Crystal structure of the Vibrio cholerae ferric uptake regulator (Fur) reveals insights into metal co-ordination

The ferric uptake regulator (Fur) is a metal-dependent DNA-binding protein that acts as both a repressor and an activator of numerous genes involved in maintaining iron homeostasis in bacteria. It has also been demonstrated in Vibrio cholerae that Fur plays an additional role in pathogenesis, opening up the potential of Fur as a drug target for cholera. Here we present the crystal structure of V. cholerae Fur that reveals a very different orientation of the DNA-binding domains compared with that observed in Pseudomonas aeruginosa Fur . Each monomer of the dimeric Fur protein contains two metal binding sites occupied by zinc in the crystal structure. In the P. aeruginosa study these were designated as the regulatory site (Zn1) and structural site (Zn2). This V. cholerae Fur study, together with studies on Fur homologues and paralogues, suggests that in fact the Zn2 site is the regulatory iron binding site and the Zn1 site plays an auxiliary role. There is no evidence of metal binding to the cysteines that are conserved in many Fur homologues, including Escherichia coli Fur. An analysis of the metal binding properties shows that V. cholerae Fur can be activated by a range of divalent metals.     

Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes

Growing evidence supports the view that enzymatic activity results from a subtle interplay between chemical kinetics and molecular motions. A systematic analysis is performed here to delineate the type and level of coupling between catalysis and conformational mechanics. The dynamics of a set of 98 enzymes representative of different EC classes are analyzed with the Gaussian network model (GNM) and compared with experimental data. In more than 70% of the examined enzymes, the global hinge centers predicted by the GNM are found to be colocalized with the catalytic sites experimentally identified. Low translational mobility (< 7%) is observed for the catalytic residues, consistent with the fine-tuned design of enzymes to achieve precise mechanochemical activities. Ligand binding sites, while closely neighboring catalytic sites, enjoy a moderate flexibility to accommodate the ligand binding. These findings could serve as additional criteria for assessing drug binding residues and could lessen the computational burden of substrate docking searches.     

New diprenylated dihyrochalcones from leaves of Artocarpus elasticus

Two new diprenylated dihydrochalcones, elastichalcone A 1 and elastichalcone B 2 and three known compounds were isolated from the leaves of Artocarpus elasticus. Their structures were determined by various spectroscopic techniques (UV, IR, MS, 1D-NMR and 2D-NMR). Elastichalcone B 2 and a known compound exhibited good free radical scavenging activity with IC₅₀ values of 11.30 and 11.89 μg/ml, respectively.     

ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors

With the existing knowledge of ATM''s role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent ‘resistance-to-apoptosis'' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.     

Tectona grandis L.f: A comprehensive review on its patents,chemical constituents,and biological activities

Tectona grandis L.f is a timber plant that is commonly referred to as teak. Its wide use as a medicine in the various indigenous systems makes it a plant of importance. A wide gamut of phytoconstituents like alkaloids, phenolic glycosides, steroids, etc. has been reported. A renewed interest in this plant has resulted in scientific investigations by various researchers towards the isolation and identification of active constituents along with scientific proof of its biological activities. The different parts of the plant have been scientifically evaluated for their antioxidant, antipyretic, analgesic, hypoglycemic, wound healing, cytotoxic, and many more biological activities. Documentation of this scientific knowledge is of importance to have consolidated precise information encompassing the various aspects of this plant, which could provide a base for future studies. This review is a compilation of the salient reports on these investigations concerning phytochemistry, the methods used to identify and quantify the constituents, the evaluation methods of the biological activity, toxicological studies, allergies and the patent/patent applications. This will further help researchers to find an area of the gap for future studies.     

A Review of the Potency of Plant Extracts and Compounds from Key Families as an Alternative to Synthetic Nematicides: History,Efficacy, and Current Developments

The global nematicides market is expected to continue growing. With an increasing demand for synthetic chemical-free organic foods, botanical nematicides are taking the lead as replacements. Consequently, in the recent years, there have been vigorous efforts towards identification of the active secondary metabolites from various plants. These include mostly glucosinolates and their hydrolysis products such as isothiocyanates; flavonoids, alkaloids, limonoids, quassinoids, saponins, and the more recently probed essential oils, among others. And despite their overwhelming potential, variabilities in quality, efficacy, potency and composition continue to persist, and commercialization of new botanical nematicides is still lagging. Herein, we have reviewed the history of botanical nematicides and regional progresses, the potency of the identified phytochemicals from the key important plant families, and deciphered some of the impediments involved in standardization of the active compounds in addition to the concerns over the safety of the purified compounds to non-target microbial communities.     

Preoptic hypothalamic warming suppresses laryngeal dilator activity during sleep

Upper airway dilator activity during sleep appears to be diminished under conditions of enhanced sleep propensity, such as after sleep deprivation, leading to worsening of obstructive sleep apnea (OSA). Non-rapid eye movement (NREM) sleep propensity originates in sleep-active neurons of the preoptic area (POA) of the hypothalamus and is facilitated by activation of POA warm-sensitive neurons (WSNs). We hypothesized that activation of WSNs by local POA warming would inhibit activity of the posterior cricoarytenoid (PCA) muscle, an airway dilator, during NREM sleep. In chronically prepared unrestrained cats, the PCA exhibited inspiratory bursts in approximate synchrony with inspiratory diaphragmatic activity during waking, NREM, and REM. Integrated inspiratory PCA activity (IA), peak activity (PA), and the lead time (LT) of the onset of inspiratory activity in PCA relative to diaphragm were significantly reduced in NREM sleep and further reduced during REM sleep compared with waking. Mild bilateral local POA warming (0.5-1.2 degrees C) significantly reduced IA, PA, and LT during NREM sleep compared with a prewarming NREM baseline. In some animals, effects of POA warming on PCA activity were found during waking or REM. Because POA WSN activity is increased during spontaneous NREM sleep and regulates sleep propensity, we hypothesize that this activation contributes to reduction of airway dilator activity in patients with OSA.     

Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line

Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases.     

Protective effects of cinnamon powder against hyperlipidemia and hepatotoxicity in butter fed female albino mice

A butter-enriched high-fat diet changes lipid metabolism, resulting in fat storage, hyperlipidemia and obesity. Effects of cinnamon powder were investigated in butter-fed mice. 40 Swiss Albino mice, aged 28 to 30 days, were randomly assigned into two groups. Group A was an untreated control group (n = 8) and another group (n = 32) was a butter-treated group fed 10% butter. In the fifth week, mice of the butter-fed group were further divided into four equal groups: B, C, D, and E (n = 8), fed 10% butter with cinnamon 200 mg, 400 mg, and 600 mg powder per liter drinking water, respectively for 10 weeks. The butter-fed group was gained the most weight. Cinnamon supplementation significantly normalized weight gain and had no harmful effects on hematological parameters. Butter supplementation significantly increased total cholesterol (TC), triglycerides, and LDL cholesterol (LDL-c) whereas, cinnamon powder significantly reduced TC, LDL-c and glucose levels. In butter-fed mice, a significant increase was observed in the liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels with subsequent fat deposition in the liver. Excitingly, these enzymes were decreased and no fat depositions were observed in the liver of cinnamon-treated mice. Applying different concentrations of cinnamon powder improved the lipid profile in butter-fed female albino mice.