Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy

Inflammatory bowel disease(IBD), consisting primarily of ulcerative colitis and Crohn's disease, is a group of debilitating auto-immune disorders, which also increases the risk of colitis-associated cancer. However, due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs(e.g., approximately 30% non-responders to anti-TNFα agents), and related serious side effects, about half of all IBD patients(in millions) turn to alternative treatment options. In this regard, mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis. However, despite the increasing clinical realization of the significance of the concept of mucosal healing, its regulation and means of therapeutic targeting remain largely unclear. Here, stemcell therapy, which uses hematopoietic stem cells or mesenchymal stem cells, remains a promising option. Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells. The overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process. Moreover, by differentiating into the mature intestinal epithelial cells, the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction, the root cause of the IBD. In this article, we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient's quality of life.     

Plant Growth-Promoting Rhizobacteria Enhance Abiotic Stress Tolerance in Solanum tuberosum Through Inducing Changes in the Expression of ROS-Scavenging Enzymes and Improved Photosynthetic Performance

In this report we address the changes in the expression of the genes involved in ROS scavenging and ethylene biosynthesis induced by the inoculation of plant growth-promoting rhizobacteria (PGPR) isolated from potato rhizosphere. The two Bacillus isolates used in this investigation had earlier demonstrated a striking influence on potato tuberization. These isolates showed enhanced 1-aminocyclopropane-1-carboxylic acid deaminase activity, phosphate solubilization, and siderophore production. Potato plants inoculated with these PGPR isolates were subjected to salt, drought, and heavy-metal stresses. The enhanced mRNA expression levels of the various ROS-scavenging enzymes and higher proline content in tubers induced by PGPR-treated plants contributed to increased plant tolerance to these abiotic stresses. Furthermore, the photosynthetic performance indices of PGPR-inoculated plants clearly exhibited a positive influence of these bacterial strains on the PSII photochemistry of the plants. Overall, these results suggest that the PGPR isolates used in this study are able to confer abiotic stress tolerance in potato plants.     

THE EFFECT OF SPERMINE AND SPERMIDINE ON THE HYDROLYSIS OF ACETYLTHIOCHOLINE IN THE PRESENCE OF RAT CAUDATE NUCLEUS HOMOGENATE OR ACETYLCHOLINESTERASE FROM ELECTROPHORUS ELECTRICUS

Abstract— The effects of spermine and spermidine tetrahydrochloride on female Agus rat brain caudate nucleus homogenates, soluble acetylcholinesterase from the electric organ of Electrophorus electricus and acetylthiocholine iodide were studied. Measurements were made using an autoanalytical spectrophotometric method which measured the initial rate of reaction rapidly and accurately. Both polyamines interacted with the substrate, acetylthiocholine, causing an increase in the rate of its non-enzymatic hydrolysis. Slight inhibitory effects on acetylcholinesterase were also observed. Combined effect of the polyamine on the substrate and the enzyme showed an inhibition at low and activation at high (above 1 m m ) substrate concentrations.     

Mapping of Xp21 translocation breakpoints in and around the DMD gene by pulsed field gel electrophoresis

Balanced translocations with a breakpoint in the Xp21 region are likely to disrupt the giant Duchenne muscular dystrophy (DMD) locus and can be demonstrated in females suffering from the disease. Pulsed field gel electrophoresis allows the positioning of these breakpoints by detecting junction fragments on the derived chromosomes; DNA probes hybridizing to these fragments may be located as many as several hundred kilobases away from the breakpoints. By using this approach, 11 translocation breakpoints from the Xp21 region have been analyzed. The localization of three previously examined breakpoints was confirmed. Six other breakpoints, including a breakpoint flanking the DMD gene and not associated with the DMD phenotype, could be positioned relative to SfiI sites on a 3.5-Mb restriction map of the region.     

Biochemical studies and ligand-bound structures of biphenyl dehydrogenase from Pandoraea pnomenusa strain B-356 reveal a basis for broad specificity of the enzyme

Biphenyl dehydrogenase, a member of short-chain dehydrogenase/reductase enzymes, catalyzes the second step of the biphenyl/polychlorinated biphenyls catabolic pathway in bacteria. To understand the molecular basis for the broad substrate specificity of Pandoraea pnomenusa strain B-356 biphenyl dehydrogenase (BphB_B-356), the crystal structures of the apo-enzyme, the binary complex with NAD⁺, and the ternary complexes with NAD⁺-2,3-dihydroxybiphenyl and NAD⁺-4,4′-dihydroxybiphenyl were determined at 2.2-, 2.5-, 2.4-, and 2.1-Å resolutions, respectively. A crystal structure representing an intermediate state of the enzyme was also obtained in which the substrate binding loop was ordered as compared with the apo and binary forms but it was displaced significantly with respect to the ternary structures. These five structures reveal that the substrate binding loop is highly mobile and that its conformation changes during ligand binding, starting from a disorganized loop in the apo state to a well organized loop structure in the ligand-bound form. Conformational changes are induced during ligand binding; forming a well defined cavity to accommodate a wide variety of substrates. This explains the biochemical data that shows BphB_B-356 converts the dihydrodiol metabolites of 3,3′-dichlorobiphenyl, 2,4,4′-trichlorobiphenyl, and 2,6-dichlorobiphenyl to their respective dihydroxy metabolites. For the first time, a combination of structural, biochemical, and molecular docking studies of BphB_B-356 elucidate the unique ability of the enzyme to transform the cis-dihydrodiols of double meta-, para-, and ortho-substituted chlorobiphenyls.     

Logging and indigenous hunting impacts on persistence of large Neotropical animals

Areas allocated for industrial logging and community‐owned forests account for over 50% of all remaining tropical forests. Landscape‐scale conservation strategies that include these forests are expected to have substantial benefits for biodiversity, especially for large mammals and birds that require extensive habitat but that are susceptible to extirpation due to synergies between logging and hunting. In addition, their responses to logging alone are poorly understood due to their cryptic behavior and low densities. In this study, we assessed the effects of logging and hunting on detection and occupancy rates of large vertebrates in a multiple‐use forest on the Guiana Shield. Our study site was certified as being responsibly managed for timber production and indigenous communities are legally guaranteed use‐rights to the forest. We coupled camera‐trap data for wildlife detection with a spatially explicit dataset on indigenous hunting. A multi‐species occupancy model found a weak positive effect of logging on occupancy and detection rates, while hunting had a weak negative effect. Model predictions of species richness were also higher in logged forest sites compared to unlogged forest sites. Density estimates for jaguars and ocelots in our multiple‐use area were similar to estimates reported for fully protected areas. Involvement of local communities in forest management, control of forest access, and nesting production forests in a landscape that includes protected areas seemed important for these positive biodiversity outcomes. The maintenance of vertebrate species bodes well for both biodiversity and the humans that depend on multiple‐use forests.     

Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors

There is evidence of derangement of oxidant and antioxidant defense systems in depression. The present study examined the effects of fluoxetine and citalopram, standard selective serotonin re-uptake inhibitors, on lipid peroxidation, superoxide dismutase (SOD) activity and ascorbic acid concentrations. For this, a prospective open-labeled, randomized design was utilized. Patients with major depression (n = 62) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and decrease in plasma ascorbic acid levels in patients of major depression as compared to control subjects. The trend reversed significantly after treatment with fluoxetine and citalopram. Results indicate a greater reduction in oxidative stress with citalopram than fluoxetine. The Hamilton Rating Scale for Depression (HRSD) score also improved with fluoxetine and citalopram treatment. These findings indicate that major depression is associated with increased levels of serum SOD, serum MDA and decreased levels of plasma ascorbic acid. Treatment with fluoxetine and citalopram reversed these biochemical parameters. This study can be used as a predictor of drug response by fluoxetine and citalopram in major depression.     

Insights on inhibition of Plasmodium falciparum plasmepsin I by novel epoxyazadiradione derivatives – molecular docking and comparative molecular field analysis

In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) – comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q²) value of 0.967 and the non-cross-validated correlation coefficient (r²) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r²_(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied.

Communicated by Ramaswamy H. Sarma     

Antimicrobial Efficacy of Synthetic Pyranochromenones and (Coumarinyloxy)acetamides

Four (1, 2, 4 and 6) synthetic quaternary ammonium derivatives of pyranochromenones and (coumarinyloxy)acetamides were synthesized and investigated for their antimicrobial efficacy on MRSA (Methicillin-resistant Staphylococcus aureus), and multi-drug resistant Pseudomonas aeruginosa, Salmonella enteritidis and Mycobacterium tuberculosis H37Rv strain. One of the four compounds screened i.e. N,N,N-triethyl-10-((4,8,8-trimethyl-2-oxo-2,6,7,8-tetrahydropyrano[3,2-g]chromen-10-yl)oxy)decan-1-aminium bromide (1), demonstrated significant activity against S. aureus, P. aeruginosa and M. tuberculosis with MIC value of 16, 35, and 15.62 µg/ml respectively. The cytotoxicity evaluation of compound 1 on A549 cell lines showed it to be a safe antimicrobial molecule, TEM study suggested that the compound led to the rupture of the bacterial cell walls.     

The PIP2 binding mode of the C2 domains of rabphilin-3A

Phosphatidylinositol-4,5-bisphosphate (PIP2) is a key player in the neurotransmitter release process. Rabphilin-3A is a neuronal C2 domain tandem containing protein that is involved in this process. Both its C2 domains (C2A and C2B) are able to bind PIP2. The investigation of the interactions of the two C2 domains with the PIP2 headgroup IP3 (inositol-1,4,5-trisphosphate) by NMR showed that a well-defined binding site can be described on the concave surface of each domain. The binding modes of the two domains are different. The binding of IP3 to the C2A domain is strongly enhanced by Ca(2+) and is characterized by a K(D) of 55 microM in the presence of a saturating concentration of Ca(2+) (5 mM). Reciprocally, the binding of IP3 increases the apparent Ca(2+)-binding affinity of the C2A domain in agreement with a Target-Activated Messenger Affinity (TAMA) mechanism. The C2B domain binds IP3 in a Ca(2+)-independent fashion with low affinity. These different PIP2 headgroup recognition modes suggest that PIP2 is a target of the C2A domain of rabphilin-3A while this phospholipid is an effector of the C2B domain.