Studies on biochemical, oxidative and genotoxicity alterations following vas blockage with reversible inhibition of sperm under guidance and reversal in rats.

CONTEXT: Vas obstruction with reversible inhibition of sperm under guidance (RISUG) for contraception and its reversal, may cause oxidative stress or inimical effects on male reproductive functions. OBJECTIVE: To evaluate the biochemical and genotoxicity at the level of reactive oxygen species (ROS) following vas occlusion with RISUG and its reversal by Dimethyl sulphoxide (DMSO) and 5% NaHCO3 in Wistar albino rats. SETTINGS AND DESIGN: Animals were divided into seven groups (n = 10), namely sham-operated control, short-term vas occlusion with RISUG for 90 days, reversal with DMSO and 5% NaHCO3, long-term vas occlusion with RISUG for 360 days, reversal with DMSO and 5% NaHCO3. MATERIALS AND METHODS: Biochemical markers in reproductive tissues, hematology, serum biochemistry, serum electrolytes and ROS measuring indicators, e.g., lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase were examined. STATISTICAL ANALYSIS USED: One-way analysis of variance test was performed for analyses of data obtained in this study using the SPSS 10.0 software (SPSS Inc., Chicago, IL, USA). RESULTS: The tissue and clinical chemistry did not show appreciable alterations in RISUG injected and reversal Groups (II-VII) as compared to sham control. The genotoxicity and various ROS markers fluctuated within control limits following short- and long-term vas occlusion and reversal. CONCLUSIONS: The study suggested that the reversal procedures, following RISUG contraception, were not associated with any kind of toxicological manifestations.

RISUG® as a male contraceptive: journey from bench to bedside.

Even after decades of research men still lack reliable and reversible contraceptive methods comparable to female methods of contraception. Traditional methods of male contraception present a high failure rate and also involve high risk both when used for contraception and for protection against sexually transmitted diseases. Various chemical, hormonal, immunological, vas based and herbal methods of contraception have been examined by scientists world over during the past four decades. Among the possible lead approaches, exogenous hormonal contraception, either alone or in combination with progesterone or antiandrogen, is being viewed at low profile because of their insufficiency in inducing uniform suppression of spermatogenesis and steroid related long term complications. As an alternative to vasectomy, among various intravasal devices being examined, RISUG® (Reversible Inhibition of Sperm Under Guidance), a co-polymer of styrene and maleic anhydride offers long term contraception with safety, efficacy and it can be delivered by no-scalpel injection. Thus it is the only male contraceptive procedure currently under Phase- III Clinical Trial. The non-invasive reversal technique, successfully demonstrated in langur monkeys and functional reversal achieved with dimethyl sulphoxide (DMSO) and sodium bicarbonate (NaHCO3) in rats and rabbits with safety at F1 generation (first filial generation) have projected RISUG® as a better alternative to vasectomy. In this narrative review we revisit the long journey of RISUG® beginning with formulation on a bench towards reaching the market as a safe and effective contraceptive method, discussing various milestones and roadblocks of this expedition awaiting the mandatory regulatory clearance from the Government of India. Successful completion of ongoing phase III clinical trials with demonstration of reversal in human volunteers will give an indigenously developed male contraceptive to the world.

Malgré plusieurs décennies de recherche, il manque toujours pour les hommes des méthodes de contraception fiables et réversibles qui soient comparables aux méthodes de contraception féminine. Les méthodes de contraception masculine traditionnelles ont un taux d'échec élevé ; elles sont aussi à risque lors d'utilisations à la fois comme contraceptif et comme protection contre les infections sexuellement transmissibles. Au cours des 40 dernières années, le monde scientifique a évalué différentes méthodes de contraception masculine basées sur des approches chimiques, hormonales, immunologiques, déférentielles ou à base de plante.Parmi les pistes possibles d'approche, la contraception par apport d'hormone exogène, soit seule soit associée à un progestatif ou à un anti androgène, est actuellement perçue comme ayant un faible profil en raison de son incapacité à induire une suppression uniforme de la spermatogenèse et des complications à long termes des stéroïdes.Parmi les alternatives à la vasectomie, plusieurs dispositifs intra déférentiels ont été évalués dont le RISUG® (Reversible Inhibition of Sperm Under Guidance). Ce dernier est un copolymère de styrène et d'anhydride maléique qui offre une contraception de longue durée avec innocuité et efficacité, pouvant être mise en place par injection sans scalpel. C'est ainsi actuellement la seule procédure contraceptive masculine pour laquelle un essai clinique de Phase-III est en cours. La technique de réversibilité sans scalpel, démontrée avec succès chez le singe Langur, ainsi que la réversibilité fonctionnelle par le sulfoxyde de diméthyle (DMSO) et le bicarbonate de sodium (NaHCO3) confirmée chez le rat et le lapin, sans atteintes sur la génération F1 (première génération de petits), ont fait apparaître le RISUG® comme une meilleure alternative à la vasectomie.Dans cette revue narrative, nous réévaluons le long chemin du RISUG® depuis une formulation de paillasse de laboratoire jusqu'à sa mise sur le marché comme méthode de contraception sans risque et efficace, en discutant les différents jalons et obstacles rencontrés au cours de cette expédition dans l'attente de l'autorisation réglementaire obligatoire du Gouvernement Indien. Le succès des essais de Phase-III en cours par la preuve d'une réversibilité chez des hommes volontaires apportera au Monde une méthode de contraception développée localement.

Signaling beyond Punching Holes: Modulation of Cellular Responses by Vibrio cholerae Cytolysin.

Pore-forming toxins (PFTs) are a distinct class of membrane-damaging cytolytic proteins that contribute significantly towards the virulence processes employed by various pathogenic bacteria. Vibrio cholerae cytolysin (VCC) is a prominent member of the beta-barrel PFT (beta-PFT) family. It is secreted by most of the pathogenic strains of the intestinal pathogen V. cholerae. Owing to its potent membrane-damaging cell-killing activity, VCC is believed to play critical roles in V. cholerae pathogenesis, particularly in those strains that lack the cholera toxin. Large numbers of studies have explored the mechanistic basis of the cell-killing activity of VCC. Consistent with the beta-PFT mode of action, VCC has been shown to act on the target cells by forming transmembrane oligomeric beta-barrel pores, thereby leading to permeabilization of the target cell membranes. Apart from the pore-formation-induced direct cell-killing action, VCC exhibits the potential to initiate a plethora of signal transduction pathways that may lead to apoptosis, or may act to enhance the cell survival/activation responses, depending on the type of target cells. In this review, we will present a concise view of our current understanding regarding the multiple aspects of these cellular responses, and their underlying signaling mechanisms, evoked by VCC.

Transmembrane oligomeric form of Vibrio cholerae cytolysin triggers TLR2/TLR6-dependent proinflammatory responses in monocytes and macrophages.

Vibrio cholerae cytolysin (VCC) kills target eukaryotic cells by forming transmembrane oligomeric ß-barrel pores. Once irreversibly converted into the transmembrane oligomeric form, VCC acquires an unusual structural stability and loses its cytotoxic property. It is therefore possible that, on exertion of its cytotoxic activity, the oligomeric form of VCC retained in the disintegrated membrane fractions of the lysed cells would survive within the host cellular milieu for a long period, without causing any further cytotoxicity. Under such circumstances, VCC oligomers may potentially be recognized by the host immune cells. Based on such a hypothesis, in the present study we explored the interaction of the transmembrane oligomeric form of VCC with the monocytes and macrophages of the innate immune system. Our study shows that the VCC oligomers assembled in the liposome membranes elicit potent proinflammatory responses in monocytes and macrophages, via stimulation of the toll-like receptor (TLR)2/TLR6-dependent signalling cascades that involve myeloid differentiation factor 88 (MyD88)/interleukin-1-receptor-associated kinase (IRAK)1/tumour-necrosis-factor-receptor-associated factor (TRAF)6. VCC oligomer-mediated proinflammatory responses critically depend on the activation of the transcription factor nuclear factor-κB. Proinflammatory responses induced by the VCC oligomers also require activation of the mitogen-activated protein kinase (MAPK) family member c-Jun N-terminal kinase, which presumably acts via stimulation of the transcription factor activator protein-1. Notably, the role of the MAPK p38 could not be documented in the process.