The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

Mahran, Ali; Mosad, Eman; Abdel‐Raheem, Mohamed A.; Ahmed, Ehab A.; Motaleb, Amira A Abdel; Hofny, Eman R. M.

doi:10.1111/and.13341

Cited by 7 publications

(4 citation statements)

References 50 publications

(51 reference statements)

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“…Vascular endothelial growth factor A (VEGFA), the most important vascular endothelial growth factor, plays an important role in regulating angiogenesis and formation and is involved in VC-induced testicular development and spermatogenesis (Shiraishi and Naito, 2008;Wang et al, 2017). Mammalian rapamycin (mTOR) is an important regulator of cell growth and proliferation, and studies have shown a positive correlation between mTOR expression and sperm DFI (Mahran et al, 2019). The results illustrated that MLST might regulate the above targets against varicocele-associated male infertility.…”

Section: Discussionmentioning

confidence: 99%

Mailuoshutong pill for varicocele-associated male infertility—Phytochemical characterisation and multitarget mechanism

Ji²,

Zhang³

et al. 2022

Front. Pharmacol.

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Background: Varicocele (VC) is a relatively common and treatable cause of male infertility. Mailuoshutong pill (MLST), a traditional Chinese patent medicine, is widely used for treating varicose vein disease, but the underlying mechanism of MLST on varicocele-associated male infertility is unclear.Objective: To reveal the phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility.Methods: The components in MLST were determined using UHPLC-MS/MS. Through network analysis, we constructed the “Drug-Components-Targets-Disease” network and predicted the potential biological functions and signaling pathways of MLST. Finally, the therapeutic effects and potential mechanisms of MLST were discovered by pharmacological experiments.Results: By network analysis, the “Drug-Components-Targets-Disease” network was constructed, 62 components such as apigenin, limonin, kaempferol, and obacunoic acid may be the main active components of MLST for varicocele-associated male infertility, 28 targets such as VEGFA, PIK3CA, AKT1, and MTOR are considered as hub targets, signaling pathways such as HIF-1, Estrogen, PI3K/Akt, and mTOR may be key pathways for MLST against varicocele-associated male infertility. Through pharmacological experiments, we found that MLST ameliorated VC-induced testicular atrophy. Further histomorphology showed that MLST reduced VC-induced damage to testicular spermatogonia and seminiferous tubule, while MLST reduced ROS and MDA levels and increased antioxidant enzymes (GSH, GSH-Px, SOD, and CAT) levels. TUNEL staining and immunofluorescence showed that MLST reduced VC-induced apoptosis in testicular tissue, decreased BAX, and increased BCL2. Western blot results showed that MLST decreased the phosphorylation of PI3K, AKT, and mTOR proteins, and decreased the expression of HIF1α.Conclusion: The phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility were discovered using network analysis and pharmacological experiments. We verified that MLST can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, reduce the expression of HIF1α, and further attenuate VC-induced oxidative stress and apoptosis in the testis. These findings provide evidence for the therapeutic role of MLST in varicocele-associated male infertility.

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Section: Discussionmentioning

confidence: 99%

Mailuoshutong pill for varicocele-associated male infertility—Phytochemical characterisation and multitarget mechanism

Ji²,

Zhang³

et al. 2022

Front. Pharmacol.

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“…DNA damage triggers a sophisticated signal transduction pathway that detects damage to DNA and transmits this data to the cell to trigger cellular responses to DNA damage. The DNA damage response maximizes the ability of the cells to repair DNA and increases their survival once the damage is done [ 18 ]. However, in severe DNA damage, apoptosis and cell senescence occur since DNA damage response halts advancement of the cell cycle [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Novel DNA Damage-Related Subtypes Characterization Identifies Uterine Corpus Endometrial Carcinoma (UCEC) Based on Machine Learning

Qian

Wang

et al. 2022

Journal of Oncology

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Objective. Accumulating evidence suggests that DNA damage is associated with numerous gynecological illnesses, particularly advanced uterine corpus endometrial carcinoma (UCEC), illustrating the involvement of the DNA damage pathway in the advancement of UCEC. This research aimed to discover a robust subtype with the potential to contribute to the scientific treatment of UCEC. Methods. In this work, the expression patterns of prognostic DNA damage-related genes were curated, and consensus clustering analyses were undertaken to determine DNA damage subtypes in patients with UCEC in the TCGA cohort. Two DNA damage-related subtypes were identified for further investigation. Differentially expressed genes (DEGs) analysis, gene ontology analysis, mutation analysis, and immune cell infraction analysis were performed to find the molecular mechanism behind it. Finally, the polymerase chain reaction (PCR) was conducted to verify the correlation of the hub genes. Results. In total, 545 patients with UCEC were tested for two distinct DNA damage subtypes. The clinical prognosis was poorer among patients with DNA damage subtype 2 than those in subtype 1. The DEGs analysis and PPI analysis showed that ASMP, BUB1, CENPF, MAD2L1, NCAPG, SGO2, and TOP2A were expressed higher in UCEC tissues than in the normal tissues. Immune cell infraction analysis showed that hub genes were associated with the tumor microenvironment (TME). Conclusion. Altogether, our research identified two distinct DNA damage subtypes that are complicated and heterogeneous. A better knowledge of the characteristics of the TME may be gained by quantitative measurement of DNA damage subtypes in individual patients, which can also lead to the development of more successful treatment regimens.

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“…For instance, the autophagy pathway (Kegg bta04136) was found to be targeted by miRNAs whose expression peaks at epididymis. This pathway has been associated with regulation of mitochondrial function [ 59 ] and human sperm motility [ 60 , 61 ]. In addition, spermatozoa are highly susceptible to oxidative stress [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamics of cattle sperm sncRNAs during maturation, from testis to ejaculated sperm

Sellem¹,

Marthey

Rau

et al. 2021

Epigenetics & Chromatin

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Background During epididymal transit, spermatozoa go through several functional maturation steps, resulting from interactions with epididymal secretomes specific to each region. In particular, the sperm membrane is under constant remodeling, with sequential attachment and shedding of various molecules provided by the epididymal lumen fluid and epididymosomes, which also deliver sncRNA cargo to sperm. As a result, the payload of sperm sncRNAs changes during the transit from the epididymis caput to the cauda. This work was designed to study the dynamics of cattle sperm sncRNAs from spermatogenesis to final maturation. Results Comprehensive catalogues of sperm sncRNAs were obtained from testicular parenchyma, epididymal caput, corpus and cauda, as well as ejaculated semen from three Holstein bulls. The primary cattle sncRNA sperm content is markedly remodeled as sperm mature along the epididymis. Expression of piRNAs, which are abundant in testis parenchyma, decreases dramatically at epididymis. Conversely, sperm progressively acquires miRNAs, rsRNAs, and tsRNAs along epididymis, with regional specificities. For instance, miRNAs and tsRNAs are enriched in epididymis cauda and ejaculated sperm, while rsRNA expression peaks at epididymis corpus. In addition, epididymis corpus contains mainly 20 nt long piRNAs, instead of 30 nt in all other locations. Beyond the bulk differences in abundance of sncRNAs classes, K-means clustering was performed to study their spatiotemporal expression profile, highlighting differences in specific sncRNAs and providing insights into their putative biological role at each maturation stage. For instance, Gene Ontology analyses using miRNA targets highlighted enriched processes such as cell cycle regulation, response to stress and ubiquitination processes in testicular parenchyma, protein metabolism in epididymal sperm, and embryonic morphogenesis in ejaculated sperm. Conclusions Our findings confirm that the sperm sncRNAome does not simply reflect a legacy of spermatogenesis. Instead, sperm sncRNA expression shows a remarkable level of plasticity resulting probably from the combination of multiple factors such as loss of the cytoplasmic droplet, interaction with epididymosomes, and more surprisingly, the putative in situ production and/or modification of sncRNAs by sperm. Given the suggested role of sncRNA in epigenetic trans-generational inheritance, our detailed spatiotemporal analysis may pave the way for a study of sperm sncRNAs role in embryo development.

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The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

Cited by 7 publications

References 50 publications

Mailuoshutong pill for varicocele-associated male infertility—Phytochemical characterisation and multitarget mechanism

Mailuoshutong pill for varicocele-associated male infertility—Phytochemical characterisation and multitarget mechanism

Novel DNA Damage-Related Subtypes Characterization Identifies Uterine Corpus Endometrial Carcinoma (UCEC) Based on Machine Learning

Dynamics of cattle sperm sncRNAs during maturation, from testis to ejaculated sperm

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