Elevated vascular γ‐butyrobetaine levels attenuate the development of high glucose‐induced endothelial dysfunction

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Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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l‐Cysteine enhances nutrient absorption via a cystathionine‐β‐synthase‐derived H2S pathway in rodent jejunum

Hydrogen sulphide (H₂S) is generated endogenously from l ‐cysteine (l ‐Cys) by the enzymes cystathionine‐β‐synthase (CBS) and cystathionine‐γ‐lyase (CSE). In addition, l ‐Cys is commonly used as a precursor in the food and pharmaceutical industries. The aim of the present study is to determine whether l ‐Cys regulates intestinal nutrient transport. To that end, the presence of CBS and CSE in the jejunum epithelium was assessed by immunohistochemistry, Western blotting and the methylene blue assay. In addition, in vivo l ‐Cys (100 mg/kg, administered immediately after the glucose load) significantly increased blood glucose levels 30 min after the oral administration of glucose to mice. This effect of l ‐Cys was completely blocked by amino‐oxyacetic acid (AOA; 50 mg/kg; administered at the same time as l ‐Cys) an inhibitor of CBS. Measurements of the short‐circuit current (I_sc) in the rat jejunum epithelium revealed that l ‐Cys (1 mmol/L; 6 min before the administration of l ‐alanine) enhances Na⁺‐coupled l ‐alanine or glucose transport, and that this effect is inhibited by AOA (1 mmol/L;10 min before the administration of l ‐Cys), but not d ,l ‐propargylglycine (PAG;1 mmol/L; 10 min before the administration of l ‐Cys), a CSE inhibitor. Notably, l ‐Cys‐evoked enhancement of nutrient transport was alleviated by glibenclamide (Gli;0.1 mmol/L; 10 min before the administration of l ‐Cys), a K⁺ channel blocker. Together, the data indicate that l ‐Cys enhances jejunal nutrient transport, suggesting a new approach to future treatment of nutrition‐related maladies, including a range of serious health consequences linked to undernutrition.     

Effects of Long‐Term Mildronate Treatment on Cardiac and Liver Functions in Rats

Abstract: Mildronate is a cardioprotective drug that improves cardiac function during ischaemia and functions by lowering l ‐carnitine concentration in body tissues and modulating myocardial energy metabolism. The aim of the present study was to characterise cardiovascular function and liver condition after long‐term mildronate treatment in rats. In addition, changes in the plasma lipid profile, along with changes in the concentration of mildronate, l ‐carnitine and γ‐butyrobetaine were monitored in the rat tissues. Wistar rats were perorally treated daily with a mildronate dose of either 100, 200 or 400 mg/kg for 4, 8 or 12 weeks. The l ‐carnitine‐lowering effect of mildronate was dose‐dependent. However, the carnitine levels reached a plateau after about four weeks of treatment. During the additional weeks of treatment, the carnitine levels were not considerably changed. The obtained results provide evidence that even a high dose of mildronate does not alter cardiovascular parameters and the function of isolated rat hearts. Furthermore, the histological evaluation of liver tissue cryosections and measurement of biochemical markers of hepatic toxicity showed that all the measured values were within the normal reference range. Our results provide evidence that long‐term mildronate administration induces significant changes in carnitine homeostasis, but it is not associated with cardiac impairment or disturbances in liver function.     

β‐asarone and levodopa co‐administration protects against 6‐hydroxydopamine‐induced damage in parkinsonian rat mesencephalon by regulating autophagy: down‐expression Beclin‐1 and light chain 3B and up‐expression P62

In this study, we investigated Beclin‐1, light chain (LC)3B, and p62 expression in 6‐hydroxydopamine (6‐OHDA)‐induced parkinsonian rats after β‐asarone and levodopa (l ‐dopa) co‐administration. Unilateral 6‐OHDA injection into the medial forebrain bundle was used to create the models, except in sham‐operated rats. Rats were divided into eight groups: sham‐operated group; 6‐OHDA model group; madopar group (75 mg/kg, per os (p.o.)); l ‐dopa group (60 mg/kg, p.o.); β‐asarone group (15 mg/kg, p.o.); β‐asarone + l ‐dopa co‐administered group (15 mg/kg + 60 mg/kg, p.o.); 3‐methyladenine group (500 nmol, intraperitoneal injection); and rapamycin group (1 mg/kg, intraperitoneal injection). Then, Beclin‐1, LC3B, and p62 expression in the mesencephalon were detected. The mesencephalon was also observed by transmission electron microscope. The results showed that Beclin‐1 and LC3B expression decreased and that p62 expression increased significantly in the madopar, l ‐dopa, β‐asarone, and co‐administered groups when compared with the 6‐OHDA model. Beclin‐1 and LC3B expression in the β‐asarone and co‐administered groups were less than in the madopar or l ‐dopa groups, whereas p62 expression in the β‐asarone and co‐administered groups was higher than in the madopar or l ‐dopa groups. In addition, a significant decrease in autophagosome was exhibited in the β‐asarone and co‐administered groups when compared with the 6‐OHDA group. Our findings indicate that Beclin‐1 and LC3B expression decreased, whereas p62 expression increased after co‐administration treatment. In sum, all data suggest that the co‐administration of β‐asarone and l ‐dopa may contribute to the treatment of 6‐OHDA‐induced damage in rats by inhibiting autophagy activity.     

Acetyl‐l‐Carnitine Ameliorates Caerulein‐induced Acute Pancreatitis in Rats

Abstract: In the present study, we have addressed the possible protective role of acetyl‐l ‐carnitine in caerulein‐induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 µg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well‐characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione‐S‐transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl‐l ‐carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.     

Potential excitatory role of nitric oxide on 2‐deoxy‐d‐glucose‐induced gastric motility in rats

Previous studies have shown that 2‐deoxy‐d ‐glucose (2‐DG) increases gastric motility via the vagus nerve, but the underlying mechanism remains elusive. Since nitric oxide (NO) is involved in gastric motility, a possible interplay between 2‐DG and NO can be suggested. In the present study, Wistar rats (250‐350 g) of both sexes were intravenously injected with 2‐DG (200 mg/kg), and the effects of the intravenous injection of the nitric oxide synthase (NOS) inhibitors; nitro‐l ‐arginine methyl ester (l ‐NAME, 10 mg/kg) and N^ω‐nitro‐l ‐arginine (l ‐NNA, 10 mg/kg) were investigated. Animals were anaesthetized and cannulated for intravenous drug injections while the left vagal nerve was electrically stimulated (0.1‐10 Hz, 0.5 ms duration, 12 V, for 60 seconds), and intragastric pressure and gastric motility changes were monitored using a latex gastric balloon. 2‐DG increased the mean intragastric pressure (baseline, 5.0±0.4 cmH₂O; after 2‐DG, 14.4±1.5 cmH₂O; P=.0156) and significantly increased the gastric motility index, while NOS inhibitors significantly attenuated both parameters. However, pretreatment with NOS inhibitors significantly augmented the gastric responses to peripheral electrical vagal stimulation. These results suggest that NO plays an excitatory role in gastric responsiveness to 2‐DG and that this function may be effected in the central nervous system.     

Ferulic acid improves lipid and glucose homeostasis in high‐fat diet‐induced obese mice

Ferulic acid (FA) is a plant phenolic acid that has several pharmacological effects including antihyperglycaemic activity. Thus, the objective of this study is to investigate the effect of FA on glucose and lipid metabolism in high‐fat diet (HFD)‐induced obese mice. Institute for Cancer Research (ICR) mice were fed a HFD (45 kcal% fat) for 16 weeks. At the ninth week of induction, the obese mice were orally administered with daily FA doses of 25 and 50 mg/kg for the next eight weeks. The results show that FA significantly reduced the elevated blood glucose and serum leptin levels, lowered the insulin resistance, and increased the serum adiponectin level. Moreover, serum lipid level, and liver cholesterol and triglyceride accumulations were also reduced. The histological examination showed clear evidence of a decrease in the lipid droplets in liver tissues and smaller size of fat cells in the adipose tissue in the obese mice treated with FA. Interestingly, FA reduced the expression of hepatic lipogenic genes such as sterol regulatory element‐binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl‐CoA carboxylase (ACC). It could also up‐regulate hepatic carnitine palmitoyltransferase 1a (CPT1a) gene and peroxisome proliferator‐activated receptor alpha (PPARα) proteins. The FA treatment was also found to suppress the protein expressions of hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxylase (PEPCK) and glucose‐6‐phosphatase (G6Pase). In conclusion, the findings of this study demonstrate that FA improves the glucose and lipid homeostasis in HFD‐induced obese mice probably via modulating the expression of lipogenic and gluconeogenic genes in liver tissues.     

Coadministration of β‐asarone and levodopa increases dopamine in rat brain by accelerating transformation of levodopa: A different mechanism from Madopar

The aim of the present study was to investigate the effect of coadministration of β‐asarone and levodopa (l ‐dopa) on increasing dopamine (DA) in the striatum of healthy rats. Rats were randomly divided into four groups: (i) a normal group, administered normal saline; (ii) a Madopar group, administered 75 mg/kg Madopar (l ‐dopa : benserazide, 4 : 1); (iii) an l ‐dopa group, administered 60 mg/kg l ‐dopa; and (iv) a group coadministered 15 mg/kg β‐asarone and 60 mg/kg l ‐dopa. All drugs (or normal saline) were administered intragastrically twice a day for 7 days. Then, plasma and striatum concentrations of DA, l ‐dopa, 5‐hydroxytryptamine (5‐HT), homovanillic acid (HVA), 3,4‐dihydroxyphenylacetic acid (DOPAC), tyrosine hydroxylase (TH), catechol‐O‐methyltransferase (COMT) and monoamine oxidase B (MAO‐B) were determined. In the group coadministered β‐asarone and l ‐dopa, there was a decline in plasma and striatal concentrations of l ‐dopa; however, DA and DOPAC concentrations increased in the striatum and plasma and plasma HVA concentrations increased, whereas there was no significant change in striatal levels. Concentrations of 5‐HT in the striatum and plasma were similar in the coadministered and Madopar‐treated groups. In addition, plasma and striatal COMT levels decreased after coadministration of β‐asarone and l ‐dopa, whereas there were no significant differences in MAO‐B concentrations among groups. Furthermore, coadministration of β‐asarone and l ‐dopa increased plasma TH concentrations. Altogether, β‐asarone affects the conversion of l ‐dopa to DA by modulating COMT activity and DA metabolism. The mechanism of coadministration is different from that of Madopar in Parkinson's disease (PD) treatment. Thus, the coadministration of β‐asarone and l ‐dopa may be beneficial in the treatment of PD.     

l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.     

5‐Aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre‐conditioning: Potential Role of AMP‐Activated Protein Kinase

Abstract: Late pre‐conditioning protects against myocardial ischaemic‐reperfusion injury. AMP‐activated protein kinase (AMPK) is activated by exercise and 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d ‐ribofuranoside (AICAR). Early pre‐conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre‐conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty‐four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5‐fold in AICAR‐treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre‐conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre‐conditioning.     

Antihyperglycemic and hypolipidemic effects of Melothria maderaspatana and Coccinia indica in Streptozotocin induced diabetes in rats

Antihyperglycemic and hypolipidemic effects of ethanol extract of aerial parts of Melothria maderaspatana and Coccinia indica were evaluated in STZ induced diabetes in Sprague–Dawley rats. The rats were concurrently treated with 100 or 200 mg/kg b.w. p.o. for 14 days. The changes in fasting blood glucose level and body weight were measured in 5 days interval. After 14 days experimental period, rats were sacrificed by cervical decapitation, blood and liver samples were collected. Biochemical estimation of plasma glucose, cholesterol, triglycerides, LDL, HDL, SGOT, SGPT and ALP were done from blood sample. The liver glycogen content was estimated using standard procedure from homogenized liver sample. Administration of EEMm or EECi to STZ-diabetic rats caused significant antihyperglycemic and hypolipidemic effects (p < 0.001). The extracts were also found to be significantly effective (p < 0.001; p < 0.05) on recovery of altered biochemical parameters and decreased body weight in treated animals. Glibenclamide (0.5 mg/kg b.w.) was used as standard in present study.     

Chronic toxicity of diethyl phthalate in male Wistar rats--a dose-response study

Diethyl phthalate (DEP) is widely used in personal care products, plastics and medical devices at various concentrations, but its information is limited on its toxicity associated with exposure at high as well as low doses for a prolonged period. Therefore, a study was undertaken to understand the dose-response toxic effect of DEP in male Wistar rats. Control rats were fed on normal diet and water ad libitum. Rats were given DEP dissolved individually in corn oil mixed with the diet at 10, 25 and 50 mg/kg of the diet/day, which is equal to 0.57, 1.425 and 2.85 mg/kg body wt/day. After 5 months of treatment animals were sacrificed, enzymes and other biochemical parameters in the serum and liver were assessed. Liver weight to body weight ratio showed a significant increase only in 10 ppm DEP treated rats. A significant increase was observed in the serum ACP, LDH, ALT enzyme levels of 10 mg/kg treated rats as compared to control, 25 and 50 mg/kg treated rats. Other biochemical parameters like glycogen, total cholesterol, total triglycerides and lipid peroxidation were also increased in the liver of all the three treated groups. In the 10 and 50 mg/kg diet/day treated rats, there was a significant decrease in liver total GSH as compared to controls and 25 mg/kg treated rats. Histology of liver showed severe vacuolations, fatty degeneration and loss of hepatic architecture in the 10mg/kg treated rats, whereas in the 25 and 50 mg/kg treated rats only loss of hepatic architecture and granular deposits in the hepatocytes was predominant. Histology of liver by electron micrographs showed a significant dose-dependent proliferation of mitochondria in the hepatocytes, while the 10mg/kg treated rats showed increased number of peroxisomes in the hepatocytes. It is evident from this study that treatment with higher concentrations of DEP results in mitochondrial proliferation as well as accumulation of glycogen, cholesterol and triglycerides within the liver, but exposure to lower concentrations for longer periods results in increase in peroxisome numbers leading to severe hepatocellular changes which can be confirmed by significantly increased liver weights, elevated enzyme levels in the serum and liver and impaired metabolism of glycogen, cholesterol and triglyceride as well as altered liver histology.     

Physiological Effects of a Novel Immune Stimulator Drug, (1,4)‐α‐d‐Glucan,in Rats

Abstract: The (1,4)‐α‐d ‐glucan (α‐d ‐glucan), derived from medicinal plant, Tinospora cordifolia, activates human lymphocytes with downstream synthesis of the pro‐ and anti‐inflammatory cytokines, in vitro. We investigated physiological and immunological effects of a low and a high dose of α‐d ‐glucan (0.5 and 10 mg/kg), in vivo, testing the hypothesis that intravenous administration of α‐d ‐glucan does not affect haemodynamic, respiratory, haematological, and immune responses in normal rats. Male rats (300–400 g) were anaesthetized, tracheostomized, and catheterized in one femoral artery and vein. The mean arterial blood pressure and heart rate were continuously recorded. The baselines for gas exchange, differential blood cell count, and plasma concentration of TNF‐α, IL‐1β, IL‐4, IL‐6, and IFN‐γ were determined. Rats were then randomly assigned to controls (n = 7), a low dose (0.5 mg/kg; n = 10), and a high dose (10 mg/kg; n = 7) of α‐d ‐glucan for a six 6 hr study period. Gas exchange, differential cell count, plasma concentration of TNF‐α, IL‐1β, IL‐4, IL‐6, and IFN‐γ, and mean arterial blood pressure values remained within physiological range. Intravenous administration of 10 mg/kg α‐d ‐glucan created tachycardia, associated with hyperventilation, and significant reductions in the blood haemoglobin and haematocrit concentrations. We suggest that these in vivo effects of α‐d ‐glucan should be considered for future clinical and/or experimental trials.     

Ameliorating effects of casein glycomacropeptide on obesity induced by high-fat diet in male Sprague-Dawley rats

The effect of casein glycomacropeptide (GMP) as a specific regulating mediator in obese rats induced by high-fat (HF) diet was investigated. Male obese Sprague-Dawley (SD) rats induced by high-fat diet for 8 weeks period were fed high-fat, high-fat with GMP of 100 mg/kg BW (HFLG), 200 mg/kg BW (HFMG) and 400 mg/kg BW (HFHG) for 6 weeks. Compared with the high-fat control (HFC) group GMP supplementation significantly decreased adipose tissue weight, activity of fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH). Hepatic lipid droplet size, plasma and hepatic lipid levels markedly reduced. Moreover, GMP reduces plasma total cholesterol and low-density lipoprotein (LDL) cholesterol as well as hepatic-cholesterol and triglycerides. The liver steatosis observed in obese rats was also prevented by GMP supplement. In addition, GMP significantly diminished mitochondrial and liver malondialdehyde (MDA) production, and obviously elevated the activities of mitochondrial and hepatic superoxidase dismutase (SOD) and glutathione peroxidase (GSH-Px). Leptin production and proinflammatory cytokines such as TNF-α and IL-6 secretion decreased. Taken together, GMP can reduce lipid accumulation and enhance antioxidant capability of obese rats. It suggests that GMP can counteract high-fat diet-induced obesity, which might make it a potential ingredient with anti-obesity activity.     

Lipoic acid attenuates Aroclor 1260‐induced hepatotoxicity in adult rats

The present study was aimed to investigate the mechanistic aspect of Aroclor 1260‐induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high‐density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase‐3 & ‐9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260‐induced liver injury. Lipoic acid could protect rats against Aroclor 1260‐induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913–922, 2016.     

Antioxidative and hypolipidemic efficacy of alcoholic seed extract of Swietenia macrophylla in streptozotocin diabetic rats

The present study was designed to examine the antioxidative potential and antihyperlipidemic activity of Swietenia macrophylla in streptozotocin diabetic rats. The experimental groups were rendered diabetic by intraperitoneal injection of a single dose of streptozotocin (STZ; 40 mg/kg body weight, BW). Rats with glucose levels >200 mg/dL were considered diabetic and were divided into five groups. Three groups of diabetic animals were orally administered daily with seed extract (SME) at a dosage of 50, 100 and 200 mg/kg BW. One group of STZ rats was treated as diabetic control and another group orally administered 600 μg/kg BW glibenclamide daily. Repeated daily oral administration of S. macrophylla significantly reduced blood glucose levels after 45 days of treatment. The lipid peroxidation products such as thiobarbituric acid reactive substances and lipid hydroperoxides of SME treated rats decreased in the plasma, liver and kidney. Glutathione peroxidase, superoxide dismutase and catalase activity were significantly increased in SME treated rats. Antioxidants such as reduced glutathione level in the plasma, liver and kidney and vitamins C and E levels in the plasma increased in SME treated rats. Total cholesterol, triglycerides, phospholipids and free fatty acids and lipoproteins levels increased. Altered lipid profile of treated rats lead to normality with treatment of S. macrophylla. Thus, our results indicate that the administration of 100 mg/kg BW SME restores near normal blood glucose, redox status and lipid profile in STZ-diabetic rats.     

Nitric oxide signalling is involved in diarylheptanoid‐induced increases in femoral arterial blood flow in ovariectomized rats

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Antidiabetic effect of a new peptide from Squalus mitsukurii liver (S-8300) in streptozocin-induced diabetic mice

We have evaluated the antidiabetic effect of S-8300 (a peptide extracted from shark liver (Squalus mitsukurii)) in streptozocin (streptozotocin)-diabetic mice. Diabetes was induced by a single intravenous injection of streptozocin (150 mg kg(-1)). The effects of S-8300 (3 or 10 mg kg(-1)) on diabetic mice were investigated by observing the changes in the levels of fasting plasma glucose, glycosylated haemoglobin, hepatic glycogen, triglycerides, cholesterol, free fatty acid, superoxide dismutase, and malondialdehyde. Body weight, kidney weight and the degree of injured beta-cells in pancreatic islets were recorded also. Diabetic mice treated with S-8300 showed a significant decrease in the levels of fasting plasma glucose, glycosylated haemoglobin, triglycerides, cholesterol, free fatty acid in plasma and malondialdehyde in tissues. The animals showed a significant increase in the content of hepatic glycogen and the activity of superoxide dismutase. Treatment with S-8300 attenuated the degree of injured beta-cells in the pancreatic islets. The effect of S-8300 was similar to that of glibenclamide (5 mg kg(-1)).     

Morphine hyposensitivity in streptozotocin‐diabetic rats: Reversal by dietary l‐arginine treatment

Painful diabetic neuropathy (PDN) is a long‐term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)‐diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post‐STZ and maintained for 6 months post‐STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain‐relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde) in STZ‐diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ‐diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ‐diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post‐STZ. Administration of dietary l ‐arginine (NO precursor) at 1 g/d to STZ‐diabetic rats according to a 15‐week prevention protocol initiated at 9 weeks post‐STZ prevented abolition of morphine efficacy. When given as an 8‐week intervention protocol in rats where morphine efficacy was abolished, dietary l ‐arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ‐diabetic rats.