Figure 3 - uploaded by Tito Teles Jesus
Content may be subject to copyright.
Effects of alterations in mTOR signaling pathway on spermatogenesis. Pten inactivation with the germ line-specific Vasa-Cre (Tg(Ddx4-cre)1Dcas) results in severe defects in spermatogonial maintenance and differentiation, in part through Foxo1. It was identified a role for PLZF-mediated Redd1 expression in inhibiting mTORC1 activation in spermatogonial progenitor cells. Conditional knockout of Rheb resulted in severe oligoasthenoteratozoospermia, defects in meiotic and post-meiotic stages of spermatogenesis and decreased epididymal sperm numbers. mTOR inactivation by rapamycin downregulated phosphorylated p70S6K (p-p70S6K) and rpS6 (p-rpS6). Studies, in vitro and in vivo, reported that upon mTOR inactivation by rapamycin, the number of sperms significantly decreased and spermatogonia proliferation was blocked. SCF/c-kit system also uses the rapamycin sensitive PI3K/Akt/p70S6K/cyclin D3 pathway to promote spermatogonial proliferation. PLFZ: Promyelocytic Leukemia Zinc Finger; ckit: c-kit-encoded transmembrane tyrosine kinase receptor for stem cell factor; PI3K: phosphoinositide 3-kinase; Pten: Phosphatase and tensin homolog; Foxo1: forkhead box O1; Rheb: Ras homolog enriched in brain GTPase; S6K1 or p70S6K: S6 kinase 1; rpS6: ribosomal protein S6; SCF: stem cell factor. (see color version of this figure at www.informahealthcare.com/bmg).
Source publication
Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolic phenotype and is involved in virtually all aspects of cellular function. It integrates not only nutrient and energy-sensing pathways but also actin cytoskeleton organization, in response to environmental cues including growth factors and cellular energy levels. These...
Similar publications
Background
Male infertility constitutes about 50% of overall causes of infertility and apoptosis is known to have an essential role in the control of germ cell number in testis. Cigarette smoking is common in males at reproductive age. Studying the influence of smoking on apoptosis in male genital tract and its influence on fertility helps in the m...
Citations
... Recently, we reported the ability of MLT to counteract the Cd effects on some structural proteins (OCL, CX43, and VANGL2) and regulatory kinases (Src and FAK) involved in the BTB physiology Venditti et al., 2021a). Here, considering that mTOR complexes regulate the dynamics of the BTB during the epithelial cycle (Jesus et al., 2017;Li et al., 2018;Mok et al., 2013), and that its inhibition resulted in the destabilization and disruption of IF staining of OCL and CX43, represented in Figures 3b and 4b, respectively, showed that the OCL signal is specifically localized in the cytoplasm of SC (arrowheads, Figure 3b), whereas that of CX43 was prominent in the SC (arrowheads, Figure 4b) and interstitial LC (asterisks, Figure 4b). Analysis of IF intensity showed a similar, statistically significant trend to that observed for protein level in the WB (Figures 3c and 4c). ...
The protective action of melatonin (MLT) against the harmful effects of cadmium (Cd) on testicular activity in rats has been documented previously; however, the involved molecular mechanisms have yet to be elucidated. Herein, we investigate the involvement of the mammalian target of rapamycin (mTOR) on the ability of MLT to counteract the damage induced by Cd on the rat testicular activity. Our study confirmed that Cd has harmful effects on the testes of rats and the protective action exerted by MLT. We reported, for the first time, that the addition of rapamycin (Rapa), a specific mTOR inhibitor, to animals co-treated with Cd and MLT completely abolished the beneficial effects exerted by MLT, indicating that the mTOR pathway partially modulates its helpful effects on Cd testicular toxicity. Interestingly, Rapa-alone treatment, provoking mTOR inhibition, produced altered morphological parameters, increased autophagy of germ and somatic cells, and reduced serum testosterone concentration. In addition, mTOR inhibition also reduced protein levels of markers of steroidogenesis (3β-Hydroxysteroid dehydrogenase) and blood-testis barrier integrity (occludin and connexin 43). Finally, Rapa altered sperm parameters as well as the ability of mature spermatozoa to perform a proper acrosome reaction. Although further investigation is needed to better clarify the molecular pathway involved in MLT action, we confirm that MLT alleviating Cd effects can be used as a supplement to enhance testicular function and improve male gamete quality.
... mTOR serves as a central key regulator of cell growth, proliferation, and nutritional status, influencing growth factor signaling pathways in mammalian cells. In testes and testicular cells, numerous histological and molecular events are mediated by mTOR [99]. ...
Introduction: Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor–recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. Area covered: Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.
... The analysis of the actions of rapamycin and chatenaytrienins-1, -2, -3 and -4 (1-4) (Figure 8) revealed that the action of chatenaytrienins was very similar to that of rapamycin, an mTOR kinase inhibitor and autophagy activator [74][75][76]. Each of the six histograms represents an intact control and cells treated with the test compounds. ...
The present paper details the complete stereoselective synthesis of four natural acetogenins, chatenaytrienins-1,-2,-3 and-4, previously isolated from the roots of fruit trees of the family Annonaceae (A. nutans and A. muricata), as an inseparable mixture. The novel organometallic reactions, developed by the authors, of Ti-catalyzed cross-cyclomagnesiation of O-containing and aliphatic allenes using available Grignard reagents were applied at the key stage of synthesis. We have studied the biological activity of the synthesized individual chatenaytrienins-1,-2,-3 and-4 in vitro, including their cytotoxicity in a panel of tumor lines and their ability to induce apoptosis, affect the cell cycle and mitochondria, and activate the main apoptotic signaling pathways in the cell, applying modern approaches of flow cytometry and multiplex analysis with Luminex xMAP technology. It has been shown that chatenaytrienins affect mitochondria by uncoupling the processes of mitochondrial respiration, causing the accumulation of ROS ions, followed by the initiation of apoptosis. The most likely mechanism for the death of cortical neurons from the consumption of tea from the seeds of Annona fruit is long-term chronic hypoxia, which leads to the development of an atypical form of Parkinson's disease that is characteristic of the indigenous inhabitants of Guam and New Caledonia.
... However, others found that CR decreased testosterone levels [17] and induced sperm defects in rats [16]. In addition, rapamycin -CR mimetic -can increase longevity of mice [18], but has negative effects on sperm production, testosterone levels and fertility [19]. Therefore, it is important to understand the effects of senolytics drugs on the male reproductive system to consider its clinical use in humans. ...
Cellular senescence is a defense mechanism to arrest proliferation of damaged cells. The number of senescent cells increases with age in different tissues and contributes to the development of age-related diseases. Old mice treated with senolytics drugs, dasatinib and quercetin (D+Q), have reduced senescent cells burden. The aim of this study was to evaluate the effects of D+Q on testicular function and fertility of male mice. Mice (n = 9/group) received D (5 mg kg-1) and Q (50 mg kg-1) via gavage every moth for three consecutive days from 3 to 8 months of age. At 8 months mice were breed with young non-treated females and euthanized. The treatment of male mice with D+Q increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology. Sperm motility, seminiferous tubule morphometry, testicular gene expression and fertility were not affected by treatment. There was no effect of D+Q treatment in β-galactosidase activity and in lipofuscin staining in testes. D+Q treatment also did not affect body mass gain and testes mass. In conclusion, D+Q treatment increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology, however did not affect fertility. Further studies with older mice and different senolytics are necessary to elucidate the effects in the decline of sperm output (quality and quantity) associated with aging.
... The inactivation of the PI3K/Akt pathway by LY294002 leads to an increase in oxidative stress, whereas the treatment with another inhibitor, wortmannin, inhibited capacitation and motility of hamster sperm [67,69,70]. mTOR is a crucial regulator of cellular homeostasis and metabolism, controlling several processes such as biosynthesis of proteins, lipids, amino acid synthesis, glucose metabolism, cytoskeleton organization and many other functions [71]. Metabolism is pivotal to sperm, and it determines the fertility of males, therefore, PUFA metabolism is vital for maintenance of sperm quality during cryopreservation. ...
In ram sperm, metabolites are important components of the plasma membrane, energy metabolism cycle, and precursors for other membrane lipids, and they may have important roles in maintaining plasma membrane integrity, energy metabolism, and regulation of cryotolerance. In this study, the ejaculates from 6 Dorper rams were pooled and sperm were systematically investigated by metabolomics at various steps of cryopreservation (37 °C, fresh [F]; from 37 to 4 °C, cooling [C]; and from 4 to -196 to 37 °C, frozen-thawed [FT]) to identify differential metabolites (DM). There were 310 metabolites identified, of which 86 were considered DMs. Regarding the DMs, there were 23 (0 up and 23 down), 25 (12 up and 13 down), and 38 (7 up and 31 down) identified during cooling (C vs F), freezing (FT vs C), and cryopreservation (FT vs F), respectively. Furthermore, some key polyunsaturated fatty acids (FAs), particularly, linoleic acid (LA), docosahexaenoic acid (DHA), and arachidonic acid (AA) were down-regulated during cooling and cryopreservation. Significant DMs were enriched in several metabolic pathways including biosynthesis of unsaturated FAs, LA metabolism, mammalian target of rapamycin (mTOR), forkhead box transcription factors (FoxO), adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathways, regulation of lipolysis in adipocytes, and FA biosynthesis. This was apparently the first report to compare metabolomics profiles of ram sperm during cryopreservation and provided new knowledge to improve this process.
... According to the literature, metabolic diseases are also negatively associated with infertility [47][48][49]. Since hypogonadism is closely related to endocrine disorders [50][51][52][53][54], it would be expected that both metabolic diseases (such as obesity and insulin resistance, responsible for triggering the onset of T2D, gestational diabetes, and pre-diabetes) and some non-pathological conditions related to them (such as overweight) would have a pathophysiological repercussion on hypogonadism. In fact, a bidirectional link between metabolic disorders and hypogonadism has been suggested since on one hand metabolic complications have the capacity to induce hypogonadism [20,55] and on the other hand, hypogonadism can worsen the state of certain metabolic diseases [56][57][58][59][60][61][62][63][64][65]. ...
Infertility is becoming a chronic and emerging problem in the world. There is a resistant stigma that this health condition is mostly due to the female, although the literature supports that the responsibility for the onset of infertility is equally shared between both sexes in more or less equal proportions. Nevertheless, male sex hormones, particularly testosterone (T), are key players in male-related infertility. Indeed, hypogonadism, which is also characterized by changes in T levels, is one of the most common causes of male infertility and its incidence has been interconnected to the increased prevalence of metabolic diseases. Recent data also highlight the role of aquaporin (AQP)-mediated water and solute diffusion and the metabolic homeostasis in testicular cells suggesting a strong correlation between AQPs function, metabolism of testicular cells, and infertility. Indeed, recent studies showed that both metabolic and sexual hormone concentrations can change the expression pattern and function of AQPs. Herein, we review up-to-date information on the involvement of AQP-mediated function and permeability in men with metabolic syndrome and testosterone deficit, highlighting the putative mechanisms that show an interaction between sex hormones, AQPs, and metabolic syndrome that may contribute to male infertility.
... In addition to growth signals, mechanistic target of rapamycin (mTOR) responds to a wide array of stresses, including energetic/metabolic stress, genotoxic stress, oxidative stress, osmotic stress, ER stress, proteotoxic stress, and psychological stress (Su & Dai 2017; see Heininger 2022, part 27). Compelling evidence suggests that mTOR signaling is a regulator of female and male fertility (Sobinoff et al. 2013;Jesus et al. 2017;Serra et al. 2017;Shah et al. 2018;Estienne et al. 2021). The 5′ AMP-activated protein kinase (AMPK) is a serine/threonine heterotrimeric kinase composed of one catalytic α -subunit bound with β -and γ -regulatory subunits. ...
... Activated PI3K triggers the transition from phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) [55]. Accumulation of PIP3 leads to the phosphorylation of protein kinase B (Akt) and mammalian/mechanistic target of rapamycin (mTOR) [53,[56][57][58][59]. Activated mTOR phosphorylates 70-kDa ribosomal S6 kinase (p70S6K) to promote protein translation and gene expression [53,60,61]. ...
Follicle-stimulating hormone signaling is essential for the initiation and early stages of spermatogenesis. Follicle-stimulating hormone receptor is exclusively expressed in Sertoli cells. As the only type of somatic cell in the seminiferous tubule, Sertoli cells regulate spermatogenesis not only by controlling their own number and function but also through paracrine actions to nourish germ cells surrounded by Sertoli cells. After follicle-stimulating hormone binds to its receptor and activates the follicle-stimulating hormone signaling pathway, follicle-stimulating hormone signaling will establish a normal Sertoli cell number and promote their differentiation. Spermatogonia pool maintenance, spermatogonia differentiation and their entry into meiosis are also positively regulated by follicle-stimulating hormone signaling. In addition, follicle-stimulating hormone signaling regulates germ cell survival and limits their apoptosis. Our review summarizes the aforementioned functions of follicle-stimulating hormone signaling in Sertoli cells. We also describe the clinical potential of follicle-stimulating hormone treatment in male patients with infertility. Furthermore, our review may be helpful for developing better therapies for treating patients with dysfunctional follicle-stimulating hormone signaling in Sertoli cells.
... We hypothesize that AMPK signaling plays an important role in the interplay between spermatozoa functions and their microenvironment, which potentially have negative impacts on human sperm motility [13]. mTOR, which is one of the major downstream effector of AMPK, integrates both intracellular and extracellular signals and mediates energy supply, lipid metabolism, and protein synthesis [61][62][63]. mTOR is present in two complexes, mTORC1 and mTORC2 [18,62]. Rictor is a key regulatory/structural subunit of mTORC2 [63]. ...
... Rictor is a key regulatory/structural subunit of mTORC2 [63]. Recent studies indicate that Rictor (mTORC2) signaling regulates a variety of cellular processes, such as cell metabolism and survival, under conditions of oxidative stress [18,61,63,64]. Herein, we reported that seminal Rictor expression was higher, but the ratio of phospho-Rictor/Rictor was lower in AST than in NOR. ...
Asthenozoospermia is a common form of abnormal sperm quality in idiopathic male infertility. While most sperm-mediated causes have been investigated in detail, the significance of seminal plasma has been neglected. Herein, we aimed to investigate the possible pathogenic factors leading to decreased sperm motility based on seminal plasma. Semen was collected from normo- (NOR, n=70), idiopathic oligo- (OLI, n=57), and idiopathic asthenozoospermic (AST, n=53) patients. Using attenuated total reflection-Fourier transform infrared coupled with chemometrics, distinct differences in the biochemical compositions of nucleic acids, protein structure (amides I, II, and III), lipids, and carbohydrates in seminal plasma of AST were observed when compared to NOR and OLI. Compared with NOR and OLI, the levels of peptide aggregation, protein phosphorylation, unsaturated fatty acid, and lipid to protein ratio were significantly increased in AST; however, the level of lipid saturation was significantly decreased in seminal plasma of AST. Compared with NOR, the levels of ROS, MDA, 8-iso-prostaglandin F2α (8-isoPGF2α), and the ratio of phospho-AMPKα/AMPKα1 were significantly increased in AST; however, the levels of SOD, glutathione S-transferase (GSTs), protein carbonyl derivative (PC), and the ratio of phospho-Rictor/Rictor were significantly decreased in seminal plasma of AST. Changes of the AMPK/mTORC2 signaling in the seminal microenvironment possibly induce abnormal glucose and lipid metabolism, which impairs energy production. Oxidative stress potentially damages seminal plasma lipids and proteins, which in turn leads to impaired sperm structure and function. These findings provide evidence that the changes in seminal plasma compositions, oxidative stress, and activation of the AMPK/mTORC2 signaling contribute to the development of asthenozoospermia.
... Autophagy is down-regulated by mTOR and up-regulated by an mTOR inhibitor, rapamycin. 30 Thus, we investigated whether TSLP improves the rapamycin-induced autophagy. First, the concentration of rapamycin was determined to be 2 nM, which does not exhibit cytotoxicity to EL4 cells, by an MTT assay with reference to a report 31 (10 nM, 20 nM, p < .001; Figure 2C). ...
Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL‐2 cytokine family, promotes Th2‐mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)‐injected mice. TSLP increased expression levels of autophagy‐related factors, such as Beclin‐1, LC3‐II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin‐1, LC3‐II, and p62 in TSLP‐stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS‐induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin‐1 and LC3‐II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin‐1, LC3‐II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP‐induced autophagy may be a potential therapeutic strategy for inflammatory responses.
