Synthesis of alpha-amyrin derivatives and their in vivo antihyperglycemic activity

Ficus racemosa belongs to the family of Moraceae and is commonly known as 'Gular' in north India. Bio-activity guided isolation work on the fruits of F. racemosa resulted in the identification of antidiabetic active principle, alpha-amyrin acetate 7. Compound 7 lowered the blood glucose levels by 18.4 and 17.0% at 5 and 24 h, respectively, in sucrose challenged streptozotocin induced diabetic rat (STZ-S) model at the dose of 100 mg/kg body weight. Fifteen novel derivatives viz, 9-21, 24, 25 of alpha-amyrin 8 were prepared and their antihyperglycemic activity profile was assessed. The p-chlorobenzoic acid derivative 9 and nicotinic acid derivative 14 showed potent antihyperglycemic activity at 100 mg/kg body weight.     

A facile synthesis of alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanones and their antitubercular evaluations

An economical and facile synthesis of alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanones was achieved by the reaction of cycloalkanones with different aromatic aldehydes using ethanolic KOH in good yields. Few of the selected compounds were reduced with NaBH(4) to the respective alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanols. All these compounds and our earlier synthesized cyclohexyl phenyl methanols were evaluated for their antitubercular, antifungal and antibacterial activities. Several compounds displayed moderate antitubercular activity with MIC=12.5-1.56 microg/mL. However, none of the compounds displayed any significant antifungal activity.     

The spatial attention network interacts with limbic and monoaminergic systems to modulate motivation-induced attention shifts

How does the human brain integrate information from multiple domains to guide spatial attention according to motivational needs? To address this question, we measured hemodynamic responses to central cues predicting locations of peripheral attentional targets (food or tool images) in a novel covert spatial attention paradigm. The motivational relevance of food-related attentional targets was experimentally manipulated via hunger and satiety. Amygdala, posterior cingulate, locus coeruleus, and substantia nigra showed selective sensitivity to food-related cues when hungry but not when satiated, an effect that did not generalize to tools. Posterior parietal cortex (PPC), including intraparietal sulcus, posterior cingulate, and the orbitofrontal cortex displayed correlations with the speed of attentional shifts that were sensitive not just to motivational state but also to the motivational value of the target. Stronger functional coupling between PPC and posterior cingulate occurred during attentional biasing toward motivationally relevant food targets. These results reveal conjoint limbic and monoaminergic encoding of motivational salience in spatial attention. They emphasize the interactive role of posterior parietal and cingulate cortices in integrating motivational information with spatial attention, a process that is critical for selective allocation of attentional resources in an environment where target position and relevance can change rapidly.     

Rhabdoid meningioma with cranial nerve involvement: case report of a child

CASE REPORT: A 13-year-old girl presented with off and on headache for 1 year, hearing loss for 6 months and difficulty in closing eyes for 5 months along with mild cerebellar signs. Histopathologic evaluation of the tumor showed a rhabdoid meningioma (WHO Grade III). DISCUSSION: Rhabdoid meningiomas are uncommon in children, and only 4 cases have been reported so far. None of them presented with cranial nerve involvement. This unusual presentation is reported here. CONCLUSION: Though rare, rhabdoid meningiomas can occur in children. This, to the best of the authors' knowledge, is the first case of rhabdoid meningioma presenting with cranial nerve involvement.     

Serum heat shock protein 27 and diabetes complications in the EURODIAB prospective complications study: a novel circulating marker for diabetic neuropathy

OBJECTIVE—Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients.RESEARCH DESIGN AND METHODS—A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications.RESULTS—Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11–5.24]).CONCLUSIONS—In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy.Heat shock protein 27 (HSP27), a member of the small heat shock protein family of proteins, is a highly conserved peptide of ∼27 kDa associated with cytoskeletal actin (1). In addition to its chaperone activity, HSP27 acts as a filament stabilizer under stress conditions, interferes with apoptotic pathways, and participates in cytoskeletal dynamics by controlling actin polymerization (2). Therefore, HSP27 plays an important role in both cytoprotection and cell motility.Recent studies in experimental diabetes have shown HSP27 overexpression in glomeruli (3), dorsal root ganglia (4,5), retina (6), and the area adjacent to atherosclerotic plaque (7), indicating HSP27 induction in target tissues of diabetes complications. HSP27 is also released into circulation (8). A pilot study has shown reduced plasma HSP27 levels in patients with carotid stenosis (9), but in a more recent study, HSP27 levels were increased in patients with acute coronary syndromes (7). However, no large study is yet available on circulating HSP27 in vascular disease.Type 1 diabetes is associated with a greatly increased risk of vascular complications that cannot be completely accounted for by conventional risk factors. The aim of the present study was to assess whether high serum HSP27 (sHSP27) levels increased odds ratios (ORs) of micro- and macrovascular complications in a nested case-control sample of type 1 diabetic individuals from the EURODIAB Prospective Complications Study.     

Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway

Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappaB signaling pathway, we investigated the effects of GA on NF-kappaB-mediated cellular responses and NF-kappaB-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (IAP1 and IAP2, Bcl-2, Bcl-x(L), and TRAF1), proliferation (cyclin D1 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappaB. GA suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAK1/TAB1-mediated IKK activation, inhibited IkappaBalpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappaB-dependent reporter gene expression. The NF-kappaB activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKbeta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappaB and apoptosis. Overall our results demonstrate that GA inhibits NF-kappaB signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.     

INFANTILE PYODERMA GANGRENOSUM

A six month old female infant with pyoderma gangrenosum is reported. Pyoderma gangrenosum in an infant is rare. The child responded to pulse therapy with intravenous dexamethasone and intralesional triamcinolone acetonide.     

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells

MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4alpha, and a membrane-bound growth factor-like subunit, MUC4beta. MUC4 mRNA contains unique 5' and 3' coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7-19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer. To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is comparable with that of wild-type MUC4 (930 kDa) but represents only 10% of VNTR. Stable ectopic expression of mini-MUC4 in two human pancreatic cancer cell lines, Panc1 and MiaPaCa, showed that MUC4 minigene expression follows a biosynthesis and localisation pattern similar to the wild-type MUC4. Expression of MUC4 resulted in increased growth, motility, and invasiveness of the pancreatic cancer cells in vitro. Ultra-structural examination of MUC4-transfected cells showed the presence of increased number and size of mitochondria. The MUC4-expressing cells also demonstrated an enhanced tumorigenicity in an orthotopic xenograft nude mice model, further supporting a direct role of MUC4 in inducing the cancer properties. In conclusion, our results suggest that MUC4 promotes tumorigenicity and is directly involved in growth and survival of the cancer cells.     

Doping droops

Drug abuse is a major concern in the athletic world. The misconception among athletes and their coaches is that when an athlete breaks a record it is due to some "magic ingredient" and not because of training, hard work, mental attitude and championship performance. The personal motivation to win in competitive sports has been intensified by national, political, professional and economic incentives. Under this increased pressure athletes have turned to finding this "magic ingredient". Athlete turns to mechanical (exercise, massage), nutritional (vitamins, minerals), pharmacological (medicines) or gene therapies to have an edge over other players. The World Anti-Doping Agency (WADA) has already asked scientists to help find ways to prevent gene therapy from becoming the newest form of doping. The safety of the life of athletes is compromised with all forms of doping techniques, be it a side effect of a drug or a new technique of gene doping.