Antihyperglycemic and antihyperlipidemic activity of plectranthus amboinicus on normal and alloxan-induced diabetic rats

The present study was undertaken to investigate the antihyperglycemic and antihyperlipidemic effects of ethanol extract of Plectranthus amboinicus in normal and alloxan-induced diabetic rats. Diabetes was induced in Wistar rats by single intraperitoneal administration of alloxan monohydrate (150 mg/kg). Normal as well as diabetic rats were divided into groups (n=6) receiving different treatments. Graded doses (200 mg/kg and 400 mg/kg) of ethanol extract of Plectranthus amboinicus were studied in both normal and alloxan-induced diabetic rats for a period of 15 days. Glibenclamide (600 μg/kg) was used as a reference drug. Oral administration with graded doses of ethanol extract of Plectranthus amboinicus exhibited hypoglycemic effect in normal rats and significantly reduced the peak glucose levels after 120 min of glucose loading. In alloxan-induced diabetic rats, the daily oral treatment with ethanol extract of Plectranthus amboinicus showed a significant reduction in blood glucose. Besides, administration of ethanol extract of Plectranthus amboinicus for 15 days significantly decreased serum contents of total cholesterol, triglycerides whereas HDL-cholesterol, total proteins and calcium were effectively increased. Furthermore, effect of ethanol extract of Plectranthus amboinicus showed profound elevation of serum amylase and reduction of serum lipase. Histology examination showed ethanol extract of Plectranthus amboinicus exhibited almost normalization of damaged pancreatic architecture in rats with diabetes mellitus. Studies clearly demonstrated that ethanol extract of Plectranthus amboinicus leaves possesses hypoglycemic and antihyperlipidemic effects mediated through the restoration of the functions of pancreatic tissues and insulinotropic effect.     

Report: Asian Consensus Meeting on Metabolic Surgery. Recommendations for the use of Bariatric and Gastrointestinal Metabolic Surgery for Treatment of Obesity and Type II Diabetes Mellitus in the Asian Population

Background  

The report submitted is a detailed analysis of the happenings and outcomes of a two day deliberation that was organized in Trivandrum, India on the 9th and 10th August 2009.     

Extraintestinal non-Hodgkin's lymphoma presenting as obstructive jaundice in a patient with Crohn's disease

We report the case of a 58-yr-old woman, previously diagnosed with Crohn's disease of the duodenum, who presented with jaundice and an epigastric mass. Diagnostic studies revealed an extraintestinal non-Hodgkin's lymphoma located near the head of the pancreas and causing obstructive jaundice. A review of the literature indicates the rarity of this association. We discuss the etiology, pathogenesis, and management of extraintestinal lymphomas in patients with Crohn's disease.     

Acute intestinal obstruction due to small gut hemangioma.

A 20-year-old man presented with acute intestinal obstruction due to multiple hemangiomas of small intestine extending into the adjoining mesentery. The diagnosis was made at laparotomy and subsequently confirmed on histology. Occurrence of hemangioma in the small intestine and its presentation as acute intestinal obstruction are rare.     

Role of dietary phenols in mitigating microglia-mediated neuroinflammation

Chronic neuroinflammation is a pathological feature of a number of central nervous system (CNS) diseases and is mediated by sustained activation of microglial cells, the innate immune cells of the CNS. Studies have mainly focused on identifying the molecular and epigenetic mechanisms of microglial activation. This is crucial in designing therapeutic strategies for neuropathologies in which prolonged microglial activation is known to exacerbate disease condition. In recent years, increasing evidence show that naturally occurring compounds present in regular diet could function as “nutraceuticals,” arresting microglial activation, and thus conferring neuroprotection. This review summarizes our understanding of the role of dietary phenolic nutraceuticals in mitigating microglia-mediated neuroinflammation. Studies show that these natural phenols inhibit key signaling pathways in activated microglia such as the NFκB, MAPK and JAK-STAT that trigger microglia-mediated inflammation in various neuropathological conditions such as injury, infection, stroke, autism and neurodegenerative diseases, i.e., Alzheimer’s disease and Parkinson’s disease. The anti-inflammatory and antioxidant effect exerted by these natural phenols have shown considerable success in improving disease condition in animal models of neuropathologies, and thus seem to be suitable candidates for developing therapeutic strategies.     

Antimicrobial Resistance in Salmonella in the United States from 1948 to 1995

We conducted a retrospective study of 2,149 clinical Salmonella strains to help document the historical emergence of antimicrobial resistance. There were significant increases in resistance to older drugs, including ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline, which were most common in Salmonella enterica serotype Typhimurium. An increase in multidrug resistance was observed for each decade since the 1950s. These data help show how Salmonella evolved over the past 6 decades, after the introduction of new antimicrobial agents.     

Anti-inflammatory property of n-hexadecanoic acid: structural evidence and kinetic assessment

Ester bond hydrolysis of membrane phospholipids by Phospholipase A₂ and consequent release of fatty acids are the initiating steps of inflammation. It is proposed in this study that the inhibition of phospholipase A₂ is one of the ways to control inflammation. Investigations are carried out to identify the mode of inhibition of phospholipase A₂ by the n‐hexadecanoic acid. It may help in designing of specific inhibitors of phospholipase A₂ as anti‐inflammatory agents. The enzyme kinetics study proved that n‐hexadecanoic acid inhibits phospholipase A₂ in a competitive manner. It was identified from the crystal structure at 2.5 Å resolution that the position of n‐hexadecanoic acid is in the active site of the phospholipase A₂. The binding constant and binding energy have also been calculated using Isothermal Titration Calorimetry. Also, the binding energy of n‐hexadecanoic acid to phospholipase A₂ was calculated by in silico method and compared with known inhibitors. It may be concluded from the structural and kinetics studies that the fatty acid, n‐hexadecanoic acid, is an inhibitor of phospholipase A₂, hence, an anti‐inflammatory compound. The inferences from the present study validate the rigorous use of medicated oils rich in n‐hexadecanoic acid for the treatment of rheumatic symptoms in the traditional medical system of India, Ayurveda.     

Insulin-Stimulated Cardiac Glucose Oxidation Is Increased in High-Fat Diet�CInduced Obese Mice Lacking Malonyl CoA Decarboxylase

OBJECTIVE

Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid oxidation could also impair glucose metabolism and function. We therefore determined the effects of diet-induced obesity (DIO) in wild-type (WT) mice and mice deficient for malonyl CoA decarboxylase (MCD^−/−; an enzyme promoting mitochondrial fatty acid oxidation) on insulin-sensitive cardiac glucose oxidation.

RESEARCH DESIGN AND METHODS

WT and MCD^−/− mice were fed a low- or high-fat diet for 12 weeks, and intramyocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nanomoles per gram of dry weight per minute) in isolated working hearts (+/– insulin).

RESULTS

DIO markedly reduced insulin-stimulated glucose oxidation compared with low fat–fed WT mice (167 ± 31 vs. 734 ± 125; P < 0.05). MCD^−/− mice subjected to DIO displayed a more robust insulin-stimulated glucose oxidation (554 ± 82 vs. 167 ± 31; P < 0.05) and less incomplete fatty acid oxidation, evidenced by a decrease in long-chain acylcarnitines compared with WT counterparts. MCD^−/− mice had long-chain acyl CoAs similar to those of WT mice subjected to DIO but had increased triacylglycerol levels (10.92 ± 3.72 vs. 3.29 ± 0.62 μmol/g wet wt; P < 0.05).

CONCLUSIONS

DIO does not impair cardiac fatty acid oxidation or function, and there exists disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.The incidence of obesity, insulin resistance, and diabetes is rapidly increasing (1–4), and by 2025 it is estimated that worldwide the incidence of diabetes will affect nearly 333 million individuals between 20 and 79 years of age (4). Obesity, insulin resistance, and diabetes are characterized, at least in part, by an elevation of circulating plasma fatty acid concentrations. Whereas there is a general consensus that increased circulating fatty acids lead to increased rates of fatty acid uptake in muscle, the contribution of impaired mitochondrial fatty acid oxidation to the accumulation of cytosolic intramuscular fatty acid metabolites implicated in the pathogenesis of insulin resistance (such as long-chain acyl CoAs, triacylglycerols, ceramides, and diacylglycerols) remains controversial (5–8). It has been proposed that an acceleration of mitochondrial fatty acid oxidation may alleviate or attenuate skeletal muscle insulin resistance by preventing the cytosolic accumulation of these fatty acid metabolites (9,10).We have recently demonstrated that insulin resistance in response to high-fat feeding (diet-induced obesity [DIO]) in skeletal muscle does not arise from an impairment of mitochondrial fatty acid oxidation per se but rather is associated with excessive rates of incomplete fatty acid oxidation (11,12). DIO leads to an accumulation of intramuscular long-chain acyl CoAs, the vast majority of which are localized and oxidized in the mitochondria (13). However, in the absence of high energy demand, often observed in obese sedentary individuals, flux through the tricarboxylic acid (TCA) cycle is unable to increase to such a rate to accommodate the large increase in acyl CoAs oxidized. Interestingly, we also demonstrated in mice that preventing the mitochondrial uptake of fatty acids attenuates the development of fatty acid–induced whole-body insulin resistance (11). This was achieved by genetic deletion of malonyl CoA decarboxylase (MCD^−/−), which degrades malonyl CoA, a potent endogenous inhibitor of the rate-limiting enzyme in mitochondrial fatty acid uptake (carnitine palmitoyl transferase-1). A similar beneficial effect of MCD inhibition on insulin-stimulated glucose metabolism in skeletal muscle cells was also demonstrated recently (14). In our studies, MCD inhibition was associated with a reduction in the accumulation of long-chain acylcarnitines and a prevention in the downregulation of TCA cycle intermediates observed during DIO (11). It can be argued that such a strategy would increase the intramuscular accumulation of the aforementioned fatty acid metabolites (15). However, there was not any increase in long-chain acyl CoAs and triacylglycerols beyond that induced by high-fat feeding itself.The accumulation of intramyocardial fatty acid metabolites is also implicated in mediating myocardial dysfunction (16,17). It is not clear what effect modifying fatty acid oxidation has on insulin sensitivity in cardiac muscle. Previous findings in the obese Zucker rat demonstrate an impairment in fasting myocardial fatty acid oxidation compared with lean controls, an effect accompanied by elevated levels of intramyocardial lipid and an inability to increase the expression of peroxisome proliferator–activated receptor (PPAR)-α target genes (17). Conversely, we showed previously no difference in the rates of myocardial fatty acid oxidation in either the fed or fasted states between insulin-resistant JCR:LA-cp rats and lean controls (18). Furthermore, in insulin-resistant JCR:LA-cp rats there was nearly a doubling in myocardial triacylglycerol stores, supporting the observation that the accumulation of intramyocardial fatty acid metabolites is the result of excessive fatty acid supply, opposed to impaired fatty acid oxidation. Also, we have demonstrated that myocardial fatty acid oxidation rates are elevated in transgenic PPAR-α–overexpressing mice, a phenotype resembling that of type 2 diabetes (19). Therefore, debate still exists with regards to the accumulation of fatty acid metabolites, fatty acid oxidation rates, and myocardial insulin resistance.In this study, we investigated the relationship between myocardial fatty acid metabolite accumulation, fatty acid oxidation, and insulin-stimulated glucose oxidation in wild-type (WT) and MCD^−/− mice fed either low- or high-fat diet. We hypothesized that inhibition of mitochondrial fatty acid uptake via ablation of MCD preserves insulin-sensitive myocardial glucose oxidation, despite elevated levels of intramyocardial long-chain acyl CoAs and triacylglycerols.