Anti-diabetic action of Punica granatum flower extract: activation of PPAR-gamma and identification of an active component

Peroxisome proliferator-activated receptor (PPAR)-gamma activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-gamma mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-gamma mRNA and protein expression and increased PPAR-gamma-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-gamma is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF.     

Anaerobic bacteria associated with cervical neoplasia

The possible association between cervical neoplasia and anaerobic bacteria was examined by correlating the histopathology of cervical biopsies with anaerobic cultures obtained from the cervix in 90 patients. Fourteen patients had invasive carcinoma of the cervix (ICC). All but one of them had Stage I or II disease. Severe dysplasia was present in 11 patients, moderate dysplasia in 9, mild dysplasia in 11, and carcinoma in situ in 26. Cultures from patients with ICC were characterized by a relative sparsity of anaerobes. The cultures of 3 of 14 patients with ICC contained anaerobes, in contrast to 53 of 76 patients in the other categories. Further, none of the 14 patients with ICC had anaerobic gram-negative bacilli whereas they were present in 18 of 76 patients in the other categories. ICC was not associated with any specific anaerobic bacteria. These data suggest that anaerobic bacteria are sparse and anaerolic gram-negative bacilli are rare in early invasive carcinoma of the cervix.     

Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation

5,6-epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxation. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 micromol/L) induced concentration-dependent relaxations, with maximal relaxation of 86+/-5% and EC50 of 1 micromol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 micromol/L; max relaxation 43+/-9%); the ATP-sensitive K+ channel inhibitor glybenclamide (10 micromol/L; max relaxation 49+/-6%); and the large conductance calcium-activated K+ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38+/-6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K+ to 20 mmol/L. Whole-cell outward K+ current was increased nearly 6-fold by PTPA (10 micromol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy)pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46+/-13% and 52+/-7%, respectively; EC50 1micromol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether-containing prostaglandins that activate ATP-sensitive K+ channels and (2) activation of smooth muscle large conductance calcium-activated K+ channels. PDPAs only activate large conductance calcium-activated K+ channels.     

Approach to pancreatic cystic lesions

Pancreatic cystic lesions are detected more frequently as a result of increasing use of high-resolution cross-sectional imaging. The ability of imaging and cyst fluid analysis to predict the biologic behavior of the lesions has aroused much interest recently. A precise diagnosis is critical to help guide further management. The diagnostic criteria and the management principles have evolved dramatically over the past 10 years with the advant of endoscopic ultrasound and fine-needle aspiration. In this review, we summarize the recent publications that have examined the key issues in the diagnosis and management of cystic lesions of the pancreas.     

Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ) gene. There is no information on AIRE mutations in Indians. In a cross-sectional study, nine patients (eight families), from four referral hospitals in India, were studied for AIRE mutations by direct sequencing. We screened for new mutations in 150 controls by allele-specific PCR. The patients had 1–7 known components of APECED. Three patients had unusual manifestations: presentation with type 1 diabetes; chronic sinusitis and otitis media; and facial dysmorphism. All patients carried homozygous, probably recessive, AIRE mutations. Two unrelated patients from a small in-bred community (Vanika Vaisya) in south India carried an unreported missense mutation, p.V80G, in the N-terminal caspase recruitment domain. Another unique mutation, p.C302X, resulting in a truncated protein with deletion of both zinc-finger domains, was detected in a patient from Gujarat. Neither mutation was detected in controls. Other mutations, previously described in Caucasians, were: 13 base pair deletion (p.C322fsX372) in 4 (38%), and Finn-major (p.R257X) and p.R139X (Sardinian) mutation in one subject each. In conclusion, in this first series of APECED in Indians, we detected AIRE mutations previously reported in Caucasians, as well as unique mutations. Of these, p.V80G is possibly an ancestral mutation in an in-bred community.     

Linking agriculture and health in low- and middle-income countries: an interdisciplinary research agenda

Recent global fluctuations in food prices and continuing environmental degradation highlight the future challenge of feeding a growing world population. However, current dialogues rarely address the relationship between agricultural changes and health. This relationship is traditionally associated with the role of food in nutrition and with food safety, and while these are key interactions, we show in this paper that the relationship is far more complex and interesting. Besides the direct effects of agriculture on population nutrition, agriculture also influences health through its impact on household incomes, economies and the environment. These effects are felt particularly in low- and middle-income countries, where dramatic changes are affecting the agriculture-health relationship, in particular the growth of nutrition-related chronic disease and the associated double burden of under- and over-nutrition. Greater understanding of the negative effects of agriculture on health is also needed. While lengthening food value chains make the chain of influence between agricultural policy, food consumption, nutrition and health more complex, there remain opportunities to improve health by changing agricultural systems. The first challenge in doing this, we suggest, is to improve our capacity to measure the impact of agricultural interventions on health outcomes, and vice versa.