Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases

Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulationsbased structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis,and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas

Maternal obesity and gut microbiota are associated with fetal brain development

Obesity in pregnancy induces metabolic syndrome, low-grade inflammation, altered endocrine factors, placental function, and the maternal gut microbiome. All these factors impact fetal growth and development, including brain development. The lipid metabolic transporters of the maternalfetal- placental unit are dysregulated in obesity. Consequently, the transport of essential long-chain PUFAs for fetal brain development is disturbed. The mother’s gut microbiota is vital in maintaining postnatal energy homeostasis and maternal-fetal immune competence. Obesity during pregnancy changes the gut microbiota, affecting fetal brain development. Obesity and a high-fat diet in pregnancy can induce placental and intrauterine inflammation and thus influence the neurodevelopmental outcomes of the offspring. Several epidemiological studies observed an association between maternal obesity and adverse neurodevelopment. This review discusses the effects of maternal obesity and gut microbiota on fetal neurodevelopment outcomes. In addition, the possible mechanisms of the impacts of obesity and gut microbiota on fetal brain development are discussed

A Follow-Up Study on the Efficacy of the Homeopathic Remedy Arsenicum album in Volunteers Living in High Risk Arsenic Contaminated Areas

In continuation of our short-term pilot studies reported earlier, results on certain toxicity biomarkers in volunteers who continued to take the potentized Arsenicum album 200C till 2 years are presented. Out of some 130 “verum”-fed volunteers of pilot study, 96 continued to take the remedy till 6 months, 65 till 1 year and 15 among them continued till 2 years. They provided samples of their urine and blood at 6 months, 1 year and finally at 2 years. None out of 17 who received “placebo” turned up for providing blood or urine at these longer intervals. Standard methodologies were used for determination of arsenic content in blood and urine, and for measurement of toxicity biomarkers like acid and alkaline phosphatases, alanine and aspartate amino transferases, lipid peroxidation and reduced glutathione and anti-nuclear antibody titers. Most of the volunteers reported status quo maintained after the improvement they achieved within the first 3 months of homeopathic treatment, in respect of their general health and spirit, and appetite and sleep. A few with skin symptoms and burning sensation, however, improved further. This was supported by the data of toxicity biomarkers, levels of all of which remained fairly within normal range. Therefore, administration of Arsenicum album 200C considerably ameliorates symptoms of arsenic toxicity on a long-term basis, and can be recommended for interim use, particularly in high risk remote villages lacking modern medical and arsenic free drinking water facilities. Similar studies by others are encouraged

Can Administration of Potentized Homeopathic Remedy, Arsenicum Album, Alter Antinuclear Antibody (ANA) Titer in People Living in High-Risk Arsenic Contaminated Areas? I. A Correlation with Certain Hematological Parameters

To examine whether elevated antinuclear antibody (ANA) titers reported in random human population of arsenic contaminated villages can be reverted to the normal range by administration of a potentized homeopathic drug, Arsenicum album, randomly selected volunteers in two arsenic contaminated villages and one arsenic-free village in West Bengal (India) were periodically tested for their ANA titer as well as various blood parameters in two types of experiments: ‘placebo-controlled double blind’ experiment for shorter duration and ‘uncontrolled verum fed experiment’ for longer duration. Positive modulation of ANA titer was observed along with changes in certain relevant hematological parameters, namely total count of red blood cells and white blood cells, packed cell volume, hemoglobin content, erythrocyte sedimentation rate and blood sugar level, mostly within 2 months of drug administration. Thus, Arsenicum album appears to have great potential for ameliorating arsenic induced elevated ANA titer and other hematological toxicities

Can Homeopathic Arsenic Remedy Combat Arsenic Poisoning in Humans Exposed to Groundwater Arsenic Contamination?: A Preliminary Report on First Human Trial

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans

MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis

Abnormal levels of microRNA (miR)-155, which regulate inflammation and immune responses, have been demonstrated in the colonic mucosa of patients with inflammatory bowel diseases (IBD), although its role in disease pathophysiology is unknown. We investigated the role of miR-155 in the acquisition and maintenance of an activated phenotype by intestinal myofibroblasts (IMF), a key cell population contributing to mucosal damage in IBD. IMF were isolated from colonic biopsies of healthy controls, ulcerative colitis (UC) and Crohn's disease (CD) patients. MiR-155 in IMF was quantified by quantitative reverse transcription-PCR in basal condition and following exposure to TNF-alpha, interleukin (IL)-1 beta, lipopolysaccharide (LPS) or TGF-beta 1. The effects of miR-155 mimic or inhibitor transfection on cytokine release and suppressor of cytokine signaling 1 (SOCS1) expression were assessed by enzyme-linked immunosorbent assay and western blot, respectively. Regulation of the target gene SOCS1 expression by miR-155 was assessed using luciferase reporter construct. We found that miR-155 was significantly upregulated in UC as compared with control-and CD-derived IMF. Moreover, TNF-alpha and LPS, but not TGF-beta 1 and IL-1 beta, significantly increased miR-155 expression in IMF. Ectopic expression of miR-155 in control IMF augmented cytokines release, whereas it downregulated SOCS1 expression. MiR-155 knockdown in UC-IMF reduced cytokine production and enhanced SOCS1 expression. Luciferase reporter assay demonstrated that miR-155 directly targets SOCS1. Moreover, silencing of SOCS1 in control IMF significantly increased IL-6 and IL-8 release. In all, our data suggest that inflammatory mediators induce miR-155 expression in IMF of patients with UC. By downregulating the expression of SOCS1, miR-155 wires IMF inflammatory phenotype

A Brief Review on the Regulatory Roles of MicroRNAs in Cystic Diseases and Their Use as Potential Biomarkers

miRNAs are small endogenous conserved non-coding RNA molecules that regulate post-transcriptional gene expression through mRNA degradation or translational inhibition, modulating nearly 60% of human genes. Cystic diseases are characterized by the presence of abnormal fluid-filled sacs in the body, and though most cysts are benign, they can grow inside tumors and turn malignant. Recent evidence has revealed that the aberrant expression of a number of miRNAs present in extracellular fluids, including plasma or serum, urine, saliva, follicular fluid, and semen, contribute to different cystic pathologies. This review aims to describe the role of different miRNAs in three worldwide relevant cystic diseases: polycystic ovarian syndrome (PCOS), polycystic kidney disease (PKD), and pancreatic cyst tumors (PCTs), as well as their potential use as novel biomarkers.publishedVersio

Microbe-Based Strategy for Plant Nutrient Management

The rapid industrialization and urbanization of developing countries such as India have encroached on cultivable lands to meet the demands of an ever-increasing population. The altered land use patterns with increased fertilizer use has increased crop yields with leaching of major portion of the applied nutrients from the soil. Nitrates and phosphates are the agricultural pollutants that are discharged into aquifers due to anthropogenic reasons causing severe environmental and health problems. Production of these nutrients requires energy and finite resources (rock phosphate, which has gradually depleting reserves). An alternative management strategy would be to sequester excess nutrients within a biomass that is reused for agriculture. Two discrete enriched microbial consortia with the potential of simultaneous nitrate and phosphate sequestration upon application as biofertilizer restricted them within the plant root zone, ensuring prevention of eutrophication through leaching while making it available for uptake by plants. The nutrient accumulated biomass enhanced the crop yield by 21.88% during mung bean cultivation with maintained elemental content and other nutritional qualities. The major drawback of conventional biofertilizer application (slow release and action) could be overcome using this formulation leading to environmental protection, crop yield enhancement and soil fertility maintenance post-cultivation