Rakshamani Tripathi

Bio: Rakshamani Tripathi is an academic researcher from University of Kentucky. The author has contributed to research in topics: ABL & MAPK/ERK pathway. The author has an hindex of 10, co-authored 13 publications receiving 686 citations. Previous affiliations of Rakshamani Tripathi include Veer Bahadur Singh Purvanchal University.

Male germ cell apoptosis: regulation and biology

Abstract: Cellular apoptosis appears to be a constant feature in the adult testis and during early development. This is essential because mammalian spermatogenesis is a complex process that requires precise homeostasis of different cell types. This review discusses the latest information available on male germ cell apoptosis induced by hormones, toxins and temperature in the context of the type of apoptotic pathway either the intrinsic or the extrinsic that may be used under a variety of stimuli. The review also discusses the importance of mechanisms pertaining to cellular apoptosis during testicular development, which is independent of exogenous stimuli. Since instances of germ cell carcinoma have increased over the past few decades, the current status of research on apoptotic pathways in teratocarcinoma cells is included. One other important aspect that is covered in this review is microRNA-mediated control of germ cell apoptosis, a field of research that is going to see intense activity in near future. Since knockout models of various kinds have been used to study many aspects of germ cell development, a comprehensive summary of literature on knockout mice used in reproduction studies is also provided.

Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

Abstract: Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7 respectively while combination treatment activated all four caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by shRNA during drug treatment decreased p21 levels but caused survivin increase thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells.

Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

Abstract: The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.

The Blood-Testis Barrier and Its Implications for Male Contraception

Abstract: The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium into the basal and the apical (adluminal) compartments. Meiosis I and II, spermiogenesis, and spermiation all take place in a specialized microenvironment behind the BTB in the apical compartment, but spermatogonial renewal and differentiation and cell cycle progression up to the preleptotene spermatocyte stage take place outside of the BTB in the basal compartment of the epithelium. However, the BTB is not a static ultrastructure. Instead, it undergoes extensive restructuring during the seminiferous epithelial cycle of spermatogenesis at stage VIII to allow the transit of preleptotene spermatocytes at the BTB. Yet the immunological barrier conferred by the BTB cannot be compromised, even transiently, during the epithelial cycle to avoid the production of antibodies against meiotic and postmeiotic germ cells. Studies have demonstrated that some unlikely partners, namely adhesion protein complexes (e.g., occludin-ZO-1, N-cadherin-β-catenin, claudin-5-ZO-1), steroids (e.g., testosterone, estradiol-17β), nonreceptor protein kinases (e.g., focal adhesion kinase, c-Src, c-Yes), polarity proteins (e.g., PAR6, Cdc42, 14-3-3), endocytic vesicle proteins (e.g., clathrin, caveolin, dynamin 2), and actin regulatory proteins (e.g., Eps8, Arp2/3 complex), are working together, apparently under the overall influence of cytokines (e.g., transforming growth factor-β3, tumor necrosis factor-α, interleukin-1α). In short, a “new” BTB is created behind spermatocytes in transit while the “old” BTB above transiting cells undergoes timely degeneration, so that the immunological barrier can be maintained while spermatocytes are traversing the BTB. We also discuss recent findings regarding the molecular mechanisms by which environmental toxicants (e.g., cadmium, bisphenol A) induce testicular injury via their initial actions at the BTB to elicit subsequent damage to germ-cell adhesion, thereby leading to germ-cell loss, reduced sperm count, and male infertility or subfertility. Moreover, we also critically evaluate findings in the field regarding studies on drug transporters in the testis and discuss how these influx and efflux pumps regulate the entry of potential nonhormonal male contraceptives to the apical compartment to exert their effects. Collectively, these findings illustrate multiple potential targets are present at the BTB for innovative contraceptive development and for better delivery of drugs to alleviate toxicant-induced reproductive dysfunction in men.

Oxidative stress and male infertility

Abstract: Male infertility accounts for up to half of the infertility cases and affects 13–15% couples worldwide. An optimal level of reactive oxygen species is crucial for maintaining spermatogenesis and sperm functions. However, excessive production of reactive oxygen species may cause oxidative stress. Oxidative stress has been identified as one of the major risk factors which affects the fertilizing potential of spermatozoa. Oxidative stress occurs due to excessive production of ROS and causes germ cell DNA damage, sperm fragility and defects in motility, culminating in infertility. Poor sperm quality and DNA damage may also result in pregnancy loss. This article highlights the significance of ROS in human male fertility and that of oxidative stress in infertility.