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Fertility and Sterility Jun 2021Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several... (Review)
Review
Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Hormonal approaches to male contraception have been stymied by adverse effects, formulations requiring injections or implants, a 5% to10% nonresponse rate, as well as poor understanding of user acceptability. In the last several years, research has focused on novel, orally bioavailable androgens such as dimethandrolone undecanoate and 11β-methyl-19-nor-testosterone. Additionally, combinations of a topical testosterone gel combined with a gel containing segesterone acetate, a potent progestin, have shown promise in clinical trials recently. Simultaneously, significant preclinical progress has been made in several approaches to nonhormonal male contraceptives, including compounds that inhibit sperm motility such as eppin, compounds that inhibit retinoic acid binding or biosynthesis, and reversible approaches to obstruction of the vas deferens. It is imperative for these areas of research to continue making strides so that there is a gamut of contraceptive options for couples to choose from. Some of these approaches will hopefully reach clinical utility soon, greatly improving contraceptive choice for couples.
Topics: Animals; Antispermatogenic Agents; Contraceptive Agents, Hormonal; Contraceptive Effectiveness; Female; Fertility; Humans; Male; Men's Health; Pregnancy; Pregnancy, Unplanned; Pregnancy, Unwanted; Spermatogenesis; Treatment Outcome
PubMed: 33931201
DOI: 10.1016/j.fertnstert.2021.03.047 -
Biomedicine & Pharmacotherapy =... Jun 2023Celastrol, triptolide and triptonide are the most significant active ingredients of Tripterygium wilfordii Hook F (TWHF). In 2007, the 'Cell' journal ranked celastrol,... (Review)
Review
A comprehensive review on celastrol, triptolide and triptonide: Insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes.
Celastrol, triptolide and triptonide are the most significant active ingredients of Tripterygium wilfordii Hook F (TWHF). In 2007, the 'Cell' journal ranked celastrol, triptolide, artemisinin, capsaicin and curcumin as the five natural drugs that can be developed into modern medicinal compounds. In this review, we collected relevant data from the Web of Science, PubMed and China Knowledge Resource Integrated databases. Some information was also acquired from government reports and conference papers. Celastrol, triptolide and triptonide have potent pharmacological activity and evident anti-cancer, anti-tumor, anti-obesity and anti-diabetes effects. Because these compounds have demonstrated unique therapeutic potential for acute and chronic inflammation, brain injury, vascular diseases, immune diseases, renal system diseases, bone diseases and cardiac diseases, they can be used as effective drugs in clinical practice in the future. However, celastrol, triptolide and triptonide have certain toxic effects on the liver, kidney, cholangiocyte heart, ear and reproductive system. These shortcomings limit their clinical application. Suitable combination therapy, new dosage forms and new routes of administration can effectively reduce toxicity and increase the effect. In recent years, the development of different targeted drug delivery formulations and administration routes of celastrol and triptolide to overcome their toxic effects and maximise their efficacy has become a major focus of research. However, in-depth investigation is required to elucidate the mechanisms of action of celastrol, triptolide and triptonide, and more clinical trials are required to assess the safety and clinical value of these compounds.
Topics: Humans; Triterpenes; Diterpenes; Phenanthrenes; Epoxy Compounds; Neoplasms
PubMed: 37062220
DOI: 10.1016/j.biopha.2023.114705 -
Best Practice & Research. Clinical... Aug 2014Clear evidence shows that many men and women would welcome new male methods of contraception, but none have become available. The hormonal approach is based on... (Review)
Review
Clear evidence shows that many men and women would welcome new male methods of contraception, but none have become available. The hormonal approach is based on suppression of gonadotropins and thus of testicular function and spermatogenesis, and has been investigated for several decades. This approach can achieve sufficient suppression of spermatogenesis for effective contraception in most men, but not all; the basis for these men responding insufficiently is unclear. Alternatively, the non-hormonal approach is based on identifying specific processes in sperm development, maturation and function. A range of targets has been identified in animal models, and targeted effectively. This approach, however, remains in the pre-clinical domain at present. There are, therefore, grounds for considering that safe, effective and reversible methods of contraception for men can be developed.
Topics: Adamantane; Administration, Cutaneous; Androgens; Animals; Antispermatogenic Agents; Azoospermia; Clinical Trials as Topic; Contraception; Contraceptive Agents, Male; Contraceptives, Oral, Synthetic; Desogestrel; Drug Implants; Estrenes; Evidence-Based Medicine; Gels; Humans; Injections, Intramuscular; Levonorgestrel; Male; Oligospermia; Progestins; Sperm Count; Testosterone; Vasectomy
PubMed: 24947599
DOI: 10.1016/j.bpobgyn.2014.05.008 -
Journal of the Chinese Medical... Jul 2015The aim of this review was to provide a comprehensive summary of medicinal plants used as antifertility agents in females throughout the world by various tribes and... (Review)
Review
The aim of this review was to provide a comprehensive summary of medicinal plants used as antifertility agents in females throughout the world by various tribes and ethnic groups. We undertook an extensive bibliographic review by analyzing classical text books and peer reviewed papers, and further consulting well accepted worldwide scientific databases. We performed CENTRAL, Embase, and PubMed searches using terms such as "antifertility", "anti-implantation", "antiovulation", and "antispermatogenic" activity of plants. Plants, including their parts and extracts, that have traditionally been used to facilitate antifertility have been considered as antifertility agents. In this paper, various medicinal plants have been reviewed for thorough studies such as Polygonum hydropiper Linn, Citrus limonum, Piper nigrum Linn, Juniperis communis, Achyanthes aspera, Azadirachta indica, Tinospora cordifolia, and Barleria prionitis. Many of these medicinal plants appear to act through an antizygotic mechanism. This review clearly demonstrates that it is time to expand upon experimental studies to source new potential chemical constituents from medicinal plants; plant extracts and their active constituents should be further investigated for their mechanisms. This review creates a solid foundation upon which to further study the efficacy of plants that are both currently used by women as traditional antifertility medicines, but also could be efficacious as an antifertility agent with additional research and study.
Topics: Abortifacient Agents; Animals; Embryo Implantation; Female; Fertility; Humans; Ovulation; Plant Extracts; Plants, Medicinal; Spermatogenesis
PubMed: 25921562
DOI: 10.1016/j.jcma.2015.03.008 -
Protein Science : a Publication of the... Jun 2018TFIIH is a 10-subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown... (Review)
Review
TFIIH is a 10-subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter-proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function.
Topics: Animals; Cell Cycle; DNA Repair; Diterpenes; Enzyme Inhibitors; Epoxy Compounds; Humans; Phenanthrenes; Promoter Regions, Genetic; RNA Polymerase II; Transcription Factor TFIIH; Transcription, Genetic
PubMed: 29664212
DOI: 10.1002/pro.3424 -
Antimicrobial Agents and Chemotherapy Sep 2011Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used...
Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use.
Topics: Antiprotozoal Agents; Female; HeLa Cells; Humans; In Vitro Techniques; Male; Metronidazole; Spermatocidal Agents; Spermatozoa; Structure-Activity Relationship; Trichomonas vaginalis
PubMed: 21709091
DOI: 10.1128/AAC.00199-11 -
Biochimica Et Biophysica Acta Dec 2016Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and... (Review)
Review
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (K 2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K and Hill coefficient values of 36-40μM and 1.65-1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC~7μM) than other substrates including glutamate (IC~20μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated l-lactic acid efflux, Complex II and glutamine/glutamate oxidation.
Topics: Animals; Antineoplastic Agents; Hexokinase; Humans; Hydrogen-Ion Concentration; Indazoles; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Pyruvic Acid
PubMed: 27497601
DOI: 10.1016/j.bbcan.2016.08.001 -
Asian Journal of Andrology Jul 2010For centuries, plants and plant-based products have been used as a valuable and safe natural source of medicines for treating various ailments. The therapeutic potential... (Review)
Review
For centuries, plants and plant-based products have been used as a valuable and safe natural source of medicines for treating various ailments. The therapeutic potential of most of these plants could be ascribed to their anticancer, antidiabetic, hepatoprotective, cardioprotective, antispasmodic, analgesic and various other pharmacological properties. However, several commonly used plants have been reported to adversely affect male reproductive functions in wildlife and humans. The effects observed with most of the plant and plant-based products have been attributed to the antispermatogenic and/or antisteroidogenic properties of one or more active ingredients. This review discusses the detrimental effects of some of the commonly used plants on various target cells in the testis. A deeper insight into the molecular mechanisms of action of these natural compounds could pave the way for developing therapeutic strategies against their toxicity.
Topics: Animals; Azadirachta; Contraceptive Agents; Gossypol; Humans; Leydig Cells; Male; Phytotherapy; Plant Extracts; Plant Preparations; Plants; Sertoli Cells; Sperm Motility; Spermatogenesis; Testis; Vinblastine; Vincristine
PubMed: 20562897
DOI: 10.1038/aja.2010.43 -
Contraception Mar 2013A non-hormonal male contraceptive is a contraceptive that does not involve the administration of hormones or hormone blockers. This review will focus on the use of... (Review)
Review
A non-hormonal male contraceptive is a contraceptive that does not involve the administration of hormones or hormone blockers. This review will focus on the use of lonidamine derivatives and inhibitors of retinoic acid biosynthesis and function as approaches to male non-hormonal contraception. Two current lonidamine derivatives, adjudin and H2-gamendazole, are in development as male contraceptives. These potent anti-spermatogenic compounds impair the integrity of the apical ectoplasmic specialization, resulting in premature spermiation and infertility. Another approach to male contraceptive development is the inhibition of retinoic acid in the testes, as retinoic acid signaling is necessary for spermatogenesis. The administration of the retinoic acid receptor antagonist BMS-189453 reversibly inhibits spermatogenesis in mice. Similarly, oral dosing of WIN 18,446, which inhibits testicular retinoic acid biosynthesis, effectively contracepts rabbits. Hopefully, one of these approaches to non-hormonal male contraception will prove to be safe and effective in future clinical trials.
Topics: Animals; Contraception; Contraceptive Agents, Male; Diamines; Humans; Hydrazines; Indazoles; Male; Retinoids; Tretinoin
PubMed: 22995542
DOI: 10.1016/j.contraception.2012.08.016 -
Theranostics 2021Triptolide, an abietane-type diterpenoid isolated from Hook. F., has significant pharmacological activity. Research results show that triptolide has obvious inhibitory... (Review)
Review
Triptolide, an abietane-type diterpenoid isolated from Hook. F., has significant pharmacological activity. Research results show that triptolide has obvious inhibitory effects on many solid tumors. Therefore, triptolide has become one of the lead compounds candidates for being the next "blockbuster" drug, and multiple triptolide derivatives have entered clinical research. An increasing number of researchers have developed triptolide synthesis methods to meet the clinical need. To provide new ideas for researchers in different disciplines and connect different disciplines with researchers aiming to solve scientific problems more efficiently, this article reviews the research progress made with analyzes of triptolide pharmacological activity, biosynthetic pathways, and chemical synthesis pathways and reported in toxicological and clinical studies of derivatives over the past 20 years, which have laid the foundation for subsequent researchers to study triptolide in many ways.
Topics: Antineoplastic Agents, Phytogenic; Diterpenes; Epoxy Compounds; Humans; Phenanthrenes; Tripterygium
PubMed: 34158845
DOI: 10.7150/thno.57745