Manjit K Sharma alias Gill alias Gill-Sharma | NIRRH (original) (raw)

Papers by Manjit K Sharma alias Gill alias Gill-Sharma

Mechanism(s) involved in regulating Intratesticular Testosterone levels (iT) have assumed importa... more Mechanism(s) involved in regulating Intratesticular Testosterone levels (iT) have assumed importance in recent years, from the point of view of hormonal contraception. Contraceptives using Testosterone (T) in combination with Progestins (P), for more effective suppression of pituitary gonadotropins thereby iT, are not 100% effective in suppressing spermatogenesis in human males, likely due to pesrsistence of Intratesticular Dihydrotestosterone (iD) in poor-responders. Several lacunae pertaining to the mechanism of action of principal male hormone T during spermatogenesis remain to be resolved. Notably, the mechanism through which T brings about the stage-specific differentiation of germ cells lacking Androgen Receptors (AR). Testosterone is a highly anabolic steroid with a rapid tissue clearance rate. T is intratesticular substrate for synthesis of Dihydrotestosterone (DHT) and Estradiol (E2) involved in spermtaogenesis. Therefore, it is important to delineate the mechanism(s) for retention of iT, in order to understand regulation of its bioavailability in testis. In depth studies, pertaining to the role of androgen-binding protein(s) in sequestration, retention and bioavailability of T/DHT are required to understand male fertility regulation. The appropriate approach to overcome this lacuna would be development of mice lacking functional testicular Androgen-Binding Protein (ABPKO), but not deficient T/DHT, Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), in order to understand its physiological functions. Insights gained about androgen retention mechanism(s) from the ABPKO murine model will be of immense help in improving the efficacy of male hormonal contraceptives and infertility management.

Pleitropism underlies the biological adverse effects induced by medicines. Drugs and vaccines are... more Pleitropism underlies the biological adverse effects induced by medicines. Drugs and vaccines are two different types of medicinal compounds which hit biological targets to produce desired beneficial effects. However, the targets may be expressed at multiple sites and therefore partly underlie some adverse effect. Vaccines, primarily designed to target immune system B lymphocytes, are a combination of several immunogens as well as non-immunogenic booster molecules, each of which harbours the potential to produce distinct biological effects by gaining access to different and multiple targets in vivo, therefore compounding the adverse effects. several molecular components. Therefore the risk of adverse biological effects is enhanced several fold [11,12]. Dosage is the second issue common to both types of meds, another potential cause of adverse effects. Dosage is an issue because all recipients receive the same dose of a these meds while some patients could be sensitive to higher doses. However, whereas adverse effects caution is mentioned on the brochures of drugs, this convention is not followed for vaccines. Third issue common to both types of meds is genetic sensitivity. Most doctors try to ascertain before prescribing a drug whether a patient suffers from sensitivity to any drugs. But this convention is again not observed during immunizations. Fourth issue pertains to duration of treatment/exposure to both types of medicines. Whereas drugs are prescribed for a limited period of infection, vaccines are delivered as preventive meds against infections acting in vivo over longer periods. Fifth issue pertains to timing of exposure. Age is relevant issue while prescribing meds. Whereas separate formulations of drugs are prescribed for adults or children most vaccines are delivered to babies during developmental years, age at which potential for adverse effects is enhanced [13]. Lastly, and most importantly, while the drugs have to undergo stringent toxicology testing before getting clearance for use in human beings, vaccines appear not to follow the clearance protocol applied to other drugs. Had the same stringent checking been applied to vaccines, VAERS would never have emerged as a serious issue with legal implications. In case of vaccines, which are a mixture of several chemical components, there is more to adverse effects/VAERS than pleiotropism. Vaccinations would be fraught with the risk of inflammations and a host immune response involving elaboration of a glut of inflammatory cytokines or hypercytokinemia [14-17].

EC ENDOCRINOLOGY AND METABOLIC RESEARCH , 2017

Spermatogenesis is the biological process that generates male gametes for the transfer of the pat... more Spermatogenesis is the biological process that generates male gametes for the transfer of the paternal chromosomes to the oo-cytes, at the time of fertilization. Neuroendocrine hormones work in tandem with testicular genes to bring about the maturation of the male gamete or spermatozoon. While some of the genes involved in the differentiation of spermatozoa are well known others are 'not so obvious'. The aim of this article is to conceptualize the molecular pathway(s) through which the 'not so obvious' Sertoli cell 'mediators' communicate with germ cells for their differentiation within the seminiferous tubules of the mammalian testes.

The Journal of steroid biochemistry and molecular biology, 2002

Adult male rats when treated with 0.4 mg tamoxifen (tam)/kg per day for 90 days show reduced circ... more Adult male rats when treated with 0.4 mg tamoxifen (tam)/kg per day for 90 days show reduced circulating testosterone (T) and LH. The present study was designed to have an in depth understanding of tam induced androgen reduction in adult male rats. Adult male rats were orally administered 0.4 mg tam/kg per day for 30, 60 or 90 days and the temporal effects on intratesticular concentrations of pregnenolone (P(5)), progesterone (P(4)), T, 5 alpha-dihydrotestosterone (5 alpha-DHT) and estradiol (E(2)) were estimated. Control group rats were fed saline. Serum hormonal profile of LH, FSH, T and E(2) was also followed on these days. Testicular levels of cytochrome P450 scc mRNA transcripts on 30, 60 and 90 days of treatment with the same dose were quantitated by biplex RT-PCR using beta Actin as internal control followed by analysis using GelPro Analysis software.A significant reduction in intratesticular P(5), P(4), T, 5 alpha-DHT and E(2) was observed from day 30 of treatment. The P450 ...

Fertility and Sterility, 2009

Objective: To determine the effect of tamoxifen treatment on global and insulin-like growth facto... more Objective: To determine the effect of tamoxifen treatment on global and insulin-like growth factor 2-H19 imprinting control region (Igf2-H19 ICR)-specific DNA methylation in rat spermatozoa and analyze its association with postimplantation loss. Design: Experimental prospective study. Setting: Animal research and academic research facility. Subject(s): Male and female 75-day-old Holtzman rats. Intervention(s): Global and Igf2-H19 ICR-specific DNA methylation was analyzed in an epididymal sperm sample in control and tamoxifen-treated rats at a dose of 0.4 mg tamoxifen/kg/day. DNA methylation status was correlated to postimplantation loss in females mated with tamoxifen-treated males. Main Outcome Measure(s): Global sperm DNA methylation level, methylation status of Igf2-H19 ICR in sperm, postimplantation loss. Result(s): Tamoxifen treatment significantly reduced methylation at Igf2-H19 ICR in epididymal sperm. However, the global methylation level was not altered. A mating experiment confirmed a significant increase in postimplantation loss upon tamoxifen treatment and showed significant correlation with methylation at Igf2-H19 ICR. Conclusion(s): Reduced DNA methylation at Igf2-H19 ICR in rat spermatozoa upon tamoxifen treatment indicated a role of estrogen-associated signaling in the acquisition of paternal-specific imprints during spermatogenesis. In addition, association between DNA methylation and postimplantation loss suggests that errors in paternal imprints at Igf2-H19 ICR could affect embryo development.

In adult male rats, tamoxifen (TAM) reduces circulating levels of luteinizing hormone (LH) and te... more In adult male rats, tamoxifen (TAM) reduces circulating
levels of luteinizing hormone (LH) and testosterone (T) with
no effect on follicle-stimulating hormone (FSH) and prolactin (PRL). It reduces the male rat’s ability to inseminate the female (potency), as well as its siring ability (fecundity). The objective of the present study was to test whether androgen supplementation could reverse all or some of the observed effects of TAM. To obviate the effects of estrogen, the study was designed to evaluate the beneficial or deleterious effect of 5-dihydrotestosterone (DHT), a 5-reduced, nonaromatizable metabolite of T, on the reproductive functions of TAM-treated adult male rats. Adult male rats received either saline
or TAM (0.2 or 0.4 mg per day PO) for 90 days. A group of TAM treated rats was implanted with 6 mg DHT from day 50 to day 90 A third group of untreated animals was implanted with 0-, 1-, 3-, or 6-mg DHT implants for 90 days. Mating studies were done to assess the fecundity, potency, and fertility index at the end of the treatment. Weights of testes, pituitary, and accessory sex organs were recorded, and circulating levels of LH, FSH, PRL, T, and 17--estradiol were estimated. DHT did not affect the fecundity or fertility index. TAM reduced fecundity, potency, and the fertility index. DHT implants improved the fertilizing ability of the TAM-treated male rat. This study discusses and reviews the role of T and 17--estradiol in sperm-fertilizing potential in light of these observations.

We have earlier reported that administration of cyproterone acetate, fluphenazine decanoate, tamo... more We have earlier reported that administration of cyproterone acetate, fluphenazine decanoate, tamoxifen citrate, oestradiol valerate to adult male rats, at doses of 50, 5.77, 0.71, 0.28 lmol kg)1 body weight given for periods of 15, 60, 60, 10 days, respectively, partially suppressed/reduced availability of one
or more reproductive hormones viz. LH, FSH, testosterone and reduced their
siring ability. The reduction in epididymal sperm counts was not considerable after treatment with these drugs, but conventional methods of assessment of spermatozoa quality viz. sperm chromatin structure assay (SCSA), nuclear
chromatin decondensation (NCD) assay, monobromobimane (mBBr) uptake, had shown quantifiable changes in caput sperm chromatin compaction and reduced the testicular levels of protamine 1. The present follow-up study attempts to quantify changes in caudal sperm chromatin which has undergone
compaction in the epididymis, in the altered hormonal microenvironment of rats treated with cyproterone acetate, tamoxifen citrate, fluphenazine decanoate, oestradiol valerate, at doses of 50, 5.77, 0.71, 0.28 lmol kg)1 body weight respectively given for periods of 15, 60, 60, 10 days, with a view to correlating these changes to reduction in their fertilising potential. During the androgen dependent transit of spermatozoa from caput to cauda epididymis, thiol group
oxidation and tyrosine phosphorylation of protamine occurs in maturing sperms concomitant with development of fertilising ability. The results indicate that conventional methods viz. SCSA, NCD, mBBr uptake fail to detect changes induced by hormone deficits in sperm chromatin condensation, as a result of maturation during transit from caput to cauda epididymis. Absence of protamine1 in epididymal sperm was observed in either testosterone or FSH deficient rats that correlated with reduced fertilising potential. The study suggests that changes in LH/T or FSH affect a hitherto unknown common molecular
mechanism in the testis, underlying the protamination of rat spermatozoa. In conclusion, loss of P1 occurs in adult male rats deprived of T or FSH and is a reliable detectable change in epididymal sperm indicative of chromatin condensation
defects associated with endocrine imbalance and poor fertility status.

Background: The putative regulatory role of the male reproductive hormones in the molecular mecha... more Background: The putative regulatory role of the male reproductive hormones in the molecular mechanism
underlying chromatin condensation remains poorly understood. In the past decade, we developed two adult male
rat models wherein functional deficits of testosterone or FSH, produced after treatments with 20 mg/Kg/d of cyproterone acetate (CPA) per os, for a period of 15 days or 3 mg/Kg/d of fluphenazine decanoate (FD) subcutaneously, for a period of 60 days, respectively, affected the rate of sperm chromatin decondensation in vitro.
These rat models have been used in the current study in order to delineate the putative roles of testosterone and
FSH in the molecular mechanism underlying remodelling of sperm chromatin.
Results: We report that deficits of both testosterone and FSH affected the turnover of polyubiquitylated histones and led to their accumulation in the testis. Functional deficits of testosterone reduced expression of MIWI, the 5-methyl cap binding RNA-binding protein (PIWIlike murine homologue of the Drosophila protein PIWI/P-element induced wimpy testis) containing a PAZ/Piwi-Argonaut-Zwille domain and levels of histone deacetylase1 (HDAC1), ubiquitin ligating enzyme (URE-B1/E3), 20S proteasome α1 concomitant with reduced expression of ubiquitin activating enzyme (ube1), conjugating enzyme (ube2d2), chromodomain Y like protein (cdyl), bromodomain testis specific protein (brdt), hdac6 (histone deacetylase6), androgen-dependent homeobox placentae embryonic protein (pem/RhoX5), histones h2b and th3 (testis-specific h3). Functional deficits of FSH reduced the expression of cdyl and brdt genes in the testis, affected turnover of ubiquitylated histones, stalled the physiological DNA repair
mechanism and culminated in spermiation of DNA damaged sperm.
Conclusions: We aver that deficits of both testosterone and FSH differentially affected the process of sperm chromatin remodelling through subtle changes in the ‘chromatin condensation transcriptome and proteome’, thereby stalling the replacement of ‘dynamic’ histones with ‘inert’ protamines, and altering the epigenetic state of condensed sperm chromatin. The inappropriately condensed chromatin affected the sperm chromatin cytoarchitecture, evident from subtle ultrastructural changes in the nuclei of immature caput epididymal sperm of
CPA- or FD-treated rats, incubated in vitro with dithiothreitol.

Manjit Gill/MK Gill/MK Sharma/MK Gill-Sharma are one and the same person

MK GILL/MK Sharma/MK Gill-Sharma are one and the same person.

MK Gill and MK Gill-Sharma/MK Sharma are one and the same person.

M.K Gill is same person as Gill-Sharma ManJit. N Lehri is the same person as NH Balasinor.

M.K Gill and Manjit Gill-Sharma and Manjit K Sharma are one and the same person.

Spermiation is the final phase of spermatogenesis leading to release of mature spermatids into th... more Spermiation is the final phase of spermatogenesis leading to release of mature spermatids into the lumen of the seminiferous tubules. Morphologically, it involves a series of events, namely removal of excess spermatid cytoplasm, removal of ectoplasmic specialization, formation of tubulobulbar complex, and final disengagement of the spermatid from the Sertoli cell. Previous studies in our
laboratory have shown that administration of 17-beta estradiol at a dose of 100g/kg body weight for 10 d resulted in failure of spermiation. This was accompanied by a suppression of FSH and intratesticular
testosterone with a concomitant rise in intratesticular 17- beta estradiol. The present study was undertaken to determine the cause of failure and subsequently the molecular events in spermiation. Electron microscopic and confocal studies revealed an absence of tubulobulbar complex in step 19 spermatids after estradiol treatment, highlighting the significance of these structures in spermiation. It was further observed that treatment affected the Sertoli cell cytoskeleton and Arp2/3 complex that is critical for de novo polymerization of actin during tubulobulbar complex formation. In conclusion, the present study reports the role of 17-beta estradiol in inhibiting the formation of tubulobulbar complex, which could be one of the mechanism by which environmental estrogens influence male fertility.

The presence of estrogen receptor beta and aromatase in the germ cell has highlighted the physiol... more The presence of estrogen receptor beta and aromatase in the germ cell has highlighted the physiological role of the traditionally female hormone, estrogen, in spermatogenesis. Estrogen receptor alpha knockouts and aromatase knockouts have further accentuated the role of estrogen in germ cell maturation. To delineate the direct action of estrogen in the seminiferous epithelium, we studied the effects of high
intratesticular estradiol. The study was based on the fact that administration of exogenous estradiol suppresses the hypothalamus pituitary gonadal axis (HPG) with a dose-dependant concomitant increase in intratesticular estrogen levels. Three doses of 17- beta estradiol, namely 20, 100 and 200 g/kg/day were administered subcutaneously to different batches of adult male rats for 10 days. The effect of the three
doses on serum hormonal profile, intratesticular testosterone (T) and estradiol (E) levels were studied. Twenty micrograms per kilograms per day of 17-beta estradiol affected the hypothalamus–pituitary axis, reducing serum gonadotropins and intratesticular testosterone; however, 100g/kg/day of 17- estradiol decreased serum FSH and intratesticular testosterone, increased intratesticular estradiol, but had no effect on serum LH. Interestingly, 200 g/kg/day of 17- beta estradiol decreased serum and intratesticular T without any effect on serum gonadotropins. This could be attributed to the positive feedback effect of estrogens on gonadotropins. In the testis, morphologically two visible effects were seen, namely ‘spermiation failure’ in all three doses attributed to the suppression of T and FSH and a ‘maintenance effect’ in the 100 g/kg/day attributed to E and/or 10% of available intratesticular T. The direct effect of an increase in intratesticular estradiol levels was observed in terms of a decrease in apoptosis in germ cell. The study, therefore, suggests that 100 g/kg/day of 17- beta estradiol could be used to study the effects of high intratesticular estradiol with a concomitant decrease in intratesticular T and serum FSH levels on spermatogenesis.

EC ENDOCRINOLOGY AND METABOLIC RESEARCH , 2017

The Journal of steroid biochemistry and molecular biology, 2002

Fertility and Sterility, 2009

Manjit Gill/MK Gill/MK Sharma/MK Gill-Sharma are one and the same person

MK GILL/MK Sharma/MK Gill-Sharma are one and the same person.

MK Gill and MK Gill-Sharma/MK Sharma are one and the same person.

M.K Gill is same person as Gill-Sharma ManJit. N Lehri is the same person as NH Balasinor.

M.K Gill and Manjit Gill-Sharma and Manjit K Sharma are one and the same person.

International Journal of Diabetes & its Complications, 2017

Diabetes mellitus (DM) is a disease of the peripheral organs while Diabetes inspidus (DI) is a di... more Diabetes mellitus (DM) is a disease of the peripheral organs while Diabetes inspidus (DI) is a disease of the brain. Both forms of diabetes are characterized by excess levels of blood sugar or glucose. Whereas the former is due to insulin resistance or insufficiency the latter is due to insufficiency of hypophyseal anti-diuretic hormone (ADH). But the causes underlying the accumulation of glucose in circulation are different for DM and DI. Diabetes mellitus is of two types. While type1 diabetes (T1D) is due to autoimmune destruction of insulin-producing pancreatic islets of Langerhans (IL), type 2 diabetes (T2D) is a lifestyle disease due to exhaustion of IL to produce insulin in response to hyperglycemia. Whereas glucose fuel unavailability in the mitochondria leads to deficit of energy production in the form of ATP, its accumulation in blood leads to complications due to inflammatory damage to blood vessels. Recently, Alzheimer's disease (AD) has been hypothesized to be type3 Diabetes (T3D), presumably caused by insulin resistance in the brain, an organ absolutely dependent upon glucose as fuel for ATP biosynthesis. Whereas AD and DM are characterized by dementia and cognitive decline respectively, their known cellular biomarkers are different namely neuronal amyloid peptide (APβ), Tau, glial TDP-43 for AD and islet amyloid polypeptide (IAPP) for DM. DM also has a genetic component namely HLA-DQB1, CTLA-4, INS genes. Biomarkers of insulin receptor (IR) desensitization/functionality like neuron-specific GLUT-8 need to be demonstrated in mouse models of AD, DM and humans before irreversible senile dementia characteristic of AD can be equated with reversible cognitive decline of type 2 DM, for it may have additional yet unknown causes.