Male factor infertility (MFI) is responsible for 50% of infertility cases and in 15% of the cases sperm is absent due to germ cell aplasia. Human induced pluripotent stem cell (hiPSC)-derived spermatogonial stem cells (hSSCs) could serve as an autologous germ cell source for MFI in patients with an insufficient sperm yield for assisted reproductive technology (ART). The endocannabinoid system (ECS) has been implicated to play a role in mouse embryonic stem cells (mESCs) and the human testicular environment. However, the contribution of the ECS in hiPSCs and hiPSC-derived hSSCs is currently unknown. Here, we aimed to assess whether hiPSCs and hiPSC-derived hSSCs are regulated by components of the ECS and whether manipulation of the ECS could increase the yield of hiPSC-derived SSCs and serve as an autologous cell-based source for treatment of MFI.

We reprogrammed human dermal fibroblasts (hDFs) to hiPSCs, induced differentiation of hSSC from hiPSCs and evaluated the presence of ECS ligands (AEA, 2-AG) by LC/MS, receptors (CB1R, CB2R, TRPV1, GPR55) by qPCR, flow cytometry and immunofluorescent labeling. We then examined the efficacy of endogenous and synthetic selective ligands (ACPA, CB65, CSP, ML184) on proliferation of hiPSCs using real-time cell analysis (RTCA) and assessed the effects of on CB2R agonism on hiPSC pluripotency and differentiation to hSSCs.

hiPSCs from hDFs expressed the pluripotency markers OCT4, SOX2, NANOG, SSEA4 and TRA-1-60; and could be differentiated into ID4+, PLZF + hSSCs. hiPSCs and hiPSC-derived hSSCs secreted AEA and 2-AG at 10- 10 - 10- 9 M levels. Broad expression of all ECS receptors was observed in both hiPSCs and hiPSC-derived hSSCs, with a higher CB2R expression in hSSCs in comparison to hiPSCs. CB2R agonist CB65 promoted proliferation and differentiation of hiPSCs to hiPSC-hSSCs in comparison to AEA, 2-AG, ACPA, CSP and ML184. The EC50 of CB65 was determined to be 2.092 × 10- 8 M for support of pluripotency and preservation of stemness on hiPSCs from 78 h. CB65 stimulation at EC50 also increased the yield of ID4 + hSSCs, PLZF + SSPCs and SCP3 + spermatocytes from day 10 to 12.

We demonstrated here for the first time that stimulation of CB2R results in an increased yield of hiPSCs and hiPSC-derived hSSCs. CB65 is a potent CB2R agonist that can be used to increase the yield of hiPSC-derived hSSCs offering an alternative source of autologous male germ cells for patients with MFI. Increasing the male germ/stem cell pool by CB65 supplementation could be part of the ART-associated protocols in MFI patients with complete germ cell aplasia.

The escalating use and legalization of cannabis (marijuana) in the United States reflect shifting societal attitudes and growing awareness of its potential therapeutic benefits. Historically viewed as a harmful psychoactive substance, contemporary research has shown the intricate pharmacology of cannabis, with its diverse array of cannabinoids and their interactions with the endocannabinoid system. Among these cannabinoids, Δ9-tetrahydrocannabinol is the primary psychoactive component, characterized by its activation of cannabinoid receptors. The discovery of endocannabinoids, including anandamide and 2-arachidonoylglycerol, illuminated the body's innate cannabinoid signaling pathways and their involvement in several physiological processes. Endocannabinoids exert both positive and negative effects on the male reproductive system. They facilitate erectile function by modulating neurotransmission and vasodilation, offering potential therapeutic avenues for conditions like erectile dysfunction and prostatitis. However, chronic exogenous cannabinoid use, mainly of tetrahydrocannabinol, poses risks to male reproductive health by disrupting spermatogenesis, causing hormonal imbalances, and potentially influencing cancer cell proliferation. Understanding endocannabinoid signaling in the male reproductive system is essential to fully comprehend both the therapeutic benefits and potential drawbacks of cannabis use. Further research is required on these mechanisms, to provide insights that can guide clinical practice and policy-making regarding cannabis use. In this narrative review, we highlight the need for additional research into how cannabinoids affect male reproductive health, particularly with prolonged use. Investigating cannabinoids' impacts on spermatogenesis, hormonal balance, and cancer cell proliferation can provide valuable insights for healthcare professionals.

Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated blood glucose levels. Type II diabetes accounts for approximately 90% of all cases. Several drugs are available for hyperglycemia treatment. However, the current therapies for managing high blood glucose do not prevent or reverse the disease progression, which may result in complications and adverse effects, including diabetic neuropathy, retinopathy, and nephropathy. Hence, developing safer and more effective methods for lowering blood glucose levels is imperative. Transient receptor potential vanilloid-1 (TRPV1) is a significant member of the transient receptor potential family. It is present in numerous body tissues and organs and performs vital physiological functions.

This review aimed to develop new targeted TRPV1 hypoglycemic drugs by systematically summarizing the mechanism of action of the TRPV1-based signaling pathway in preventing and treating diabetes and its complications.

Literature searches were performed in the PubMed, Web of Science, Google Scholar, Medline, and Scopus databases for 10 years from 2013 to 2023. The search terms included "diabetes," "TRPV1," "diabetic complications," and "capsaicin."

TRPV1 is an essential potential target for treating diabetes mellitus and its complications. It reduces hepatic glucose production and food intake and promotes thermogenesis, metabolism, and insulin secretion. Activation of TRPV1 ameliorates diabetic nephropathy, retinopathy, myocardial infarction, vascular endothelial dysfunction, gastroparesis, and bladder dysfunction. Suppression of TRPV1 improves diabetes-related osteoporosis. However, the therapeutic effects of activating or suppressing TRPV1 may vary when treating diabetic neuropathy and periodontitis.

This review demonstrates that TRPV1 is a potential therapeutic target for diabetes and its complications. Additionally, it provides a theoretical basis for developing new hypoglycemic drugs that target TRPV1.

The heat and capsaicin receptor TRPV1 channel is widely expressed in nerve terminals of dorsal root ganglia (DRGs) and trigeminal ganglia innervating the body and face, respectively, as well as in other tissues and organs including central nervous system. The TRPV1 channel is a versatile receptor that detects harmful heat, pain, and various internal and external ligands. Hence, it operates as a polymodal sensory channel. Many pathological conditions including neuroinflammation, cancer, psychiatric disorders, and pathological pain, are linked to the abnormal functioning of the TRPV1 in peripheral tissues. Intense biomedical research is underway to discover compounds that can modulate the channel and provide pain relief. The molecular mechanisms underlying temperature sensing remain largely unknown, although they are closely linked to pain transduction. Prolonged exposure to capsaicin generates analgesia, hence numerous capsaicin analogs have been developed to discover efficient analgesics for pain relief. The emergence of in silico tools offered significant techniques for molecular modeling and machine learning algorithms to indentify druggable sites in the channel and for repositioning of current drugs aimed at TRPV1. Here we recapitulate the physiological and pathophysiological functions of the TRPV1 channel, including structural models obtained through cryo-EM, pharmacological compounds tested on TRPV1, and the in silico tools for drug discovery and repositioning.

Background: At the end of the 1990s, transient receptor potential vanilloid 1 (TRPV1) was first identified and cloned, serving as a key pain and heat sensor in humans. A large body of evidence have revealed its polymodal structure, complex function and wide-spread distribution, the specific mechanism of the ion channel remains unclear. Our goal here is to perform a bibliometric analysis and visualization study to present hotspots and trends in TRPV1 channel. Materials and Methods: TRPV1-related publications from inception to 2022 were retrieved from the Web of Science database. Excel, VOSviewer, and CiteSpace software were utilized for co-authorship, co-citation and co-occurrence analysis. Results: There were 9,113 publications included in the study, the number of publications increased rapidly after 1989, from 7 in 1990 to 373 in 2007, during which the number of citations per publication (CPP) also reached a peak in 2000 (CPP = 106.52). A total of 1,486 journals published TRPV1 articles, mainly belong to Q1 or Q2 divisions; The United States published the most articles (TP = 3,080), followed by Japan (TP = 1,221), China (TP = 1,217), and England (TP = 734); In recent years, the TRPV1-related research direction has been broaden to multiple fields related to inflammation, oxidative stress, and apoptosis; Keyword clustering refined the topic distributions and could be generalized as neuralgia, endogenous cannabinoid system, TRPV1 mediated airway hyperresponsiveness, involvement of apoptosis, TRPV1 antagonists as therapy targets. Conclusion: By conducting an exhaustive bibliographic search, this review refined the topic distributions and generalized as neuralgia, endogenous cannabinoid system, TRPV1 mediated airway hyperresponsiveness, involvement of apoptosis, TRPV1 antagonists as therapy targets. It is currently being clarified how exactly TRPV1 works as an ion channel, and much more in-depth basic research is needed in the future.

Sperm are guided through the female reproductive tract. A temperature difference of about 2 °C exists between the storage site and fertilization site of the mammalian oviduct, leading to the hypothesis that sperm can sense and swim towards the oocyte along a rising temperature gradient, known as thermotaxis. Research over the past two decades has reported that sperm feature a sophisticated thermal detection system to detect and track ambient temperature gradients. More recently, thermotaxis is expected to be added to the microfluidic isolation method based on sperm tactic responses for sperm selection. In this paper, mammalian sperm thermotaxis is discussed, explaining the underlying behavioral mechanisms and molecular basis, according to the latest research. Finally, this paper explores the possible application of sperm thermotaxis in assisted reproductive technologies.