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Yan C Cheng - One of the best experts on this subject based on the ideXlab platform.

  • spermiation insights from studies on the adjudin model
    Advances in Experimental Medicine and Biology, 2021
    Co-Authors: Haiqi Chen, Dolores D. Mruk, Yu Jiang, Yan C Cheng
    Abstract:

    Spermatogenesis is comprised of a series of cellular events that lead to the generation of haploid sperm. These events include self-renewal of spermatogonial stem cells (SSC), proliferation of spermatogonia by mitosis, differentiation of spermatogonia and spermatocytes, generation of haploid spermatids via meiosis I/II, and spermiogenesis. Spermiogenesis consists of a series of morphological events in which spermatids are being transported across the apical compartment of the seminiferous epithelium while maturing into spermatozoa, which include condensation of the genetic materials, biogenesis of acrosome, packaging of the mitocondria into the mid-piece, and elongation of the sperm tail. However, the biology of spermiation remains poorly understood. In this review, we provide in-depth analysis based on the use of bioinformatics tools and an animal model that mimics spermiation through treatment of adult rats with adjudin, a non-hormonal Male Contraceptive known to induce extensive germ cell exfoliation across the seminiferous epithelium, but nost notably elongating/elongated spermatids. These analyses have shed insightful information regaridng the biology of spermiation.

  • mtorc1 rps6 and spermatogenic function in the testis insights from the adjudin model
    Reproductive Toxicology, 2019
    Co-Authors: Ming Yan, Yan C Cheng, Baiping Mao, Chris K C Wong, Qingquan Lian
    Abstract:

    mTORC1/rpS6 signaling complex promoted Sertoli blood-testis barrier (BTB) remodeling by perturbing Sertoli cell-cell adhesion site known as the basal ectoplasmic specialization (ES). mTORC1/rpS6 complex also promoted disruption of spermatid adhesion at the Sertoli-spermatid interface called the apical ES. Herein, we performed analyses using the adjudin (a non-hormonal Male Contraceptive drug under development) model, wherein adjudin was known to perturb apical and basal ES function when used at high dose. Through direct administration of adjudin to the testis, adjudin at doses that failed to perturb BTB integrity per se, overexpression of an rpS6 phosphomimetic (i.e., constitutively active) mutant (i.e., p-rpS6-MT) that modified BTB function considerably potentiated adjudin efficacy. This led to disorderly spatial expression of proteins necessary to maintain the proper cytoskeletal organization of F-actin and microtubules (MTs) across the seminiferous epithelium, leading to germ cell exfoliation and aspermatogenesis. These findings yielded important insights regarding the role of mTORC1/rpS6 signaling complex in regulating BTB homeostasis.

  • slc15a1 is involved in the transport of synthetic f5 peptide into the seminiferous epithelium in adult rat testes
    Scientific Reports, 2015
    Co-Authors: Yufei Zhang, Yan C Cheng, Will M Lee
    Abstract:

    Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising Male Contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective Male Contraceptive.

  • targeted and reversible disruption of the blood testis barrier by an fsh mutant occludin peptide conjugate
    The FASEB Journal, 2007
    Co-Authors: Chinghang Wong, Dolores D. Mruk, Will M Lee, Yan C Cheng
    Abstract:

    The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals. As such, it poses a challenge to deliver any drugs to the seminiferous epithelium of the testis, such as a nonhormonal Male Contraceptive. To circumvent this problem, a genetically engineered follicle-stimulating hormone (FSH) mutant protein was produced in Spodoptera furgiperda (Sf)-9 insect cells to serve as a testis-specific carrier. Subsequently, a 22-amino acid peptide corresponding to the second extracellular loop of occludin, which was known to disrupt BTB integrity in vivo, was inserted to the FSH mutant by polymerase chain reaction (PCR), as well as chemical cross-linking. This molecule was found to have negligible hormonal activity but was still capable of binding to FSH receptors, which are restricted to Sertoli cells in mammals. When this FSH mutant-occludin peptide conjugate was administered to adult rats at 40 μg/adult rat (∼300 gm b.w.) via intraperitoneally (i.p.) injection, it induced transient and rev...

  • af 2364 1 2 4 dichlorobenzyl 1h indazole 3 carbohydrazide is a potential Male Contraceptive a review of recent data
    Contraception, 2005
    Co-Authors: Yan C Cheng, Dolores D. Mruk, Bruno Silvestrini, Michele Bonanomi, Chinghang Wong, Michelle K Y Siu, Nikki P Y Lee, Wing-yee Lui
    Abstract:

    Earlier studies have shown that 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (AF-2364) is a potential Male Contraceptive when administered orally to adult Sprague-Dawley rats. This compound induces reversible germ cell loss from the seminiferous epithelium by disrupting cell adhesion function between Sertoli and germ cells, in particular, elongating/elongate/round spermatids and spermatocytes but not spermatogonia. Thus, this event is accompanied by a transient loss of fertility in treated rats. Once the drug is metabolically cleared, the remaining spermatogonia can begin repopulating the epithelium, and fertility bounces back. In this review, we summarize recent findings regarding the possible use of this drug for Male contraception and its mechanism of action in the rat testis. We also provide an update on the efficacy results of using different treatment regimens in adult rats where AF-2364 was administered by gavage vs. intraperitoneal and intramuscular administration. These results have clearly indicated that AF-2364 is indeed a reversible Male Contraceptive. Furthermore, the tissue distribution in multiple organs and biological fluids using [3H]-AF-2364 is also reviewed. These data have clearly illustrated the low bioavailability of AF-2364 in rats and that this compound is not specifically taken up by any organs including the testis or the epididymis. These summaries are helpful to investigators in the field who seek to understand the molecular mechanism of action of AF-2364 in the rat testis and to explore its possible use for Male contraception.

Gunda I. Georg - One of the best experts on this subject based on the ideXlab platform.

  • structural basis of aldh1a2 inhibition by irreversible and reversible small molecule inhibitors
    ACS Chemical Biology, 2018
    Co-Authors: Yan Chen, Gunda I. Georg, Alex S. Goldstein, John K Amory, J Y Zhu, Kwon Ho Hong, David C Mikles, Ernst Schonbrunn
    Abstract:

    Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for Male Contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in (R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal ...

  • The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex
    2016
    Co-Authors: Shameem Sultana Syeda, Erick J. Carlson, Melissa R. Miller, Rawle Francis, David E. Clapham, Polina V. Lishko, Jon E. Hawkinson, Derek Hook, Gunda I. Georg
    Abstract:

    The basal fungus Allomyces macrogynus (A. macrogynus) produces motile Male gametes displaying well-studied chemotaxis toward their feMale counterparts. This chemotaxis is driven by sirenin, a sexual pheromone released by the feMale gametes. The pheromone evokes a large calcium influx in the motile gametes, which could proceed through the cation channel of sperm (CatSper) complex. Herein, we report the total synthesis of sirenin in 10 steps and 8% overall yield and show that the synthetic pheromone activates the CatSper channel complex, indicated by a concentration-dependent increase in intracellular calcium in human sperm. Sirenin activation of the CatSper channel was confirmed using whole-cell patch clamp electrophysiology with human sperm. Based on this proficient synthetic route and confirmed activation of CatSper, analogues of sirenin can be designed as blockers of the CatSper channel that could provide Male Contraceptive agents

  • the orally active Male Contraceptive agent h2 gamendazole interacts with organic anion transporting polypeptides expressed in human hepatocytes 1064 18
    The FASEB Journal, 2014
    Co-Authors: Jessica Shoop, Joseph S Tash, Sudhakar Jakkaraj, Gunda I. Georg, Lesya M Holets, Colleen A Flynn, Michael Baltezor, Bruno Hagenbuch
    Abstract:

    The non-hormonal Male Contraceptive H2-gamendazole (H2-GMZ) is a lonidamine derivative that has been shown to accumulate in rat testes at levels about 10 times higher than in the liver and other or...

  • synthesis and evaluation of eight and four membered iminosugar analogues as inhibitors of testicular ceramide specific glucosyltransferase testicular β glucosidase 2 and other glycosidases
    Journal of Organic Chemistry, 2012
    Co-Authors: Jae Chul Lee, Joseph S Tash, J Y Zhu, Ernst Schonbrunn, Subhashree Francis, Dinah Dutta, Vijayalaxmi Gupta, Yan Yang, Gunda I. Georg
    Abstract:

    Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible Male Contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-...

  • a novel potent indazole carboxylic acid derivative blocks spermatogenesis and is Contraceptive in rats after a single oral dose
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Sheri Ann Hild, Ramappa Chakrasali, Sudhakar Jakkaraj, Barbara J. Attardi, Gunda I. Georg
    Abstract:

    : Women have historically been the focus for development of new Contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal Male Contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile Male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal Male Contraceptive agent can occur.

Raghuveer Kavarthapu - One of the best experts on this subject based on the ideXlab platform.

  • corrigendum gonadotropin regulated testicular rna helicase two decades of studies on its structure function and regulation from its discovery opens a window for development of a non hormonal oral Male Contraceptive
    Frontiers in Endocrinology, 2019
    Co-Authors: Maria L Dufau, Raghuveer Kavarthapu
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25) is member of the DEAD-box family of RNA helicases present in Leydig and germ cells. GRTH is the only family member regulated by hormones, luteinizing hormone, through androgen action. Male mice with knock-out of the GRTH gene are sterile, lack sperm with arrest at round spermatids. GRTH participates on the nuclear export and transport of specific mRNAs, the structural integrity of Chromatoid Bodies of round spermatids, where mRNAs are processed and stored, and in their transit to polyribosomes, where it may regulate translation of relevant genes. GRTH has a central role in the control of germ cell apoptosis and acts as negative regulator of miRNAs which regulate expression of genes involved in the progress of spermatogenesis. In Leydig cells, GRTH gene transcription is regulated by LH via autocrine actions of androgen/androgen receptor and has regulatory effects in steroidogenesis. In germ cells, androgen actions are indirect via receptors in Sertoli cells. Transgenic mice carrying GRTH 5' flanking region-GFP permitted to discern regions in the gene which directs its expression upstream, in germ cells, and downstream in Leydig cells, and the androgen-regulated transcription at interstitial (autocrine), and germ cell (paracrine) compartments. Further evidence for paracrine actions of androgen/androgen receptor is their transcriptional induction of Germ Cell Nuclear Factor as requisite up-regulator of GRTH gene transcription in round spermatids, linking androgen action to two relevant germ cell genes essential for the progress of spermatogenesis. A missense mutation of R to H at amino acid 242 of GRTH found in 5.8% of a patient population with azoospermia causes loss of the cytoplasmic phospho-GRTH species with preservation of the non-phospho form in transfected cells. Mice with knock-in of the human mutation, lack sperm due to arrest at round spermatids. This model permits to discern the function of phospho-GRTH. The GRTH phospho-site resides at a Threonine structurally adjacent to the mutant site found in patients. Molecular modeling of this site elucidated the amino acids that form the GRTH/PKA interphase and provide the basis for drug design for use as Male Contraceptive.

  • characterization of the phosphorylation site of grth ddx25 and protein kinase a binding interface provides structural basis for the design of a non hormonal Male Contraceptive
    Scientific Reports, 2019
    Co-Authors: Murugananthkumar Raju, Sergio A Hassan, Raghuveer Kavarthapu, Rajakumar Anbazhagan, Maria L Dufau
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25), expressed in the Male gonad, is essential for the completion of spermatogenesis. Our early studies revealed a missense mutation (R242H) of GRTH in 5.8% of Japanese patient population with azoospermia. Transfection of the mutant GRTH construct in COS-1 cells leads to loss of the 61 kDa cytoplasmic phospho-species. Mice with knock-in of the human GRTH mutation are sterile and lack sperm with normal androgen and mating behavior. These findings provide an avenue for the development of a non-hormonal Male Contraceptive. Using site directed mutagenesis and a site-specific phospho-antibody, we have identified T239, structurally adjacent to the patient’s mutant site as the GRTH phospho-site. Molecular modelling provided structural basis for the role of R242 and other critical solvent-exposed residues at the GRTH/PKA interface (E165/K240/D237), on the control of GRTH phosphorylation at T239. Single or double mutations of these residues caused marked reduction or abolition of the phospho-form. These effects can be ascribed to critical disruptions of intramolecular H-bonds at the GRTH/PKA interface, which leads to modest but consequential structural changes that can affect PKA catalytic efficiency. Inhibition of phosphorylation may be achieved by small, drug-like molecules that bind to GRTH and reconfigure the GRTH/PKA interface.

  • corrigendum gonadotropin regulated testicular rna helicase two decades of studies on its structure function and regulation from its discovery opens a window for development of a non hormonal oral Male Contraceptive
    Frontiers in Endocrinology, 2019
    Co-Authors: Maria L Dufau, Raghuveer Kavarthapu
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25) is member of the DEAD-box family of RNA helicases present in Leydig and germ cells. GRTH is the only family member regulated by hormones, luteinizing hormone, through androgen action. Male mice with knock-out of the GRTH gene are sterile, lack sperm with arrest at round spermatids. GRTH participates on the nuclear export and transport of specific mRNAs, the structural integrity of Chromatoid Bodies of round spermatids, where mRNAs are processed and stored, and in their transit to polyribosomes, where it may regulate translation of relevant genes. GRTH has a central role in the control of germ cell apoptosis and acts as negative regulator of miRNAs which regulate protein expression of genes involved in the progress of spermatogenesis. In Leydig cells, GRTH gene transcription is regulated by LH via autocrine actions of androgen/androgen- receptor and has regulatory effects in steroidogenesis. In germ cells, androgen actions are indirect via receptors in Sertoli cells. Transgenic mice carrying GRTH 5’ flanking region-GFP permitted to discern regions in the gene which directs its expression upstream, in germ cells and downstream in Leydig cells, and the androgen-regulated transcription at interstitial (autocrine) and germ cell (paracrine) compartments. Further evidence for paracrine actions of androgen/androgen receptor is their transcriptional induction of Germ Cell Nuclear Factor as requisite up-regulator of GRTH gene transcription in round spermatids, linking androgen action to two relevant germ cell genes essential for the progress of spermatogenesis. A missense mutation of R to H at amino acid 242 of GRTH found in 5.8% of a patient population with azoospermia causes loss of the cytoplasmic phospho-GRTH species with preservation of the non-phospho form in transfected cells. Mice with knock-in of the human mutation, lack sperm due to arrest at round spermatids. This model permits to discern the function of phospho-GRTH. The GRTH phospho-site resides at a Threonine structurally adjacent to the mutant site found in patients. Molecular modelling of this site elucidated the amino acids that form the GRTH/PKA interphase and provide the basis for drug design for use as Male Contraceptive.

Maria L Dufau - One of the best experts on this subject based on the ideXlab platform.

  • corrigendum gonadotropin regulated testicular rna helicase two decades of studies on its structure function and regulation from its discovery opens a window for development of a non hormonal oral Male Contraceptive
    Frontiers in Endocrinology, 2019
    Co-Authors: Maria L Dufau, Raghuveer Kavarthapu
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25) is member of the DEAD-box family of RNA helicases present in Leydig and germ cells. GRTH is the only family member regulated by hormones, luteinizing hormone, through androgen action. Male mice with knock-out of the GRTH gene are sterile, lack sperm with arrest at round spermatids. GRTH participates on the nuclear export and transport of specific mRNAs, the structural integrity of Chromatoid Bodies of round spermatids, where mRNAs are processed and stored, and in their transit to polyribosomes, where it may regulate translation of relevant genes. GRTH has a central role in the control of germ cell apoptosis and acts as negative regulator of miRNAs which regulate expression of genes involved in the progress of spermatogenesis. In Leydig cells, GRTH gene transcription is regulated by LH via autocrine actions of androgen/androgen receptor and has regulatory effects in steroidogenesis. In germ cells, androgen actions are indirect via receptors in Sertoli cells. Transgenic mice carrying GRTH 5' flanking region-GFP permitted to discern regions in the gene which directs its expression upstream, in germ cells, and downstream in Leydig cells, and the androgen-regulated transcription at interstitial (autocrine), and germ cell (paracrine) compartments. Further evidence for paracrine actions of androgen/androgen receptor is their transcriptional induction of Germ Cell Nuclear Factor as requisite up-regulator of GRTH gene transcription in round spermatids, linking androgen action to two relevant germ cell genes essential for the progress of spermatogenesis. A missense mutation of R to H at amino acid 242 of GRTH found in 5.8% of a patient population with azoospermia causes loss of the cytoplasmic phospho-GRTH species with preservation of the non-phospho form in transfected cells. Mice with knock-in of the human mutation, lack sperm due to arrest at round spermatids. This model permits to discern the function of phospho-GRTH. The GRTH phospho-site resides at a Threonine structurally adjacent to the mutant site found in patients. Molecular modeling of this site elucidated the amino acids that form the GRTH/PKA interphase and provide the basis for drug design for use as Male Contraceptive.

  • characterization of the phosphorylation site of grth ddx25 and protein kinase a binding interface provides structural basis for the design of a non hormonal Male Contraceptive
    Scientific Reports, 2019
    Co-Authors: Murugananthkumar Raju, Sergio A Hassan, Raghuveer Kavarthapu, Rajakumar Anbazhagan, Maria L Dufau
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25), expressed in the Male gonad, is essential for the completion of spermatogenesis. Our early studies revealed a missense mutation (R242H) of GRTH in 5.8% of Japanese patient population with azoospermia. Transfection of the mutant GRTH construct in COS-1 cells leads to loss of the 61 kDa cytoplasmic phospho-species. Mice with knock-in of the human GRTH mutation are sterile and lack sperm with normal androgen and mating behavior. These findings provide an avenue for the development of a non-hormonal Male Contraceptive. Using site directed mutagenesis and a site-specific phospho-antibody, we have identified T239, structurally adjacent to the patient’s mutant site as the GRTH phospho-site. Molecular modelling provided structural basis for the role of R242 and other critical solvent-exposed residues at the GRTH/PKA interface (E165/K240/D237), on the control of GRTH phosphorylation at T239. Single or double mutations of these residues caused marked reduction or abolition of the phospho-form. These effects can be ascribed to critical disruptions of intramolecular H-bonds at the GRTH/PKA interface, which leads to modest but consequential structural changes that can affect PKA catalytic efficiency. Inhibition of phosphorylation may be achieved by small, drug-like molecules that bind to GRTH and reconfigure the GRTH/PKA interface.

  • corrigendum gonadotropin regulated testicular rna helicase two decades of studies on its structure function and regulation from its discovery opens a window for development of a non hormonal oral Male Contraceptive
    Frontiers in Endocrinology, 2019
    Co-Authors: Maria L Dufau, Raghuveer Kavarthapu
    Abstract:

    Gonadotropin Regulated Testicular Helicase (GRTH/DDX25) is member of the DEAD-box family of RNA helicases present in Leydig and germ cells. GRTH is the only family member regulated by hormones, luteinizing hormone, through androgen action. Male mice with knock-out of the GRTH gene are sterile, lack sperm with arrest at round spermatids. GRTH participates on the nuclear export and transport of specific mRNAs, the structural integrity of Chromatoid Bodies of round spermatids, where mRNAs are processed and stored, and in their transit to polyribosomes, where it may regulate translation of relevant genes. GRTH has a central role in the control of germ cell apoptosis and acts as negative regulator of miRNAs which regulate protein expression of genes involved in the progress of spermatogenesis. In Leydig cells, GRTH gene transcription is regulated by LH via autocrine actions of androgen/androgen- receptor and has regulatory effects in steroidogenesis. In germ cells, androgen actions are indirect via receptors in Sertoli cells. Transgenic mice carrying GRTH 5’ flanking region-GFP permitted to discern regions in the gene which directs its expression upstream, in germ cells and downstream in Leydig cells, and the androgen-regulated transcription at interstitial (autocrine) and germ cell (paracrine) compartments. Further evidence for paracrine actions of androgen/androgen receptor is their transcriptional induction of Germ Cell Nuclear Factor as requisite up-regulator of GRTH gene transcription in round spermatids, linking androgen action to two relevant germ cell genes essential for the progress of spermatogenesis. A missense mutation of R to H at amino acid 242 of GRTH found in 5.8% of a patient population with azoospermia causes loss of the cytoplasmic phospho-GRTH species with preservation of the non-phospho form in transfected cells. Mice with knock-in of the human mutation, lack sperm due to arrest at round spermatids. This model permits to discern the function of phospho-GRTH. The GRTH phospho-site resides at a Threonine structurally adjacent to the mutant site found in patients. Molecular modelling of this site elucidated the amino acids that form the GRTH/PKA interphase and provide the basis for drug design for use as Male Contraceptive.

Smritinath Chakraborty - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive agent
    Contraception, 2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Abstract Background The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)-3-(3′-indolyl) quinoline in Male rats. Study Design Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive agent.

  • original research article synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive agent
    2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Background: The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)3-(3′-indolyl) quinoline in Male rats. Study Design: Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results: Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion: The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive agent.