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Singh D.,Central Drug Institute Council of Scientific and Industrial Research | Sanyal S.,Central Drug Research Institute Council of Scientific and Industrial Research | Chattopadhyay N.,Central Drug Institute Council of Scientific and Industrial Research
Cell Health and Cytoskeleton | Year: 2011

A high peak bone mass (PBM) at skeletal maturity is a good predictor for lower rate of fracture risks in later life. Growth during puberty contributes significantly to PBM achievement in women and men. The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis has a critical role in pubertal bone growth. There is an increase in GH and IGF-1 levels during puberty; thus, it is assumed that sex steroids contribute to higher GH/IGF-1 action during growth. Recent studies indicate that estrogen increases GH secretion in boys and girls, and the major effect of testosterone on GH secretion is via aromatization to estrogen. Estrogen is pivotal for epiphyseal fusion in young men and women. From studies of individuals with a mutated aromatase gene and a case study of male patient with defective estrogen receptor-alpha (ER-α), it is clear that estrogen is indispensable for normal pubertal growth and growth plate fusion. ER-αand estrogen receptor-beta (ER-β) have been localized in growth plate and bone. ER knockout studies have shown that ER-α -/-female mice have reduced linear appendicular growth, while ER-β -/-mice have increased appendicular growth. No such effect is seen in ER-β -/-males; however, repressed growth is seen in ER-α -/-males, resulting in shorter long bones. Thus, ER-βrepresses longitudinal bone growth in female mice, while it has no function in the regulation of longitudinal bone growth in male mice. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females © 2011 Singh et al, publisher and licensee Dove Medical Press Ltd.

Tewari R.,University of Lucknow | Rajender S.,Central Drug Research Institute Council of Scientific and Industrial Research | Natu S.M.,University of Lucknow | Dalela D.,University of Lucknow | And 3 more authors.
Journal of Andrology | Year: 2012

Prostate problems, such as benign prostatic hyperplasia, prostatic intra-epithelial neoplasia, prostatitis, and prostate cancer have been recognized as problems largely related to androgens and genetic factors. They affect a large fraction of the elderly population, contributing significantly to morbidity and mortality. Estrogen has also now been recognized as one of the important regulators of prostate growth. Diet, general health, and obesity were disregarded as the causative or complicating factors until very recently. Increasing episodes of prostate problems, complications in overweight/obese individuals, or both have attracted attention toward these contemporary risk factors. Prostate problems are reportedly less frequent or less severe in areas in which a plant-based diet is predominant. Consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. As adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems. Adipose tissue is now known to affect circulating levels of several bioactive messengers and therefore could affect the risk of developing prostate problems in addition to several other well-recognized health problems. Nevertheless, increased plasma volume, excess tissue growth, and fat deposition could affect resection and number of biopsies required, thus adding further complications because of a delayed diagnosis. In short, evidence is gathering to support the influence of diet and obesity on prostate health. In this review article, we have tried to make this connection more apparent using supporting published data. © American Society of Andrology.

Rajender S.,Central Drug Research Institute Council of Scientific and Industrial Research | Avery K.,Cleveland Clinic | Agarwal A.,Cleveland Clinic
Mutation Research - Reviews in Mutation Research | Year: 2011

Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in a number of biological processes, including spermatogenesis. Several genes in the testes are regulated through epigenetic mechanisms, indicating a direct influence of epigenetic mechanisms on the process of spermatogenesis. In the present article, we have provided a comprehensive review of the epigenetic processes in the testes, correlation of epigenetic aberrations with male infertility, impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations in assisted reproduction. The literature review suggested a significant impact of epigenetic aberrations (epimutations) on spermatogenesis, and this could lead to male infertility. Epimutations (often hypermethylation) in several genes, namely MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, and SNRPN, have been reported in association with poor semen parameters or male infertility. Environmental toxins/drugs may affect fertility via epigenetic modifications. For example, 5-aza-2'-deoxycytidine, an anticancer agent, causes a decrease in global DNA methylation that leads to altered sperm morphology, decreased sperm motility, decreased fertilization capacity, and decreased embryo survival. Similarly, Endocrine disruptors, such as methoxychlor (an estrogenic pesticide) and vinclozolin (an anti-androgenic fungicide) have been found by experiments on animals to affect epigenetic modifications that may cause spermatogenic defects in subsequent generations. Assisted reproduction procedures that have been considered rather safe, are now being implicated in inducing epigenetic changes that could affect fertility in subsequent generations. Techniques such as intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) may increase the incidence of imprinting disorders and adversely affect embryonic development by using immature spermatozoa that may not have established proper imprints or global methylation. Epigenetic changes, in contrast to genetic aberrations, may be less deleterious because they are potentially reversible. Further research could identify certain drugs capable of reversing epigenetic changes. © 2011 Elsevier B.V.

Tyagi A.M.,Central Drug Research Institute Council of Scientific and Industrial Research | Srivastava K.,Central Drug Research Institute Council of Scientific and Industrial Research | Kureel J.,Central Drug Research Institute Council of Scientific and Industrial Research | Kumar A.,Central Drug Research Institute Council of Scientific and Industrial Research | And 5 more authors.
Osteoporosis International | Year: 2012

Presently the relationship between CD28, biological marker of senescence, and ovariectomy is not well understood. We show that ovariectomy leads to CD28 loss on T cells and estrogen (E2) repletion and medicarpin (Med) inhibits this effect. We thus propose that Med/E2 prevents bone loss by delaying premature T cell senescence. Introduction: Estrogen deficiency triggers reproductive aging by accelerating the amplification of TNF-α-producing T cells, thereby leading to bone loss. To date, no study has been carried out to explain the relationship between CD4 +CD28null T cells and ovariectomy or osteoporosis. We aim to determine the effect of Ovx on CD28 expression on T cells and effects of E2 and medicarpin (a pterocarpan phytoalexin) with proven osteoprotective effect on altered T cell responses. Methods: Adult, female Balb/c mice were taken for the study. The groups were: sham, Ovx, Ovx + Med or E2. Treatments were given daily by oral gavage. At autopsy bone marrow and spleen were flushed out and cells labelled with antibodies for FACS analysis. Serum was collected for ELISA. Results: In Ovx mice, Med/E2 at their respective osteoprotective doses resulted in thymus involution and lowered Ovx-induced increase in serum TNF-α level and its mRNA levels in the BM T cells. Med/E2 reduced BM and spleen CD4 + T cell proliferation and prevented CD28 loss on CD4 + T cells. Further, Med abrogated TNF-α-induced loss of CD28 expression in the BM T cells. Conclusions: To our knowledge this is the first report to determine the mechanism of CD28 loss on T cells as a result of ovariectomy. Our study demonstrates that Ovx leads to the generation of premature senescent CD4 +CD28null T cells, an effect inhibited by E2 and Med. We propose that one of the mechanisms by which Med/E2 alleviates Ovx-induced bone loss is by delaying T cell senescence and enhancing CD28 expression. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.

Kumar S.,Central Drug Research Institute Council of Scientific and Industrial Research | Barthwal M.K.,Central Drug Research Institute Council of Scientific and Industrial Research | Dikshit M.,Central Drug Research Institute Council of Scientific and Industrial Research
Free Radical Biology and Medicine | Year: 2010

Nitric oxide (NO), a multifaceted signaling molecule, regulates a wide array of cell functions, including proliferation, differentiation, cytostasis, and apoptosis, which depend on the cell type and redox status. This study systematically explores the effects of NO donors on promyelocytic HL-60 cell proliferation and apoptosis. The NO donor DETA-NO modulated the HL-60 cell cycle in a biphasic manner. DETA-NO in lower concentrations (1-100 μM) had a proliferative effect as investigated by [3H]thymidine incorporation, BrdU labeling, and cell cycle analysis, whereas cells treated with higher concentrations (250 μM-1 mM) showed cytostasis, apoptosis, mitochondrial membrane potential loss, caspase-3 activity, and dUTP nick-end labeling. The proliferative effect of DETA-NO was NO dependent and redox sensitive, as the effect was abolished by cPTIO and DTT pretreatment, respectively. Expression of various cell cycle regulators such as Cdk2, cyclin B, and cyclin E was significantly augmented in cells treated with 10-50 μM DETA-NO. The proliferative effect of NO was blocked by roscovitine, a Cdk2 inhibitor. S-nitrosylation of Cdk2 and an increase in the Cdk2-associated kinase activity was observed for the first time in DETA-NO-treated cells. This study demonstrates that the DETA-NO-mediated biphasic effect was dependent on Cdk2 nitrosylation/activation and the loss of mitochondrial potential at low and high concentrations, respectively. © 2010 Elsevier Inc. All rights reserved.

Shukla K.K.,Central Drug Research Institute Council of Scientific and Industrial Research | Shukla K.K.,University of Lucknow | Mahdi A.A.,University of Lucknow | Singh R.,Central Drug Research Institute Council of Scientific and Industrial Research
Frontiers in Bioscience - Elite | Year: 2012

Apoptosis is an essential physiological process demonstrated to play important roles in diverse physiological processes. As true for several other organs, apoptosis occurs at a high rate in the primary male reproductive organ, testis. Apoptosis is also exhibited by spermatozoa in the human ejaculate. Caspase activation, externalization of phosphatidylserine, alteration of mitochondrial membrane potential and DNA fragmentation are markers of apoptosis found in ejaculated human spermatozoa. These markers appear in excess in sub-fertile men and functionally incompetent spermatozoa. The importance of apoptotic pathway in spermatogenesis and sperm maturation is also indicated by the expression of several markers of this pathway in the testis and epididymis, respectively. This process of regulated cell death serves several important functions in the testis, a few of which include maintaining appropriate germ cell to Sertoli cells ratio, removing defective germ cells and maintenance of overall quality control in sperm production. This review presents an update on the role of apoptosis in male reproduction and fertility, and implications of altered apoptosis in male infertility.

Dama M.S.,Central Drug Research Institute Council of Scientific and Industrial Research | Singh N.M.P.,Central Drug Research Institute Council of Scientific and Industrial Research | Rajender S.,Central Drug Research Institute Council of Scientific and Industrial Research
PLoS ONE | Year: 2011

Adaptive theory predicts that mothers would be advantaged by adjusting the sex ratio of their offspring in relation to their offspring's future reproductive success. In the present study, we tested the effect of housing mice under crowded condition on the sex ratio and whether the fat content of the diet has any influence on the outcome of pregnancies. Three-week-old mice were placed on the control diet (NFD) for 3 weeks. Thereafter the mice were allotted randomly to two groups of 7 cages each with 4, 6, 8, 10, 12, 14, and 16 mice in every cage to create increasing crowding gradient and fed either NFD or high fat diet (HFD). After 4 weeks, dams were bred and outcomes of pregnancy were analyzed. The average dam body weight (DBW) at conception, litter size (LS) and SR were significantly higher in HFD fed dams. Further, male biased litters declined with increasing crowding in NFD group but not in HFD. The LS and SR in NFD declined significantly with increasing crowding, whereas only LS was reduced in HFD group. We conclude that female mice housed under overcrowding conditions shift offspring SR in favor of daughters in consistent with the TW hypothesis and high fat diet reduces this influence of overcrowding. © 2011 Dama et al.

Gupta N.,Central Drug Research Institute Council of Scientific and Industrial Research | Gupta S.,Ajanta Hospitals and Center Pvt. Ltd. | Dama M.,Central Drug Research Institute Council of Scientific and Industrial Research | David A.,Ajanta Hospitals and Center Pvt. Ltd. | And 3 more authors.
PLoS ONE | Year: 2011

Background: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. Methodology/Principal Findings: We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility. Conclusions/Significance: 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor. © 2011 Gupta et al.

Tyagi A.M.,Central Drug Research Institute Council of Scientific and Industrial Research | Srivastava K.,Central Drug Research Institute Council of Scientific and Industrial Research | Sharan K.,Central Drug Research Institute Council of Scientific and Industrial Research | Yadav D.,Central Drug Research Institute Council of Scientific and Industrial Research | And 2 more authors.
PLoS ONE | Year: 2011

Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4+CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4+ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4+CD28null T cells, however, treatment with Daid increased the percentage of CD4+CD28+ T cells. Co-culture of CD4+CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4+CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220+ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency. © 2011 Tyagi et al.

Sankhwar M.,University of Lucknow | Sankhwar S.N.,University of Lucknow | Abhishek A.,University of Lucknow | Rajender S.,Central Drug Research Institute Council of Scientific and Industrial Research
Cancer Biomarkers | Year: 2015

OBJECTIVE: To investigate the correlation of Vascular Endothelial Growth Factor (VEGF) and micro-vessel density (MVD) with urinary bladder tumor and its stage. MATERIAL AND METHODS: The study was conducted between January 2010 and December 2012. The study included screening of 122 patients at elevated risk for bladder cancer, of which 35 patients were finally enrolled in the study. Diagnosis was made on the basis of urine cytology, radiological investigation (ultrasound KUB, and CT-scan) and histopathology. Thirty-five normal cancer-free individuals were enrolled as controls. Human VEGF levels were measured using an enzyme linked immunoassay and protein content (pg/mg protein) by Lowry method. SPSS for Windows version 10.0.7 (SPSS, Chicago, IL, USA) was used for statistical analysis of the data. RESULTS: Mean urine VEGF level in the cases was significantly higher in comparison to the control group. There was a direct correlation between VEGF level and tumor stage. Mean urine VEGF values were minimum in the control group (22.75 ± 15.41 pg/mg creatinine) and maximum in stage IV patients (180.15 ± 75.93 pg/mg creatinine). Tissue VEGF levels also showed a similar trend of increase with increase in stage. Urine VEGF level also showed a correlation with tissue VEGF level. Similarly, MVD showed a significant increase with increase in tumor stage. DISCUSSION: A correlation between bladder cancer and MVD and VEGF suggest that the latter can serve as markers for therapeutic guidance. This is the first study from India on clinical and pathological correlation among urine VEGF, tumor tissue VEGF levels, and Micro Vessel Density (MVD) in urinary bladder cancer patients. © 2015 - IOS Press and the authors. All rights reserved.

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