Pathophysiology of diabetic hepatopathy and molecular mechanisms underlying the hepatoprotective effects of phytochemicals.

Patients with diabetes are at risk for liver disorders including glycogen hepatopathy, non-alcoholic fatty liver disease, cirrhosis, and hepatic fibrosis. The pathophysiological mechanisms behind diabetic hepatopathy are complex, some of them include fatty acid accumulation, increased reactive oxygen species, increased advanced glycation end-products, hyperactivity of polyol pathways, increased apoptosis and necrosis, and promotion of fibrosis. A growing number of studies have shown that herbal extracts and their active phytochemicals have antihyperglycemic properties and beneficial effects on diabetic complications. The current review, for the first time, focused on herbal agents that showed beneficial effects on diabetic hepatopathy. For example, animal studies have shown that Moringa oleifera and Morus alba improve liver function in both type-1 and type-2 diabetes. Also, evidence from clinical trials suggests that Boswellia serrata, Juglans regia, Melissa officinalis, Portulaca oleracea, Silybum marianum, Talapotaka Churna, and Urtica dioica reduce serum liver enzymes in diabetic patients. The main active ingredient of these plants to protect the liver seems to be phenolic compounds such as niazirin, chlorogenic acid, resveratrol, etc. Mechanisms responsible for the hepatoprotective activity of herbal agents include improving glucose metabolism, restoring adipokines levels, antioxidant defense, and anti-inflammatory activity. Several signaling pathways are involved in hepatoprotective effects of herbal agents in diabetes, such as phosphoinositide 3-kinase, adenosine monophosphate-activated protein kinase, mitogen-activated protein kinase, and c-Jun NH2-terminal kinase.

Vitamin C improves liver and renal functions in hypothyroid rats by reducing tissue oxidative injury.

Background: The effects of Vit C on liver and renal function and the tissues oxidative damage was investigated in hypothyroid rats. Materials and methods: The pregnant rats were divided into 5 groups (n=6): (1) Control; (2) Propylthiouracil (PTU; 0.005%), (3-5) PTU plus 10, 100 or 500 mg/kg b.w. Vit C. The drugs were added to the drinking water of the dams and their pups during lactation period and then continued for the offspring through the first 8 weeks of their life. Finally, 7 male offspring from each group were randomly selected. Results: Thyroxine, protein and albumin concentrations in the serum and thiol content and superoxide dismutase (SOD) and catalase (CAT) activities in renal and liver tissues of hypothyroid group was lower (all P<0.001) while, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK-P), creatinine and blood urea nitrogen (BUN) concentrations in the serum and malondialdehyde (MDA) in the liver and renal tissues were higher than the control (all P<0.001). All doses of Vit C increased thyroxine, protein and albumin and thiol content in in renal and liver tissues while, decreased AST, ALT and ALK-P concentration and MDA in liver and renal tissues compared to PTU group (P<0.05-P<0.001). Creatinine, BUN and SOD and CAT were improved by both 100 and 500 mg/kg of Vit C in the renal (P<0.05-P<0.001) and by 100 mg/kg in the liver (P<0.05-P<0.001). Conclusion: Vit C improved liver and renal function of hypothyroid rats which might be due to its protective effects against tissues oxidative damage.

Effects of ethanolic extract of Ferula gummosa oleo-resin in a rat model of streptozotocin-induced diabetes.

Previous studies have shown that some plants in the genus of Ferula (Apiaceae) have antidiabetic effects. The present work was aimed to evaluate effects of Ferula gummosa oleo-resin in a rat model of streptozotocin-induced diabetes. Male Wistar rats were randomized into five groups (n = 6): normal control, diabetic control, diabetic rats treated with insulin (3 IU/day), and diabetic rats treated with 100 or 400 mg/kg/day of an ethanolic extract of the oleo-resin. After 4 weeks, blood samples were collected for measuring fasting blood glucose (FBG), lipid profile, aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, blood urea nitrogen, and creatinine. In addition, levels of lipid peroxidation, thiol groups, and superoxide dismutase (SOD) activity were evaluated in the liver and kidney. At the end of the fourth week, the level of FBG in rats treated with 100 mg/kg of the extract was lower than that in diabetic control rats (273 ± 39 mg/dL vs 471 ± 32 mg/dL). Administration of insulin and the extract had no significant effects on the serum lipids. Insulin and both doses of the extract significantly reduced the activity of ALT. In addition, the extract inhibited lipid peroxidation in the kidney and restored the elevated level of SOD in the liver and kidneys. Ferula gummosa oleo-resin has the potential to prevent or delay the complications of diabetes by inhibiting the progression of hyperglycemia and attenuating oxidative stress-induced damage in the liver and kidneys.

Protective effects of gallic acid against methotrexate-induced toxicity in rats.

BACKGROUND: Methotrexate, as a chemotherapy drug, can cause chronic liver damage and oxidative stress. Aim of this study was to evaluate the preventive effect of gallic acid (GA) on methotrexate (MTX)-induced oxidative stress in rat liver. METHODS: Twenty-eight male rats were randomly divided into four groups as control, MTX (20 mg/kg, i.p.), MTX + GA (30 mg/kg/day, orally) and GA treated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. Malondialdehyde (MDA) and glutathione (GSH) levels and hepatic antioxidant enzymes activities including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed in liver tissue. The expression of SOD2 and GPx1 genes were evaluated by real-time RT-PCR and liver histopathology was evaluated by light microscopy. RESULTS: The result obtained from current study showed that GA remarkably reduced MTX-induced elevation of AST, ALT and ALP and increased MTX-induced reduction in GSH content, GPx, CAT and SOD activity as well as GPx1 and SOD2 gene expressions. Histological results showed that MTX led to liver damage and GA could improve histological changes. CONCLUSIONS: Our results indicate that GA ameliorates biochemical and oxidative stress parameters in the liver of rats exposed to MTX.

Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats.

Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.

Toxicity assessment of Ferula gummosa administration during pregnancy, lactation, and juvenile period in rat.

Ferula gummosa is widely used in traditional medicine to treat a variety of ailments. This work evaluated the safety of F. gummosa root in pregnancy, lactation, and juvenile periods. This study was performed in three parts: (1) pregnant rats were received diet containing 0 (control), 150 , or 700 mg/kg of F. gummosa root during pregnancy; (2) Lactating rats were treated with diet containing the root (0, 150, or 700 mg/kg) during lactation period; (3) juvenile rats were received 4 weeks diet containing the root (0, 150, or 700 mg/kg). F. gummosa at both doses had no significant effects on the duration of pregnancy, maternal weight, and the number of delivered pups, but at dose of 700 mg/kg decreased birthweight of the pups. In lactation period, F. gummosa had no significant effects on mortality, body weight, body length, the weight of organs, and blood biochemical parameters of offspring. In juvenile rats, food consumption, body weight, and WBCs number were decreased in treated groups. No histopathological lesions were detected in the brain, heart, liver, lungs and kidney of offspring, and juvenile rats in treated groups. LC/MS/MS analysis confirmed systemic absorption of active constituents of the root by the oral route of administration. In conclusion, F. gummosa root did not produce significant toxic effects during pregnancy, lactation, and juvenile period. But, decrease in birthweight of delivered pups and in weight gain of juvenile rats should be considered in the long-term consumption of this plant.

Pharmacological properties of Salvia officinalis and its components.

Salvia officinalis (Sage) is a plant in the family of Labiatae/Lamiaceae. It is native to Middle East and Mediterranean areas, but today has been naturalized throughout the world. In folk medicine, S. officinalis has been used for the treatment of different kinds of disorders including seizure, ulcers, gout, rheumatism, inflammation, dizziness, tremor, paralysis, diarrhea, and hyperglycemia. In recent years, this plant has been a subject of intensive studies to document its traditional use and to find new biological effects. These studies have revealed a wide range of pharmacological activities for S. officinalis. Present review highlights the up-to-date information on the pharmacological findings that have been frequently reported for S. officinalis. These findings include anticancer, anti-inflammatory, antinociceptive, antioxidant, antimicrobial, antimutagenic, antidementia, hypoglycemic, and hypolipidemic effects. Also, chemical constituents responsible for pharmacological effects of S. officinalis and the clinical studies on this plant are presented and discussed.

The effect of climatic conditions on exercise-induced bronchoconstriction in 10-12 year old students.

Exercise-induced asthma is seen following vigorous or prolonged exercise or physical exertion. It has been suggested that climatic conditions have an influence on exercise-induced asthma. Therefore, the aim of the present study was to examine the effect of two climatic conditions on exercise-induced deterioration of pulmonary function tests in 10-12 year old students. Two hundred and fifty six students were randomly chosen from two cities namely Kerman and Gorgan (128 subjects in each who were equally from both cities) including 62 girls and 66 boys of 10-12 years old. A questionnaire was used to obtain demographic information and to identify the prevalence of asthma symptoms. Each subject performed a seven-minute free run exercise with maximum effort and sufficient motivation until they reached 70-75% heart rate. Pulmonary function tests (PFT) including, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and maximum expiratory flow at 50% of vital capacity (MEF50) were measured before, at the beginning, and 7 and 20 min after physical activity. The prevalence of both asthma (28.12%) and exercise-induced asthma (20.31%) in Kerman students was higher than those of Gorgan students (21.09% and 17%, respectively). All PFT values declined 7 and 20 min post-exercise in both groups. Although all baselines PFT in Kerman students were higher than those of Gorgan students, the decline in PFT values in Kerman students was greater than those of Gorgan students. At 20 min post exercise, the decline in FEV1, PEF and MEF50 in Kerman students was significantly higher than those of Gorgan students (p < 0.05 to p < 0.01). The results of the present study showed that prevalence of both asthma and exercise-induced asthma in a city with dry and cool climate such as Kerman was higher than in a city with humid climate such as Gorgan. In addition, the results showed that in a humid climate, post-exercise decline in PFT values was less than in a dry climate.

Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta-analysis.

OBJECTIVE: In this study, we aimed at evaluation of the efficacy of Hypericum perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women. MATERIALS AND METHODS: We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (RCT) to explore trials that assessed the effectiveness of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. In this regard, the following terms were used "menopause AND H. perforatum OR flaxseed OR Linum usitatissimum. Only randomized controlled trials were included in the study. RESULTS: Nine RCTs were included in this systematic review. Based on the literature, flaxseed showed beneficial effect on hot flash frequency and intensity, which was not statistically significant. According to two trials, flaxseed showed estrogenic effects; however, no conclusion regarding cancer promoting or protecting effects can be made. The evidence of the efficacy of the flaxseed on alleviating vaginal atrophy was also limited due to inconsistent findings in this regard. One trial declared that Vitex agnus-castus and H. perforatum showed comparable decrease in the frequency of hot flashes. CONCLUSION: The results of our systematic review suggest beneficial effect on vasomotor symptom with both of flaxseed and H. perforatum. Consistent conclusion regarding estrogen-dependent cancers and maturation value is limited due to small number of trials related to flaxseed. Further trials are still needed to confirm the results of our systematic review.

Effect of crocin on nitric oxide synthase expression in post-ischemic isolated rat heart.

OBJECTIVE: Oxidative stress damages cells and brings about the pathogenesis of ischemia/reperfusion injury. This study was carried out to investigate the preconditioning and cardio protective potential effects of crocin and vitamin E by the eNOS and iNOS express gene in ischemia/reperfusion in rats. MATERIAL & METHODS: Male rats were divided into seven groups, namely: sham, control group and experimental groups treated with crocin(10, 20 and 40 mg/kg), vitamin E (100 mg/kg) and combination of crocin (40 mg/kg) with vitamin E (100 mg/kg) that were gavaged The heart was removed and relocated to a Langendorff apparatus and subjected to global ischemia and then the left ventricular end diastolic pressure (LVEDP) were measured as a hemodynamic parameter. Total RNA was extracted from heart frozen tissues. RT-PCR technique was performed by specific primers designed for nitric oxide gene and the results were assessed by agarose gel electrophoresis. RESULTS: Results after ischemia and reperfusion showed that crocin 40 mg/kg produced a significant improvement of LVEDP as a mechanical function (p<0.05), associated with a reduction of iNOS release (p<0.05). The eNOS mRNA levels were significantly higher in crocin-treated 40 mg/kg compared to controls treated by RT-PCR technique. The combination of crocin and vitamin E have shown more effective on the reduction of iNOS release (p<0.01). CONCLUSION: In the isolated rat heart, protective effect of crocin, may possibly be explained by regulating eNOS and iNOS expressions. The Results resultsconfirmed the hypothesis that cardioprotective effect of crocin is partly mediated by nitric oxide. This could explain the cardioprotective action of crocin following ischemia and reperfusion.

Effects of hydroalcoholic extract of Coriandrum sativum on oxidative damage in pentylenetetrazole-induced seizures in rats.

BACKGROUND: An important role for oxidative stress, as a consequence of epileptic seizures, has been suggested. Coriandrum sativum has been shown that have antioxidant effects. Central nervous system depressant effects of C. sativum have also been reported. In this study, the effects of hydroalcoholic extract of aerial parts of the plants on brain tissues oxidative damages following seizures induced by pentylenetetrazole (PTZ) was investigated in rats. METHODS: The rats were divided into five groups and treated: (1) Control (saline), (2) PTZ (90 mg/kg, i.p.), (3-5) three doses (100, 500 and 1000 mg/kg of C. sativum extract (CSE) before PTZ. Latencies to the first minimal clonic seizures (MCS) and the first generalized tonic-clonic seizures (GTCS) were recorded. The cortical and hippocampal tissues were then removed for biochemical measurements. RESULTS: The extract significantly increased the MCS and GTCS latencies (P < 0.01, P < 0.001) following PTZ-induced seizures. The malondialdehyde (MDA) levels in both cortical and hippocampal tissues of PTZ group were significantly higher than those of the control animals (P < 0.001). Pretreatment with the extract prevented elevation of the MDA levels (P < 0.010-P < 0.001). Following PTZ administration, a significant reduction in total thiol groups was observed in both cortical and hippocampal tissues (P < 0.050). Pre-treatment with the 500 mg/kg of the extract caused a significant prevention of decreased in total thiol concentration in the cortical tissues (P < 0.010). CONCLUSION: The present study showed that the hydroalcoholic extract of the aerial parts of C. sativum possess significant antioxidant and anticonvulsant activities.

Protective Effects of Crocin on Ischemia-reperfusion Induced Oxidative Stress in Comparison With Vitamin E in Isolated Rat Hearts.

BACKGROUND: Myocardial Injury caused by ischemia-reperfusion leads to cardiac dysfunction, tissue injury and metabolic changes. The production of reactive oxygen species (ROS) and lipid peroxidation are accompanied by ischemia-reperfusion injury. OBJECTIVES: The aim of this study was to assess the cardio protective potential effects of crocin in comparison with vitamin E on antioxidant capacity in ischemia-reperfusion of isolated rat hearts. MATERIALS AND METHODS: Seventy male Sprague-Dawley rats were randomly divided into seven groups, including: sham, control and experimental groups treated with different doses of crocin (10, 20 and 40 mg/kg) or vitamin E (100 mg/kg) and a combination of crocin (40 mg/kg) with vitamin E (100 mg/kg) that were administrated orally for 21 days. The heart was quickly excised, transferred to a Langendorff apparatus at constant pressure and subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion. Cardiac damage markers and antioxidant enzymes were measured. RESULTS: The results showed that superoxide dismutase and catalase enzyme activities increased and Mallon de aldehyde (MDA) decreased in animals pretreated by crocin (40 mg/kg) and vitamin E (100 mg/kg). Moreover, there was a significant improvement in post ischemic recovery of antioxidant capacity during reperfusion in rats receiving a combination of crocin (40 mg/kg) and vitamin E (100 mg/kg). CONCLUSIONS: The results demonstrated the protective role of crocin on antioxidant capacity, which may partially be related to stability or amplification of antioxidant systems. Like vitamin E, crocin may be beneficial for prevention or treatment of cardiac dysfunction and myocardial infarction in patients with ischemic heart disease.

Protective effects of crocin on hemodynamic parameters and infarct size in comparison with vitamin E after ischemia reperfusion in isolated rat hearts.

Although reperfusion is a useful method for the survival of ischemic heart, harmful effects have been observed. This study was carried out to investigate the preconditioning and cardioprotective potential effects of crocin and vitamin E on the hemodynamic and infarct size in the ischemia-reperfusion model of isolated rat hearts. Animals were divided into a control group, an ischemia-reperfusion control group and three treatment groups: crocin (10, 20, and 40 mg/kg), vitamin E (100 mg/kg), and combination (crocin 40 mg/kg with vitamin E 100 mg/kg). The hearts were excised, quickly transferred to a Langendorff apparatus, and subjected to 30 min of global ischemia followed by 60 min of reperfusion. Left ventricular developed pressure, coronary perfusion pressure, left ventricular systolic pressure, myocardial contractility, rate pressure product, coronary flow, and infarct size were assessed. The successful induction of ischemia was determined by ST elevation on the electrocardiogram.The results showed that crocin significantly improved cardiac dysfunction and also reduced infarct size in the rat hearts. However, the combination of crocin 40 mg/kg and vitamin E 100 mg/kg had an even more significantly improved effect on the hemodynamic parameters and infarct size.Therefore, it can be suggested that the protective role of crocin may be due to the stability or reinforcement of antioxidant systems, and crocin could be useful for the treatment or prevention of cardiac dysfunction.