Expression profile of markers of oxidative stress, injury and apoptosis in anti-tuberculosis drugs induced nephrotoxicity.

AIM: Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA) are part of first-line anti-tuberculosis therapy used against infection caused by Mycobacterium tuberculosis. However, these drugs are known to be potentially harmful as these are associated with numerous side effects and when taken together their harmful outcomes are elevated in a synergistic manner. Identification of possible mechanism underlying RIF + INH + PZA induced nephrotoxicity may be advantageous in developing strategies to prevent their toxic implications. METHODS: In this study rats were distributed in two groups of six each: Control (tap water) and Toxicant (INH + RIF + PZA) in dosage derived through extrapolation from human dosage for 28 days once in a day. Antioxidant activity and histology of kidney were examined. In addition, apoptosis was also studied using pro and anti-apoptotic markers and TUNEL staining to check nephrotoxicity. RESULTS: Findings indicated that combined (INH, RIF and PZA) 28 day exposure in Wistar rats caused increase in number of free radicals/ reactive oxygen species which further cause changes in levels of enzymatic antioxidants such as glutathione, Superoxide dismutase, Catalase, and Glutathione-s-transferase. Altered content of pro (BAD&BAX) and anti-apoptotic genes (BCL-2&BCL2L1) genes, TUNEL positive cells and DNA fragmentation emphasized involvement of apoptosis. CONCLUSION: This study concluded that nephrotoxicity is accompanied during combinational anti-tuberculosis drug therapy.

Decreased expression of neuregulin1 in the lesional skin of vitiligo patients.

BACKGROUND: Paracrine cross-talk exists between the fibroblasts of dermis and epidermal cells through secretions of various growth factors. Melanocytes present at the basement layer of the epidermis and respond to various factors secreted by underlying dermal fibroblasts in the dermis to regulate the function of the skin. OBJECTIVE: Therefore the study was planned to check the expression of fibroblast-derived factor neuregulin1 (NRG1) in vitiligo skin and its effect on melanocytes. METHODS: For this study, relative gene expression at mRNA level of NRG1 in the vitiligo skin was analyzed by qRT-PCR, and protein analysis was done by immunohistochemistry. Effect of different concentrations of NRG1 was checked on the cultured melanocytes by melanin content assay, proliferation assay, and tyrosinase (TYR) assay. The effect of NRG1 was also checked on the level of melanocyte regulatory genes (MITF, c-KIT, TYR, DCT). RESULTS: Expression of NRG1 was significantly less in lesional dermis of vitiligo patients as compared to nonlesional and healthy control dermis both at mRNA as well as protein level. NRG1 treatment showed significant increase in proliferation, melanin content, TYR level, and gene expression level of melanocyte specific genes. CONCLUSION: Treatment of NRG1 to the cultured melanocytes increases proliferation and pigmentation. Lower expression of NRG1 in the lesional dermis of vitiligo patients inhibits the melanocyte growth. Therefore this study hypothesized that low expression of NRG1 in lesional skin of vitiligo patients might have a possible role in the melanocyte loss and vitiligo pathogenesis.

Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats.

Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85 mg/kg b.wt., INH + 61.7 mg/kg b.wt., RIF + 132.65 mg/kg b.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28 days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity.

Early Life Pb Exposure and its Effect on Later Life Retinal Degeneration.

The study presents the longitudinal effect of early life lead exposure on retinal ischemia. Swiss albino mice were exposed to lead acetate at two different timepoints viz. postnatal day 1-20 and at 7th week of age. These mice were then followed till 10 week of age and subjected to retinal ischemia. Retinal ischemia was induced using pterygopalatine artery ligation. The effect of prior lead exposure on ischemic insult was determined using various histological and molecular parameters. Although toxic effects of Pb are well reported, but the results in this study showed not much significant effect of early life Pb exposure on later life retinal degeneration. While retinal thickness was decreased in surgery group and 7th week Pb exposed group, PND Pb exposed mice showed retinal thickness comparable to normal control. There was no difference in TUNEL positive cells in Pb exposed group when compared to surgery group. The molecular studies revealed overexpression of BDNF and GFAP in PND Pb exposed mice reflecting more injury and inflammation. The combined results revealed that Pb exposure have mild effect on overall susceptibility to retinal damage in later life. The Pb may exert its toxic effects at longer duration and thus the toxic effects may be mapped at longer timepoints. The study provides a new dimension to the already well known toxic effects of lead which needs to be further explored. J. Cell. Biochem. 118: 3213-3224, 2017. © 2017 Wiley Periodicals, Inc.

Deleterious effects of 28-day oral co-administration of first-line anti-TB drugs on spleen, blood and bone marrow chromosomes in normal rat.

CONTEXT: Isoniazid, rifampicin and pyrazinamide are most reliable and cost-effective remedy for tuberculosis treatment and prophylaxis among first-line anti-tuberculosis (TB) drugs and have a pronounced tendency to cause adverse drug reactions. Hepatotoxicity is well-studied side effect of these drugs but their effects on other organs like spleen and blood are still needed to be explored. OBJECTIVE: To explore the probable outcome of co-administration these three major antitubercular drugs (ATDs), rifampicin, isoniazid and pyrazinamide on spleen, blood and bone marrow. MATERIALS AND METHODS: Different parameters were evaluated like lipid peroxidation, glutathione (GSH) and protein content in spleen by spectrophotometric evaluation, hematological evaluation by determining total hemoglobin, total leukocyte count, differential leukocyte count and scanning electron microscopy studies in blood, genotoxicity studied by bone marrow chromosomal analysis and DNA fragmentation. The female rats n = 12 (150-200 g) were grouped as control group orally given saline and toxicant group given INH (30.85 mg/kg b.wt.) + RIF (61.7 mg/kg b.wt.) + PZA (132.65 mg/kg b.wt.) dosage extrapolated from dose that is used in human for 28 d once daily. RESULTS: After 28 d-oral co-administration of anti-TB drugs (INH (30.85 mg/kg b.wt.) + RIF (61.7 mg/kg b.wt.) + PZA (132.65 mg/kg b.wt.)), it was revealed that there were an increase thiobarbituric acid reactive substances, decrease in GSH and protein contents in spleen. Marked changes in hematological parameters, DNA fragmentation and chromosomes were also observed. CONCLUSION: This can be concluded from this work that co-administration of first-line ATDs is toxic to spleen and blood also these drugs can cause damage at genetic level.

Role of early life exposure and environment on neurodegeneration: implications on brain disorders.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases. Although genetic analysis of these diseases has also been described, yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved. Recent studies have, therefore, focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life, explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases. This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration. The SNPs mediating gene environment interaction are also described. Further, preventive and therapeutic strategies are suggested for effective intervention.

The complexities of malaria disease manifestations with a focus on asymptomatic malaria.

Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted.