A hypothalamic pathway for Augmentor α-controlled body weight regulation.

Augmentor α and ß (Augα and Augß) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augα functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augα fragment and monomeric Augß also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Augα and Augß are poorly understood. Here, we investigate the physiological roles of Augα and Augß by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augα single knockout and double knockout of Augα and Augß exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augα-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augß-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Augα is robustly expressed and metabolically regulated in agouti-related peptide (AgRP) neurons, cells that control whole-body energy homeostasis in part via their projections to the paraventricular nucleus (PVN). Moreover, both Alk and melanocortin receptor-4 are expressed in discrete neuronal populations in the PVN and are regulated by projections containing Augα and AgRP, respectively, demonstrating that two distinct mechanisms that regulate pigmentation operate in the hypothalamus to control body weight. These experiments show that Alk-driven cancers were co-opted from a neuronal pathway in control of body weight, offering therapeutic opportunities for metabolic diseases and cancer.

Regulation of prefrontal patterning and connectivity by retinoic acid.

The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory1 and are thought to be altered in disorders such as autism2,3 and schizophrenia4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents6-9, the mechanisms that underlie the development of PFC-mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function12-15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC-mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.

Lipid profile of hyperlipidemic males after supplementation of multigrain bread containing sunflower (Helianthus annuus) seed flour.

Sunflower seeds are produced and consumed worldwide due to their richness in heart friendly nutrients in the bakery products. Its effect on reducing the incidences of cardio vascular diseases have not been studied, through supplementary studies therefore present supplementation study was planned in which five samples of bread were prepared by using various multigrain flours and sunflower seed flour at five different levels of 2.5, 5, 7.5, 10 and 12.5%. The bread sample supplemented with 7.5% sunflower seed flour was found to be highly acceptable. Sunflower seeds were roasted at 60 °C for 10-15 min. Chemical analysis of sunflower seed flour (raw and roasted) and highly acceptable bread pertaining to proximate composition, in vitro protein digestibility, antioxidant activity, bioactive compounds, essential fatty acids and minerals was done using standard methods. Roasting of seeds resulted in significant increase in carbohydrates, protein digestibility, phosphorus, magnesium and copper contents. The most acceptable sample had good amount of energy (324.48 kcal), protein (10.61 g), fat (2.92 g), fibre (11.36 g), ash (3.29 g), antioxidant activity (12.13%), total phenols (31.54 mg), flavonoids (17.53 mg), omega 3 fatty acids (186.16 mg), omega 6 fatty acids (13,701.40 mg), phosphorus (68.74 mg), magnesium (28.13 mg) and copper (0.12 mg) per 100 g. Sixty hyperlipidemic males aged 30-50 years were supplemented with highly acceptable bread for four months. After the intervention period, mean daily intake of and nuts and oilseeds increased significantly (p < 0.01) and a significant increase (p < 0.01) in the intake of total fat, dietary fibre, PUFA, linoleic acid, ascorbic acid, alpha tocopherols and phosphorus was observed. The weight, BMI, total cholesterol, LDL cholesterol and triglycerides significantly reduced after the supplementation.

Alpha-amylase as molecular target for treatment of diabetes mellitus: A comprehensive review.

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.

A review of germination and early growth as a proxy for plant fitness under petrogenic contamination - knowledge gaps and recommendations.

Germination-an important stage in the life cycle of plants-is susceptible to the presence of soil contaminants. Since the early 1990s, the use of germination tests to screen multiple plant species to select candidates for phytoremediation has received much attention. This is due to its inexpensive methodology and fast assessment relative to greenhouse or field growth studies. Surprisingly, no comprehensive synthesis is available of these studies in the scientific literature. As more plant species are added to phytoremediation databases, it is important to encapsulate the knowledge thus far and revise protocols. In this review, we have summarised previously-documented effects of petroleum hydrocarbons on germination and seedling growth. The methods and materials of previous studies are presented in tabulated form. Common practice includes the use of cellulose acetate filter paper, plastic Petri dishes, and low numbers of seeds and replicates. A general bias was observed for the screening of cultivated crops as opposed to native species, even though the latter may be better suited to site conditions. The relevance of germination studies as important ecotoxicological tools is highlighted with the proposed use of root imaging software. Screening of novel plant species, particularly natives, is recommended with selection focussed on (i) species phylogeny, (ii) plant morphological and functional traits, and (iii) tolerance towards harsh environmental stresses. Recommendations for standardised protocols for germination and early growth monitoring are made in order to improve the robustness of statistical modelling and species selection in future phytoremediation evaluations and field programs.

Terminalia arjuna in Chronic Stable Angina: Systematic Review and Meta-Analysis.

Background. Terminalia arjuna is a popular Indian medicinal plant with its bark been used for over centuries as cardiotonic. The bark has been found to contain several bioactive compounds including saponins and flavonoids. A number of experimental and clinical studies have been conducted to explore therapeutic potential of Terminalia arjuna in cardiovascular ailments specially in patients of coronary heart disease. A number of narrative reviews have been done but no systematic review has been conducted to date. Objective. To systematically review and conduct a meta-analysis on the available literature evaluating the efficacy of Terminalia arjuna in patients of chronic stable angina. Study selection. We included randomised, pseudo-randomized and before-after comparative studies which compared Terminalia arjuna/commercial preparation of Terminalia arjuna with current standard/ conventional treatment regimens in patients with chronic stable angina. Findings. Studies were found to be of poor methodological design. We found no significant difference in the Terminalia arjuna group as compared to control arm in the outcomes for which we were able to pool data and undertake meta-analysis. Conclusions. Currently, the evidence is insufficient to draw any definite conclusions in favour of or against Terminalia arjuna in patients of chronic stable angina. Further, well-controlled multicentric clinical trials need to be conducted in large number of patients to explore the therapeutic potential of Terminalia arjuna if any.

Pregnanolone sulfate promotes desensitization of activated NMDA receptors.

Neurosteroids are potent neuromodulators which act in part by binding to and modifying the activity of neurotransmitter-gated channels. Pregnanolone sulfate (PAS) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective in vivo. To delineate the mechanism of NMDA receptor inhibition by pregnanolone sulfate we used kinetic analyses of equilibrium single-channel currents recorded from individual GluN1/GluN2A receptors. Results show that PAS (0.1 mM) reduces single-channel open probability by 50% solely by increasing approximately 5-fold the mean time spent by receptors in closed conformations. From these data we derive a kinetic scheme that summarizes the effects of PAS on single channel kinetics, accounts for the PAS effects on macroscopic responses and leads us to propose that PAS inhibits NMDA receptor activity by shifting active receptors into desensitized conformations. These findings highlight the neurosteroid inhibitory site on NMDA receptors as a valuable therapeutic target against excitotoxic pathologies including acute and chronic neurodegeneration.

A novel antiproliferative and antifungal lectin from Amaranthus viridis Linn seeds.

A lectin from the seeds of Amaranthus viridis Linn has been purified by affinity chromatography on asialofetuin-linked amino activated silica. Amaranthus viridis lectin (AVL) has a native molecular mass of 67 kDa. It is a homodimer composed of two 36.6 kDa subunits. The lectin gave a single band in non-denaturing PAGE at pH 4.5 and pH 8.3 and a single peak on HPLC size exclusion and cation exchange columns. The purified lectin was specific for both T-antigen and N-acetyl-D-lactosamine, markers for various carcinomas, in addition to N-acetyl-D-galactosamine, asialofetuin and fetuin. This lectin reacted strongly with red blood cells (RBCs) from human ABO blood groups and rat. It also reacted with rabbit, sheep, goat and guinea pig RBCs. The lectin is a glycoprotein having no metal ion requirement for its activity. Denaturing agents such as urea, thiourea and guanidine-HCl had no effect on its activity when treated for 15 minutes. AVL showed significant antiproliferative activity towards HB98 and P388D1 murine cancer cell lines. It also exerted antifungal activity against phytopathogenic fungi Botrytis cincerea and Fusarium oxysporum but not against Rhizoctonia solani, Trichoderma reesei, Alternaria solani and Fusarium graminearum.