blot法观察肾脏Smad3蛋白的表达。结果：与正常对照组大鼠相比,模型组大鼠血糖、肾重/体重和肾脏TGF-β1、Smad3蛋白的表达均明显升高（P〈0.01）。丝胶治疗组、丝胶预防组和二甲双胍组大鼠的血糖和肾脏TGF-β1、Smad3蛋白的表达明显低于模型组（P〈0.01）,且丝胶治疗组、丝胶预防组与二甲双胍组比较无明显差别（P〉0.05）;丝胶治疗组、丝胶预防组和二甲双胍组大鼠的肾重/体重明显低于模型组（P〈0.01）,且丝胶治疗组、丝胶预防组大鼠的肾重/体重明显低于二甲双胍组（P〈0.05）。结论：丝胶可抑制糖尿病肾病大鼠肾脏TGF-β1/Smda3信号通路的激活,减轻肾小球硬化和肾间质纤维化,发挥对糖尿病肾病肾脏损伤的保护和预防保护作用,且作用与二甲双胍相当。     

Effect of a novel insulinotropic agent, succinic acid monoethyl ester, on lipids and lipoproteins levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes

In the present study, the effect of succinic acid monoethyl ester (EMS) on the pattern of lipids and lipoproteins in streptozotocin-nicotinamide induced type 2 diabetes was investigated. Type 2 diabetes was induced in male Wistar rats by single intraperitoneal injection (i.p.) of 45 mg/kg streptozotocin, 15 min after the i.p administration of 110 mg/kg body weight of nicotinamide. The carboxylic nutrient EMS was administered intraperitonially at a dose of 8 Μmol/g body weight for 30 days. At the end of experimental period, the effect of EMS on plasma glucose, insulin, thiobarbituric acid reactive substances (TBARS) and hydroperoxide (HP) and serum triglycerides (TG), phospholipids (PL), free fatty acids (FFA), total cholesterol (TC), very low density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and the percentage of antiatherogenic index (AAI) (ratio of HDL-C to total cholesterol) were studied. Administration of EMS to diabetic rats resulted in a signi. cant reduction in the elevated levels of plasma glucose, TBARS and hydroperoxides as well as TG, PL, FFA, TC, VLDL-C and LDC-C levels. The decreased plasma insulin and serum HDL-C and percentage of AAI in diabetic rats were also reversed towards near normal. The effect produced by EMS was compared with metformin, a reference drug. The results indicates that the administration of EMS and metformin to nicotinamide-streptozotocin diabetic rats normalized plasma glucose, insulin concentrations and caused marked improvement in altered lipids, lipoprotein and lipid peroxidation markers during diabetes. Our results show the antihyperlipidemic properties of EMS and metformin in addition to its antidiabetic action. Moreover, the antihyperlipidemic effect could represent a protective mechanism against the development of atherosclerosis.     

Histological evidence that metformin reverses the adverse effects of diabetes on orthodontic tooth movement in rats

This study evaluated the effects of metformin on orthodontic tooth movement in a rat model of type 2 diabetes mellitus. Rats were fed a high-fat diet for 4 weeks to induce fat accumulation and insulin resistance, and then injected with a low dose of streptozotocin (35 mg/kg) intraperitoneally to induce type 2 diabetes. An orthodontic appliance was placed in normoglycemic, type 2 diabetes, and type 2 diabetes with metformin-administrated rats. After 14 days, type 2 diabetes rats exhibited greater orthodontic tooth movement and had a higher number of tartrate-resistant acid phosphatase-positive osteoclasts, stronger cathepsin K expression, and weaker alkaline phosphatase immunostaining than normoglycemic rats. Metformin administration resulted in normalization of osteoclast numbers, cathepsin K immunostaining, and of tooth movement as well as partly recovery of alkaline phosphatase expression in diabetic rats. Metformin also reduced sclerostin expression and improved the immunolocalization of dentin matrix protein 1 in osteocytes of type 2 diabetes rats. These results suggest that metformin administration reversed the adverse effects of diabetes on orthodontic tooth movement.     

Hepatoprotective potential of flavonoid-rich extracts from Gongronema latifolium benth leaf in type 2 diabetic rats via fetuin-A and tumor necrosis factor-alpha

Background

This study assessed the hepatoprotective potential of flavonoid-rich extracts from Gongronema latifolium Benth on diabetes-induced type 2 rats via Fetuin-A and tumor necrosis factor-alpha (TnF-α).

Methods

In a standard procedure, the flavonoid-rich extract was prepared. For experimental rats, streptozotocin was injected intraperitoneally (45 mg/kg body weight) to induce diabetes mellitus. Following this, rats were given 5% of glucose water for 24 h. Hence, the animals were randomly divided into five groups of ten rats each, consisting of non-diabetic rats, diabetic controls, diabetic rats treated with low and high doses of flavonoid rich-extracts from Gongronema latifolium leaf (FREGL) (13 and 26 mg/kg, respectively), and diabetic rats treated with 200 mg/kg of metformin glibenclamide orally for 3 weeks. Afterwards, the animals were sacrificed, blood and liver were harvested to evaluate different biochemical parameters, hepatic gene expressions and histological examinations.

Results

The results revealed that FREGL (especially at the low dose) significantly (p?<?0.05) reduced alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphate (ALP) activities, lipid peroxidation level, as well as relative gene expressions of fetuin-A and TNF-α in diabetic rats. Furthermore, diabetic rats given various doses of FREGL showed an increase in antioxidant enzymes and hexokinase activity, as well as glucose transporters (GLUT 2 and GLUT 4), and glycogen levels. In addition, histoarchitecture of the liver of diabetic rats administered FREGL (especially at the low dose) was also ameliorated.

Conclusion

Hence, FREGL (particularly at a low dose) may play a substantial role in mitigating the hepatopathy complication associated with diabetes mellitus.

     

The Effects of Sunitinib in Healthy and Cisplatin-Induced Rats

Sunitinib is a multitargeted kinase inhibitor that inhibits many receptor tyrosine kinases and has been used in the treatment of gastrointestinal stromal tumors, metastatic renal cell carcinoma, and pancreatic neuroendocrine tumors. In this study, the effects of sunitinib given to rats, both alone and after stress with cisplatin, were investigated. The animals were divided into four groups – (1) control group (C) administered interperitoneally with a single dose 0.9 % saline, (2) Cis group administered a single dose (7 mg/kg) of cisplatin, (3) Sun group administered 10 mg/kg sunitinib for seven days, and (4) Cis+Sun group administered 10 mg/kg sunitinib for seven days after a single dose (7 mg/kg) of cisplatin. After these applications, the rats were sacrificed, and blood and tissue samples were taken for biochemical and histopathological evaluations. Sunitinib did not show any effect on urea, creatine, and kidney IL1β and TGF-β3 expression levels when administered alone; it increased ALT, AST, and IL-38 levels. When sunitinib was given to the cisplatin-induced rats, it was observed that the increase in ALT, AST, and IL-38 levels increased more than the rats that was given only sunitinib. According to the data obtained, sunitinib does not cause a significant change in kidney tissue under both normal and stress conditions, while it creates stress in liver tissue. In addition, its toxicity in the liver becomes more certain as a result of its combination with cisplatin.     

Effect of subtherapeutic doses of docetaxel (taxotere) on the efficacy of radiotherapy and pro-oxidant-antioxidant balance in rats with Guerin's carcinoma

In the experiments at Wistar male rats the effect of subtherapeutic doses of docetaxel (5 and 10 mg/kg) on the radiotherapy efficacy (20 Gy of single-dose X-rays) namely growth rate of Guerin's tumor and prooxidant-antioxidant balance in liver and blood of animals bearing tumors was investigated. It has been demonstrated that docetaxel at dose 5 mg/kg given 18 hours before irradiation resulted in significant tumor growth delay (2.3-2.7-fold) in comparison with group of rats that received only irradiation. After application of higher dose of docetaxel there was no statistically significant change of tumor size along the whole experiment (14 and 21 days after tumor implantation). Content of lipid peroxidation products was revealed to be considerably increased after chemotherapy and concurrent irradiation when docetaxel was used in a dose of 10 mg/kg. At the same time glutatione peroxidase activity and antioxidative activity of blood plasma were reduced. In the rat liver chemoradiotherapy led to decrease of glutathion peroxidase and glutathione-S-transferase activity to greater degree at docetaxel dose of 10 mg/kg. The obtained results allow to conclude that higher dose of docetaxel and concurrent irradiation resulted in the most effective Guerin's carcinoma growth delay and considerable deviation of antioxidant-prooxidant balance of tissues in the direction of the last.