Sunanda Panda

Apigenin (4‘,5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice

The potential of apigenin (4′,5,7‐trihydroxyflavone) in regulating hyperglycaemia, thyroid dysfunction and lipid peroxidation (LPO) has been revealed. While in alloxan‐treated diabetic animals, a significant decrease in the concentrations of serum insulin, thyroxine (T4) and triiodothyronine (T3), with a parallel increase in serum glucose and hepatic glucose‐6‐phospatase (G‐6‐Pase) activity, was observed, administration of 0.78 mg kg−1 of apigenin for 10 consecutive days increased the levels of serum insulin and thyroid hormones with a parallel decrease in glucose concentration and hepatic G‐6‐Pase activity. Alloxan‐induced elevation in serum cholesterol was also reduced by the compound. With respect to LPO, while in alloxan‐treated animals an increase in hepatic LPO and a decrease in the activity of cellular antioxidants, such as catalase (CAT) and superoxide dismutase (SOD), and in glutathione (GSH) content was observed, administration of apigenin to alloxan‐treated mice reversed all these changes, suggesting its hepatoprotective potential. Similar effects of apigenin were also observed in most of the parameters in normoglycaemic animals. It appears that apigenin has a potential to regulate diabetes mellitus, as well as disease‐induced thyroid dysfunction and lipid peroxidation.

Changes in Thyroid Hormone Concentrations after Administration of Ashwagandha Root Extract to Adult Male Mice

The importance of ashwagandha root extract in the regulation of thyroid function with special reference to type‐I iodothyronine 5′‐monodeiodinase activity in mice liver has been investigated.

Gugulu (Commiphora mukul) induces triiodothyronine production: possible involvement of lipid peroxidation.

An investigation was made to find out the importance of gugulu (Commiphora mukul) in thyroid function of mice and to reveal the possible involvement of lipid peroxidation (LPO), if any. While no marked change in the concentrations of serum thyroxine (T4) was observed, triiodoth yronine (T3) concentration and T3/T4 ratio were enhanced following the administration of gugulu extract (0.2 g/kg b. wt./d for 15 days). A concomitant decrease in LPO was also noticed in liver, the principal site of T3 generation, suggesting that gugulu induced increase in T3 concentration is LPO mediated.

Cardioprotective potential of N,α-L-rhamnopyranosyl vincosamide, an indole alkaloid, isolated from the leaves of Moringa oleifera in isoproterenol induced cardiotoxic rats: in vivo and in vitro studies.

Hitherto unknown protective effect of N,α-L-rhamnopyranosyl vincosamide (VR), isolated from Moringa oleifera leaves in isoproterenol (ISO)-induced cardiac toxicity was evaluated in rats. Oral administration of VR at 40 mg/kg for 7 days markedly reduced the ISO-induced increase in the levels of serum cardiac markers such as troponin-T, creatine kinase-MB, lactate dehydrogenase and glutamate pyruvate transaminase as well as cardiac lipid peroxidation with a parallel increase in the cellular antioxidants suggesting its cardio-protective and free radical scavenging potential, which was latter confirmed by in vitro study. Rats treated with test compound also improved the ISO-induced abnormal changes in ECG as well as in cardiac histology. A reduction in myocardial necrosis was further evidenced by the tri-phenyl tetrazolium chloride (TTC) stain in isolated test drug pretreated rats. These findings suggest the cardio-protective potential of the isolated alkaloid and possibly the beneficial action is mediated through its free radical scavenging property.

The effect of Anethum graveolens L. (dill) on corticosteroid induced diabetes mellitus: involvement of thyroid hormones.

An investigation was made to evaluate the role of Anethum graveolens L. (dill) leaf extract in the regulation of corticosteroid‐induced type 2 diabetes mellitus in female rats. In dexamethasone‐treated animals (1 mg/kg for 22 days) an increase in serum concentration of insulin and glucose and in hepatic lipid peroxidation (LPO) was observed. However, there was a decrease in serum concentration of thyroid hormones and in the endogenous antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) in liver. In animals treated with an equivalent amount of dexamethasone for a similar period (22 days) when received the leaf extract (100 mg/kg b.wt/d.) for last 15 days a decrease in the concentration of both serum glucose and insulin was observed, indicating the potential of the plant extract in the regulation of corticosteroid‐induced diabetes. Dexamethasone‐induced alterations in the levels of thyroid hormones as well as in hepatic LPO, SOD, CAT and GSH were also reversed by the plant extract. Copyright

Periplogenin‐3‐O‐ ‐D‐Glucopyranosyl ‐(1→6)‐ ‐D‐Glucopyaranosyl‐ ‐(1→4) ‐D‐Cymaropyranoside, Isolated from Aegle marmelos Protects Doxorubicin Induced Cardiovascular Problems and Hepatotoxicity in Rats

Doxorubicin is a common chemotherapeutic anticancer drug. Its use is associated with adverse effects including cardiotoxicity. Several therapeutics interventions have been attempted to reduce the toxicity and to improve the efficacy of the drug. However, on phytochemicals very few investigations have been made. In the present study we have evaluated the potential of a cardenolide, periplogenin, isolated from the leaves of Aegle marmelos in protecting the doxorubicin induced cardiotoxicity and lipid peroxidation (LPO) in rats. Doxorubicin induced cardiac and hepatotoxicity were characterized by marked biochemical changes including an increase in serum creatine kinase-MB (CK-MB), glutamate-pyruvate transaminase (SGPT), and tissue LPO, with a decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). It also increased the levels of different serum lipids, but decreased the amount of high-density lipoprotein (HDL). Cotherapy of the test cardenolide and doxorubicin for 4 weeks reversed all these adverse effects. However, out of three different concentrations (12.5, 25, and 50 mg/kg p.o.) of the test periplogenin, 25 mg/kg appeared to be most effective. When its efficacy was compared with that of vitamin E (alpha-tocopherol) the isolated compound exhibited a better therapeutic potential. The isolated periplogenin from the leaves of A. marmelos could potentially inhibit doxorubicin-induced cardiovascular problems in rats. However, its moderate dose was found to be most effective.

Cardioprotective effect of vincristine on isoproterenol-induced myocardial necrosis in rats

This study investigated the protective effect of vincristine (VCR) on isoproterenol (ISO)-induced cardiac necrosis (CN) in rats. Animals (n=7 in each group) were pretreated with vincristine (25µg/kg) intraperitoneal (i.p.) daily in 5-day cycles with 2 days pause between cycles using a 5-day-on, 2-day-off schedule for two weeks and then intoxicated with isoproterenol (100mg/kg, s.c., for 2 consecutive days). ISO-induced myocardial damage was indicated by changes in electrocardiographic (ECG) patterns, increased activities of marker enzymes such as creatine kinase-MB, serum glutamate pyruvate transaminase and lactate dehydrogenase and the levels of troponin-T in the serum. The levels of lipid peroxide products, (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (HP)) were increased with a parallel decrease in the activities of antioxidants (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione) in ISO-induced rats. Furthermore, ISO-induced rats showed increase in the activities of membrane bound enzymes such as Ca(2+)-ATPase and Mg(2+)-ATPase with a decreased activity of Na(+)/K(+)-ATPase. Triphenyl tetrazolium chloride (TTC) staining of the heart section showed increased area of necrosis in ISO-induced rats. Pretreatment with VCR (25µg/kg) eliminated all ISO-induced biochemical and histopathological changes, and decreased the myocardial necrosis to a greater extent. Transmission electron microscopic findings on the structure of the heart mitochondria confirmed the protective effects of VCR. Present study provides first scientific report on protective effect of vincristine against ISO-induced cardiac damage in rats.

Trigonelline isolated from fenugreek seed protects against isoproterenol-induced myocardial injury through down-regulation of Hsp27 and αB-crystallin

OBJECTIVE Protective effects of trigonelline (TRG) isolated from fenugreek seed were evaluated in isoproterenol (ISO)-induced myocardial dysfunctions in adult rats and a proteomic approach was applied to understand its mechanism of action. METHODS In a preliminary experiment, effects of TRG at 20, 40, and 80 mg/kg for 20 d were studied in ISO-induced (100 mg/kg) adult rats. As 40 mg/kg was found the most effective concentration, in the final experiment, effects of 40 mg/kg of the test drug were investigated using different indices including cardiac marker enzymes, lipid peroxidation, antioxidants, cardiac histology, and electrocardiogram. Proteomic analyses were also done in cardiac myocytes. RESULTS ISO administration increased serum levels of cardiac markers (creatine kinase-MB, glutamate pyruvate transaminase, and lactate dehydrogenase) and exhibited a positive reaction in the TROP-T test. It also increased the cardiac lipid peroxidation and decreased the cellular antioxidants. Proteomic data revealed nine protein spots, seven were down-regulated and two up-regulated. The overexpressions of two small stress proteins, heat shock protein (Hsp)27 and αB crystallin were confirmed by Western blot analysis. All these alterations were restored to nearly normal values in 40 mg/kg of TRG-pretreated animals, suggesting its cardioprotective effects, which were further confirmed by histologic examinations and triphenyl tetrazolium chloride staining assay. CONCLUSION For the first time, our study revealed the down-regulation of Hsp27 and αB-crystallin and (CaMKII delta) isoform by TRG. As the test compound prevented the ISO-induced myocardial injury, its therapeutic use may further be explored.

ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

PRIP-Interacting protein with methyl transferase domain (PIMT) serves as a molecular bridge between CREB-binding protein (CBP)/ E1A binding protein p300 (Ep300) -anchored histone acetyl transferase and the Mediator complex sub-unit1 (Med1) and modulates nuclear receptor transcription. Here, we report that ERK2 phosphorylates PIMT at Ser298 and enhances its ability to activate PEPCK promoter. We observed that PIMT is recruited to PEPCK promoter and adenoviral-mediated over-expression of PIMT in rat primary hepatocytes up-regulated expression of gluconeogenic genes including PEPCK. Reporter experiments with phosphomimetic PIMT mutant (PIMTS298D) suggested that conformational change may play an important role in PIMT-dependent PEPCK promoter activity. Overexpression of PIMT and Med1 together augmented hepatic glucose output in an additive manner. Importantly, expression of gluconeogenic genes and hepatic glucose output were suppressed in isolated liver specific PIMT knockout mouse hepatocytes. Furthermore, consistent with reporter experiments, PIMTS298D but not PIMTS298A augmented hepatic glucose output via up-regulating the expression of gluconeogenic genes. Pharmacological blockade of MAPK/ERK pathway using U0126, abolished PIMT/Med1-dependent gluconeogenic program leading to reduced hepatic glucose output. Further, systemic administration of T4 hormone to rats activated ERK1/2 resulting in enhanced PIMT ser298 phosphorylation. Phosphorylation of PIMT led to its increased binding to the PEPCK promoter, increased PEPCK expression and induction of gluconeogenesis in liver. Thus, ERK2-mediated phosphorylation of PIMT at Ser298 is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia.

AMELIORATION OF l‐THYROXINE‐INDUCED HYPERTHYROIDISM BY COUMARIN (1,2‐BENZOPYRONE) IN FEMALE RATS

1 The efficacy of coumarin (1,2‐benzopyrone) was examined for the regulation of hyperthyroidism in female rats. 2 Coumarin was administered (10 mg/kg per day for 15 days) to l‐thyroxine (L‐T4)‐induced hyperthyroid as well as to euthyroid rats and changes in serum concentrations of thyroid hormones and in associated parameters, such as serum cholesterol, activity of hepatic 5′‐monodeiodinase (5′DI) and glucose‐6‐phosphatase (G‐6‐Pase), glycogen content, bodyweight and daily food consumption, were analysed. Simultaneously, changes in hepatic lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were also investigated. 3 Although L‐T4 administration increased serum levels of thyroid hormones, the activity of hepatic 5′DI, G‐6‐Pase and LPO and daily food consumption, it decreased the level of serum cholesterol, hepatic glycogen content and the activities of anti‐oxidant enzymes, such as SOD, CAT and GSH. 4 However, simultaneous administration of coumarin for 15 days to a group of hyperthyroid animals reversed most of the aforementioned changes, indicating its potential to ameliorate hyperthyroidism. Moreover, the drug did not increase, but rather decreased, hepatic LPO, suggesting its safe nature. 5 The present findings reveal a positive role for coumarin in the regulation of hyperthyroidism without any hepatotoxicity. It also appears that the test compound inhibits thyroid function at both a glandular level and at the level of peripheral conversion of T4 to tri‐iodothyronine.