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Aging Jan 2024(, a novel cancer/testis-associated gene, may facilitate the initiation and progression of human malignancies, warranting comprehensive investigations. Single-cell and...
MAEL in human cancers and implications in prognostication and predicting benefit from immunotherapy over VEGFR/mTOR inhibitors in clear cell renal cell carcinoma: a bioinformatic analysis.
(, a novel cancer/testis-associated gene, may facilitate the initiation and progression of human malignancies, warranting comprehensive investigations. Single-cell and tissue-bulk transcriptomic data demonstrated higher expression in testis (spermatogonia/spermatocyte), kidney (proximal tubular cell), and brain (neuron/astrocyte), and corresponding cancers, including testicular germ cell tumor, glioma, papillary renal cell carcinoma, and clear cell renal cell carcinoma (ccRCC). Of these cancers, only in ccRCC did expression exhibit associations with both recurrence-free survival and overall survival. High expression was associated with an anti-inflammatory tumor immune microenvironment and VEGFR/mTOR activation in ccRCC tissues and high sensitivities to VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Consistent with these, low rather than high expression indicated remarkable progression-free survival benefits from immune checkpoint inhibitor (ICI)-based immunotherapies over VEGFR/mTOR inhibitors in two large phase III trials (JAVELIN Renal 101 and CheckMate-025). is a biologically and clinically significant determinant with potential for prognostication after nephrectomy and patient selection for VEGFR/mTOR inhibitors and immunotherapy-based treatments.
Topics: Humans; Male; Carcinoma, Renal Cell; Immunotherapy; Kidney Neoplasms; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Prognosis; Tumor Microenvironment
PubMed: 38301040
DOI: 10.18632/aging.205470 -
Nature Communications Jan 2024Recent studies reveal that de novo gene origination from previously non-genic sequences is a common mechanism for gene innovation. These young genes provide an...
Recent studies reveal that de novo gene origination from previously non-genic sequences is a common mechanism for gene innovation. These young genes provide an opportunity to study the structural and functional origins of proteins. Here, we combine high-quality base-level whole-genome alignments and computational structural modeling to study the origination, evolution, and protein structures of lineage-specific de novo genes. We identify 555 de novo gene candidates in D. melanogaster that originated within the Drosophilinae lineage. Sequence composition, evolutionary rates, and expression patterns indicate possible gradual functional or adaptive shifts with their gene ages. Surprisingly, we find little overall protein structural changes in candidates from the Drosophilinae lineage. We identify several candidates with potentially well-folded protein structures. Ancestral sequence reconstruction analysis reveals that most potentially well-folded candidates are often born well-folded. Single-cell RNA-seq analysis in testis shows that although most de novo gene candidates are enriched in spermatocytes, several young candidates are biased towards the early spermatogenesis stage, indicating potentially important but less emphasized roles of early germline cells in the de novo gene origination in testis. This study provides a systematic overview of the origin, evolution, and protein structural changes of Drosophilinae-specific de novo genes.
Topics: Male; Animals; Drosophila; Drosophila melanogaster; Evolution, Molecular; Testis; Spermatogenesis
PubMed: 38280868
DOI: 10.1038/s41467-024-45028-1 -
Computational and Structural... Dec 2024Infertility is becoming increasingly common, affecting one in six people globally. Half of these cases can be attributed to male factors, many driven by abnormalities in...
Infertility is becoming increasingly common, affecting one in six people globally. Half of these cases can be attributed to male factors, many driven by abnormalities in the process of sperm development. Emerging evidence from genome-wide association studies, genetic screening of patient cohorts, and animal models highlights an important genetic contribution to spermatogenic defects, but comprehensive identification and characterization of the genes critical for male fertility remain lacking. High divergence of gene regulation in spermatogenic cells across species poses challenges for delineating the genetic pathways required for human spermatogenesis using common model organisms. In this study, we leveraged post-translational histone modification and gene transcription data for 15,491 genes in four mammalian species (human, rhesus macaque, mouse, and opossum), to identify human-specific patterns of gene regulation during spermatogenesis. We combined H3K27me3 ChIP-seq, H3K4me3 ChIP-seq, and RNA-seq data to define epigenetic states for each gene at two stages of spermatogenesis, pachytene spermatocytes and round spermatids, in each species. We identified 239 genes that are uniquely active, poised, or dynamically regulated in human spermatogenic cells distinct from the other three species. While some of these genes have been implicated in reproductive functions, many more have not yet been associated with human infertility and may be candidates for further molecular and epidemiologic studies. Our analysis offers an example of the opportunities provided by evolutionary and epigenomic data for broadly screening candidate genes implicated in reproduction, which might lead to discoveries of novel genetic targets for diagnosis and management of male infertility and male contraception.
PubMed: 38274996
DOI: 10.1016/j.csbj.2023.12.037 -
Bio-protocol Jan 2024All living organisms require the division of a cell into daughter cells for their growth and maintenance. During cell division, both genetic and cytoplasmic contents are...
All living organisms require the division of a cell into daughter cells for their growth and maintenance. During cell division, both genetic and cytoplasmic contents are equally distributed between the two daughter cells. At the end of cell division, cytoplasmic contents and the plasma membrane are physically separated between the two daughter cells via a process known as cytokinesis. Hundreds of proteins and lipids involved in the cytokinetic process have been identified; however, much less is known about the mechanisms by which these molecules regulate cytokinesis, being therefore an intense area of current research. Male meiotic cytokinesis in testes has been shown to be an excellent model to study cytokinesis in vivo. Currently, several excellent protocols are available to study cytokinesis in testes. However, improved methods are required to study cytokinesis under in vitro and ex vivo conditions. Here, we demonstrate a simple method to perform live imaging on individual spermatocyte cysts isolated from adult testes. We evaluate amenability of this in vitro method for treatment with pharmacological agents. We show that cytokinesis is strongly inhibited upon treatment with Dynasore, a dynamin inhibitor known to block clathrin-mediated endocytosis. In addition, we also demonstrate an ex vivo method to perform live imaging on whole mount adult testes on gas permeable membrane chambers. We believe the protocols described here are valuable tools to study cytokinetic mechanisms under various genetic and treatment conditions. Key features • In vitro method to study male meiotic cytokinesis in dissected spermatocyte cysts. • In vitro method allows acute treatment with various pharmacological agents to study cytokinesis. • Ex vivo method to image male meiosis cytokinesis in intact adult testes. • Requires 15-60 min to set up and could be imaged up to 6-12 h.
PubMed: 38268980
DOI: 10.21769/BioProtoc.4918 -
Ecotoxicology and Environmental Safety Feb 2024The decline in male fertility caused by environmental pollutants has attracted worldwide attention nowadays. Tris(2-chloroisopropyl) phosphate (TCPP) is a...
N-acetylcysteine alleviated tris(2-chloroisopropyl) phosphate-induced sperm motility decline and functional dysfunction in mice through reversing oxidative stress and DNA damage.
The decline in male fertility caused by environmental pollutants has attracted worldwide attention nowadays. Tris(2-chloroisopropyl) phosphate (TCPP) is a chlorine-containing organophosphorus flame retardant applied in many consumer products and has multiple side effects on health. However, whether TCPP impairs spermatogenesis remains unclear. In this study, we found that TCPP reduced the sperm motility and blastocyst formation, inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Moreover, TCPP induced imbalance of oxidant and anti-oxidant, DNA damage and mitochondrial dysfunction, thus induced abnormal spermatogenesis. In this process, p53 signaling pathway was activated and N-acetylcysteine treatment partially alleviated the side effects of TCPP, including decrease of sperm motility, activation of p53 signaling pathway and DNA damage. Finally, our study verified that TCPP elevated reactive oxygen species (ROS), decreased mitochondrial membrane potential and induced apoptosis in human semen samples. Overall, ROS mediated TCPP-induced germ cell proliferation inhibition and apoptosis, which finally led to the decline of sperm motility.
Topics: Male; Mice; Humans; Animals; Phosphates; Reactive Oxygen Species; Organophosphates; Acetylcysteine; Organophosphorus Compounds; Flame Retardants; Sperm Motility; Tumor Suppressor Protein p53; Oxidative Stress; DNA Damage
PubMed: 38266359
DOI: 10.1016/j.ecoenv.2024.116000 -
Theriogenology Mar 2024Heat shock proteins are the most evolutionarily conserved protein families induced by stressors including hyperthermia. In the context of pathologies of the male...
Heat shock proteins are the most evolutionarily conserved protein families induced by stressors including hyperthermia. In the context of pathologies of the male reproductive tract, cryptorchidism is the most common genital defect that compromises the reproductive potential of the male because it induces an increase in intratesticular temperature. In equine species, cryptorchidism affects almost 9 % of newborns and few studies have been carried out on the molecular aspects of the retained testis. In this study, the expression pattern of HSP60, 70, and 90 in abdominal and inguinal testes, in their contralateral descended normally testes, and in testes of normal horses were investigated by Western blot and immunohistochemistry. The histomorphological investigation of retained and scrotal testes was also investigated. The seminiferous epithelium of the retained testes showed a vacuolized appearance and displayed a completely blocked spermatogenesis for lacking meiotic and spermiogenetic cells. On the contrary, the contralateral scrotal testes did not show morphological damage and the seminiferous epithelium displayed all phases of the spermatogenetic cycle as in the normal testes. The morphology of Leydig cells was not affected by the cryptorchid state. Western blot and immunohistochemistry evidenced that equine testis (both scrotal and retained) expresses the three investigated HSPs. More in detail, the Western blot evidenced that HSP70 is the more expressed chaperone and that together with HSP90 it is highly expressed in the retained gonad (P < 0.05). The immunohistochemistry revealed the presence of the three HSPs in the spermatogonia of normal and cryptorchid testes. Spermatogonia of retained testes showed the lowest expression of HSP60 and the highest expression of HSP90. Spermatocytes, spermatids of scrotal testes, and the Sertoli cells of retained and scrotal testes did not display HSP60 whereas expressed HSP70 and HSP90. These two proteins were also localized in the nucleus of the premeiotic cells. The Leydig cells displayed the three HSPs with the higher immunostaining of HSP70 and 90 in the cryptorchid testes. The results indicate that the heat stress condition occurring in the cryptorchid testis influences the expression of HSPs.
Topics: Male; Animals; Horses; Testis; Cryptorchidism; Chaperonin 60; Sertoli Cells; Leydig Cells; Horse Diseases
PubMed: 38262223
DOI: 10.1016/j.theriogenology.2024.01.019 -
Cell Proliferation May 2024The mammalian Pre-B cell leukaemia transcription factors 1-4 (PBX1-4) constitutes the PBC class of the homeodomain (HD)-containing proteins, which play important roles...
The mammalian Pre-B cell leukaemia transcription factors 1-4 (PBX1-4) constitutes the PBC class of the homeodomain (HD)-containing proteins, which play important roles in diverse developmental processes. The functions and the underlying molecular mechanisms of PBX1-3 but not PBX4 have been extensively studied, and they have been reported to direct essential morphogenetic processes and organogenesis. In the present study, we generated knockin mice of FLAG-tagged PBX4 and the Pbx4 knockout (KO) mice and carried out in-depth characterisation of PBX4 expression and function. PBX4 was initially detected only in the testis among several organs of the adult mice and was expressed in spermatocytes and spermatids. However, no abnormality in spermatogenesis, but growth retardation and premature death after birth were observed in most adult Pbx4 KO mice. These animals were inactive and had shorter hindlimbs and lower numbers of reticulocytes and lymphocytes, probably caused by abnormalities at earlier developmental stages. Pbx4 mRNAs were indeed detected in several embryonic cell types related to limb development by in situ hybridisation and single-cell RNA-sequencing analysis. Pbx4 protein was also detected in the bone marrow of adult mice with a lower level compared with that in the testis. PBX4 preferentially binds to the promoters of a large number of genes including those for other HD-containing proteins and ribosomal proteins whose mutations are related to anaemia. PBX4-binding sites are enriched in motifs similar to those of other HD-containing proteins such as PKNOX1 indicating that PBX4 may also act as a co-transcription factor like other PBC proteins. Together, these results show that PBX4 participates in limb development and haematopoiesis while its function in spermatogenesis has not been revealed by gene KO probably due to the complementary effects of other genes.
Topics: Animals; Male; Mice; Extremities; Gene Expression Regulation, Developmental; Hematopoiesis; Homeodomain Proteins; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; Testis; Transcription Factors; DNA-Binding Proteins
PubMed: 38230761
DOI: 10.1111/cpr.13580 -
Urology Case Reports Mar 2024Both Leydig cell tumor (LCT), which is a sex cord-stromal tumor, and spermatocytic tumor (ST), which is a germ cell tumor, are rare testicular tumors. Synchronous LCT...
Both Leydig cell tumor (LCT), which is a sex cord-stromal tumor, and spermatocytic tumor (ST), which is a germ cell tumor, are rare testicular tumors. Synchronous LCT and ST in the unilateral testis are extremely rare because of their different origins. Herein, we report the case of an 84-year-old male patient with right scrotal swelling due to a testicular tumor. His age was out of the onset peak age of LCT but within ST. To the best of our knowledge, this is the first case with synchronous LCT and ST in the unilateral testis.
PubMed: 38229735
DOI: 10.1016/j.eucr.2024.102648 -
Archives of Razi Institute Aug 2023(TT) is a common herbal plant with different categories that grows in many countries of the world. Traditional Chinese and Indian therapies have used TT for infertility...
(TT) is a common herbal plant with different categories that grows in many countries of the world. Traditional Chinese and Indian therapies have used TT for infertility treatment and also as a powerful antioxidant agent. Therefore, this study aimed to use this plant supplemented with vitamin E to study their combined effects on the histological condition of the testicle and epididymis of rabbits. This study was performed on 28 healthy male rabbits (445-950 g, 2.0-3.0 months old) that were randomly divided into four groups (n=7). All animals were subjected to clinical examination to ensure that they were free of external and internal parasites with the use of some preventive treatments. The animals were housed individually (cage size: 50 cm×50 cm×40 cm) over the 60-day study period starting from January 2022, with an adaptation period of two weeks. and vitamin E treatments were as follows: the first group (G1) was daily fed on a standard diet and kept as the control group, the second group (G2) was daily fed on the same ration plus 1 g of TT (animal/daily), the third group (G3) was daily fed on the same ration plus 1 g of TT supplemented with 60 mg of vitamin E (orally) (animal /daily), and the fourth group (G4) was daily fed on the same ration, with the addition of 60 mg vitamin E per animal (orally). The morphometric investigation, macroscopic variables (including body weight, testicular weight, and volume), and the microscopic parameters of the testicular seminal tubule were measured. The histological section showed the absence of negative effects after the oral administration of TT at a dose of 1 g per day and 60 IU vitamin E for each animal. However, there was a positive effect on spermatogonia and spermatocytes in all animals, while the spermatogonia in the experimental groups were more dense, especially in the second and third groups, compared to the control group. The seminiferous tubules were significantly lined with spermatogonia, spermatocytes, and round spermatids (<0.5) in the experimental groups, compared to the control group. Nevertheless, the epididymis tissue did not show traces of histological changes, such as epididymal hyperplasia. Sperms were more frequent in the lumens of the epididymis as well as the lumens larger than those of the control. Based on the results of this study, it can be concluded that the pole plant and vitamin E have a positive effect on the epithelial lining of the seminiferous tubules and the epididymis with an increase in sperm formation and differentiation towards maturity.
Topics: Rabbits; Male; Animals; Testis; Epididymis; Vitamin E; Tribulus; Spermatogenesis; Seeds
PubMed: 38226379
DOI: 10.32592/ARI.2023.78.4.123 -
Cell Reports Jan 2024Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male...
Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2-9 disrupt its secondary structure and charge properties, impeding phase separation. Maps pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. Maps male mice expressing MAPS protein lacking aa 2-9 phenocopy Maps mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.
Topics: Humans; Male; Mice; Animals; Chromatin; Meiosis; Pachytene Stage; Phase Separation; Meiotic Prophase I; Spermatocytes; Mammals
PubMed: 38175751
DOI: 10.1016/j.celrep.2023.113651