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Medicine Aug 2023Taohong Siwu Decoction (THSWD) was widely used for the treatment of varicocele-associated male infertility. However, the pharmacological mechanism of action is not... (Review)
Review
Researching the molecular mechanisms of Taohong Siwu Decoction in the treatment of varicocele-associated male infertility using network pharmacology and molecular docking: A review.
Taohong Siwu Decoction (THSWD) was widely used for the treatment of varicocele-associated male infertility. However, the pharmacological mechanism of action is not completely clear. Therefore, network pharmacology and molecular docking were performed to explore potential mechanism of THSWD in the treatment of varicocele-associated male infertility. The Traditional Chinese Medicine Systems Pharmacology (TCMSP), Swiss Target Prediction, and GeneCards were used to retrieve candidate compounds, action targets, and disease-related targets. The construction of the protein-protein interaction (PPI) network and the screening of core genes were completed by the STRING and Cytoscape 3.9.1, respectively. The DAVID was used to obtain results of gene ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The Mcule analysis platform was used to perform molecular docking. There were a total of 53 candidate compounds and 782 relevant targets in THSWD. There were 45 common targets between THSWD, varicocele, and male infertility, and 23 core genes were found in the PPI network. Biological processes involved response to hypoxia, regulation of blood pressure, cellular response to hypoxia, and regulation of the nitric oxide biosynthetic process. Furthermore, the KEGG pathway enrichment analysis showed that the common targets mainly regulated the disease of varicocele-associated male infertility through the HIF-1 signaling pathway, PI3K-Akt signaling pathway, Relaxin signaling pathway, and TNF signaling pathway. Finally, the molecular docking showed that luteolin, quercetin, and kaempferol had good intercalation with major targets. As predicted by network pharmacology, THSWD regulated varicocele-associated male infertility through multiple compounds and targets, and its mechanism was closely related to inflammatory response, reactive oxygen species damage, and function of blood vessels.
Topics: Humans; Male; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Varicocele; Drugs, Chinese Herbal; Medicine, Chinese Traditional; Hypoxia
PubMed: 37543801
DOI: 10.1097/MD.0000000000034476 -
Journal of Clinical Medicine May 2024Infertility is a globally underestimated public health concern affecting almost 190 million people, i.e., about 17.5% of people during their lifetime, while the... (Review)
Review
Infertility is a globally underestimated public health concern affecting almost 190 million people, i.e., about 17.5% of people during their lifetime, while the prevalence of male factor infertility is about 7%. Among numerous other causes, the prevalence of male genital tract infections reportedly ranges between 10% and 35%. Leukocytospermia is found in 30% of infertile men and up to 20% in fertile men. Bacterial infections cause an inflammatory response attracting leukocytes, which produce reactive oxygen species (ROS) and release cytokines, both of which can cause damage to sperm, rendering them dysfunctional. Although leukocytospermia and bacteriospermia are both clinical conditions that can negatively affect male fertility, there is still debate about their impact on assisted reproduction outcomes and management. According to World Health Organization (WHO) guidelines, leukocytes should be determined by means of the Endtz test or with monoclonal antibodies against CD15, CD68 or CD22. The cut-off value proposed by the WHO is 1 × 10 peroxidase-positive cells/mL. For bacteria, Gram staining and semen culture are regarded as the "gold standard", while modern techniques such as PCR and next-generation sequencing (NGS) are allowing clinicians to detect a wider range of pathogens. Whereas the WHO manual does not specify a specific value as a cut-off for bacterial contamination, several studies consider semen samples with more than 10 colony-forming units (cfu)/mL as bacteriospermic. The pathogenic mechanisms leading to sperm dysfunction include direct interaction of bacteria with the male germ cells, bacterial release of spermatotoxic substances, induction of pro-inflammatory cytokines and ROS, all of which lead to oxidative stress. Clinically, bacterial infections, including "silent" infections, are treatable, with antibiotics being the treatment of choice. Yet, non-steroidal antiphlogistics or antioxidants should also be considered to alleviate inflammatory lesions and improve semen quality. In an assisted reproduction set up, sperm separation techniques significantly reduce the bacterial load in the semen. Nonetheless, contamination of the semen sample with skin commensals should be prevented by applying relevant hygiene techniques. In patients where leukocytospermia is detected, the causes (e.g. infection, inflammation, varicocele, smoking, etc.) of the leukocyte infiltration have to be identified and addressed with antibiotics, anti-inflammatories or antioxidants in cases where high oxidative stress levels are detected. However, no specific strategy is available for the management of leukocytospermia. Therefore, the relationship between bacteriospermia and leukocytospermia as well as their specific impact on functional sperm parameters and reproductive outcome variables such as fertilization or clinical pregnancy must be further investigated. The aim of this narrative review is to provide an update on the current knowledge on leukocytospermia and bacteriospermia and their impact on male fertility.
PubMed: 38792382
DOI: 10.3390/jcm13102841 -
Human Fertility (Cambridge, England) Dec 2023The relationship between infertility and varicocele is still a controversial topic. This study aimed to find the association between the venous blood gas (VBG) pattern...
The relationship between infertility and varicocele is still a controversial topic. This study aimed to find the association between the venous blood gas (VBG) pattern of the spermatic veins and peripheral veins with varicocele grade and spermogram variables in infertile patients. A total of 47 patients with a varicocele were enrolled in this study. Blood samples were drawn simultaneously from the spermatic vein and a peripheral vein. The pH, partial pressure of oxygen, the partial pressure of carbon dioxide, oxygen saturation, and bicarbonate values of these samples were analysed. The mean age of participants was 30.48 ± 6.08. The mean volume of semen was 3.92 ± 1.57 mL, and the mean semen pH was 7.88 ± 0.22. The pH was higher ( < 0.01) in the spermatic vein compared with the peripheral vein. However, level of other parameters including pO ( = 0.662), pCO ( < 0.001), HCO concentration of serum ( < 0.01), and base excess ( = 0.172) were lower in the spermatic vein in comparison with the peripheral vein. Correlations between VBGs determinants of the varicocele patients' spermatic vein and sperm morphology and motility were insignificant. In conclusion, although the clinical significance of VBGs is evident, there are limited studies that investigated the VBGs in varicocele patients. We should consider that the deviation in blood gases may be the missing piece in the puzzle to understand the pathophysiology of varicocele. By knowing the pathophysiology more precisely, we can better decide the ideal treatment option for the patients.
Topics: Humans; Male; Varicocele; Semen; Infertility, Male; Spermatozoa; Gases
PubMed: 35266418
DOI: 10.1080/14647273.2022.2046294 -
Urology Annals 2023Varicocelectomy is the prevailing management of scrotal pain secondary to varicocele. However, the literature is controversial on this topic. Some data showed that pain...
INTRODUCTION
Varicocelectomy is the prevailing management of scrotal pain secondary to varicocele. However, the literature is controversial on this topic. Some data showed that pain may persist after the surgery even if the varicocele is not detected postoperatively.
OBJECTIVES
The objectives of the study were to identify the effect of varicocelectomy in patients with chronic scrotal pain, to report the association between the clinical grade and postoperative pain resolution, and to identify the need for a secondary procedure after varicocelectomy to control the pain.
MATERIALS AND METHODS
This was a retrospective study of 47 patients who underwent varicocelectomy between March 2016 and December 2018.
RESULTS
Postoperatively, the pain totally resolved after surgery in 64.3% of patients with scrotal pain; it improved in 21.4%, 11.9% have persistent pain, and the pain got worse in only 2.4%. Our study showed 100% complete resolution or improvement with Grade I, 85.7% in Grade II, and 81.3% in Grade III. In addition, all patients who underwent bilateral varicocelectomy had pain that either completely resolved or improved postoperatively. On the other hand, all patients who had persistent pain or pain worsening postoperatively had unilateral varicocelectomy. An additional intervention for postoperative pain control was needed in only 14% of patients, 7% of them underwent embolization, 4.7% had a cord block, and 2.3% were sent to a pain clinic.
CONCLUSION
Varicocelectomy offers good outcomes in most patients with varicocele-related scrotal pain. The most significant predictor for success was low grade and bilaterality. However, there is a subset of patients whose symptoms will not improve postoperatively. Careful preoperative counseling and expectation management are crucial when discussing surgical options for those patients.
PubMed: 37664099
DOI: 10.4103/UA.UA_64_20 -
Cellular & Molecular Biology Letters Sep 2023In recent years, N6-methyladenosine (mA) methylation modification of mRNA has been studied extensively. It has been reported that mA determines mRNA fate and...
BACKGROUND
In recent years, N6-methyladenosine (mA) methylation modification of mRNA has been studied extensively. It has been reported that mA determines mRNA fate and participates in many cellular functions and reactions, including oxidative stress. The PLOD2 gene encodes a protein that plays a key role in tissue remodeling and fibrotic processes.
METHODS
The mA methylation and expression levels of PLOD2 were determined by mA methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-quantitative polymerase chain reaction (qPCR) in the testes of varicocele rats compared with control. To determine whether IGF2BP2 had a targeted effect on the PLOD2 mRNA, RNA immunoprecipitation-qPCR (RIP-qPCR) and luciferase assays were performed. CRISPR/dCas13b-ALKBH5 could downregulate mA methylation level of PLOD2, which plays an important role in PLOD2-mediated cell proliferation and apoptosis in GC-2 cells.
RESULTS
PLOD2 was frequently exhibited with high mA methylation and expression level in the testes of varicocele rats compared with control. In addition, we found that IGF2BP2 binds to the mA-modified 3' untranslated region (3'-UTR) of PLOD2 mRNA, thereby positively regulating its mRNA stability. Targeted specific demethylation of PLOD2 mA by CRISPR/dCas13b-ALKBH5 system can significantly decrease the mA and expression level of PLOD2. Furthermore, demethylation of PLOD2 mRNA dramatically promote GC-2 cell proliferation and inhibit cell apoptosis under oxidative stress.
CONCLUSION
As a result, we found that varicocele-induced oxidative stress promoted PLOD2 expression level via mA methylation modification. In addition, targeting mA demethylation of PLOD2 by CRISPR/dCas13b-ALKBH5 system can regulate GC-2 cell proliferation and apoptosis under oxidative stress. Taken together, our study has acquired a better understanding of the mechanisms underlying male infertility associated with oxidative stress, as well as a novel therapeutic target for male infertility.
Topics: Male; Animals; Rats; Humans; Spermatocytes; Varicocele; 3' Untranslated Regions; Adenosine; Infertility, Male; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; RNA-Binding Proteins
PubMed: 37670228
DOI: 10.1186/s11658-023-00475-4 -
Frontiers in Endocrinology 2024As an important gas signaling molecule, hydrogen sulfide (HS) affects multiple organ systems, including the nervous, cardiovascular, digestive, and genitourinary,... (Review)
Review
As an important gas signaling molecule, hydrogen sulfide (HS) affects multiple organ systems, including the nervous, cardiovascular, digestive, and genitourinary, reproductive systems. In particular, HS not only regulates female reproductive function but also holds great promise in the treatment of male reproductive diseases and disorders, such as erectile dysfunction, prostate cancer, varicocele, and infertility. In this review, we summarize the relationship between HS and male reproductive organs, including the penis, testis, prostate, vas deferens, and epididymis. As lower urinary tract symptoms have a significant impact on penile erection disorders, we also address the potential ameliorative effects of HS in erectile dysfunction resulting from bladder disease. Additionally, we discuss the regulatory role of HS in cavernous smooth muscle relaxation, which involves the NO/cGMP pathway, the RhoA/Rho-kinase pathway, and K channel activation. Recently, various compounds that can alleviate erectile dysfunction have been reported to be at least partly dependent on HS. Therefore, understanding the role of HS in the male reproductive system may help develop novel strategies for the clinical treatment of male reproductive system diseases.
Topics: Hydrogen Sulfide; Humans; Male; Genitalia, Male; Animals; Erectile Dysfunction; Signal Transduction
PubMed: 38883604
DOI: 10.3389/fendo.2024.1377090 -
Journal of Clinical Ultrasound : JCU Apr 2024The aim of this study was to investigate the relationship between left-sided varicocele and epididymitis or epididymo-orchitis.
OBJECTIVE
The aim of this study was to investigate the relationship between left-sided varicocele and epididymitis or epididymo-orchitis.
MATERIALS AND METHODS
The study included 72 patients with left side epididymitis (EP) or epididymo-orchitis (EPO) (Group 1) and a control group of 72 patients without EP or EPO (Group 2). Those with right EP-EPO were excluded due to possible other underlying retroperitoneal pathologies causing varicocele. Groups were evaluated for presence of left side varicocele, varicocele grade and pampiniform plexus vein diameter.
RESULTS
The average age was 38 ± 8.4 years (range, 18-50 years) in Group 1, and 36 ± 9.1 years (range, 16-47 years) in Group 2. Varicocele was significantly more common in patients with EP or EPO (p < .001). The rate of varicocele was 66.7% (48/72) in Group 1, and 22.3% (16/72) in Group 2. The median grade of varicocele was 2 in Group 1, and 0 in Group 2. Pampiniform plexus vein diameters were found to be significantly larger in patients with EP or EPO compare to patients without EP and EPO. The median vein diameter was 3.3 mm with the 25th and 75th percentiles at 2.7 and 3.8 mm, and was 1.9 mm with the 25th and 75th percentiles at 1.7 and 2.3 mm, respectively (p < .001).
CONCLUSIONS
Left-sided varicocele was significantly more common in patients with EP or EPO and it is an important cause for the development of EP/EPO because of chronic venous stasis.
PubMed: 38651691
DOI: 10.1002/jcu.23694 -
Cytokine Sep 2023Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied...
Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied apelin/APJ-R in human semen and testis. Semen of 41 infertile patients with varicocele, genitourinary infections, unexplained infertility and 12 fertile men was analysed (WHO guidelines, 2021). Apelin was quantified by ELISA in seminal fluid and spermatozoa, interleukin (IL)-1β in seminal fluid. Apelin/APJ-R were immunolocalized in spermatozoa and testis. Apelin was present in spermatozoa and its levels were negatively correlated with normal sperm morphology% (r = -0.857; p < 0.001), and positively with IL-1β levels (r = 0.455; p < 0.001). Apelin and IL-1β concentrations were increased in patients' samples with varicocele (apelin p < 0.01; IL-1β p < 0.05) and infections (apelin p < 0.01; IL-1β p < 0.001). By logistic regression analysis, apelin (OR 1.310; p = 0.011) and IL-1β (OR 1.572; p = 0.005) were predictors of inflammatory diseases (varicocele, infections). Apelin and APJ-R immunofluorescence labels were weak in sperm tail of fertile men and intense along tail, cytoplasmic residues and post-acrosomal sheath of sperm from infertile men. In testis, apelin and APJ-R labels were evident in Leydig cells and weak inside the seminiferous tubule. Apelin/APJ-R system is present in human spermatozoa and testicular tissue and probably involved in human fertility.
Topics: Humans; Male; Apelin; Infertility, Male; Semen; Spermatozoa; Testis; Varicocele
PubMed: 37352775
DOI: 10.1016/j.cyto.2023.156281 -
F1000Research 2023Azoospermia is the most severe type of male infertility. This study aimed to identify useful clinical parameters to predict sperm retrieval success. This could assist...
BACKGROUND
Azoospermia is the most severe type of male infertility. This study aimed to identify useful clinical parameters to predict sperm retrieval success. This could assist clinicians in accurately diagnosing and treating patients based on the individual clinical parameters of patients.
METHODS
A retrospective cohort study was performed involving 517 patients with azoospermia who underwent sperm retrieval in Jakarta, Indonesia, between January 2010 and April 2023. Clinical evaluation and scrotal ultrasound, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were evaluated before surgery. Multivariate analyses were conducted to determine clinical parameters that could predict overall sperm retrieval success. Further subgroup analysis was performed to determine the factors that the diagnosis of non-obstructive azoospermia (NOA) diagnosis and sperm retrieval success among patients with NOA.
RESULTS
A total of 2,987 infertile men attended our clinic. Men with azoospermia (n=517) who met the inclusion criteria and did not fulfil any exclusion criteria were included in the study. The overall sperm retrieval success was 47.58%. Logistic regression revealed that FSH 7.76 mIU/mL (sensitivity: 60.1%, specificity: 63.3%, p<0.001); longest testicular axis length 3.89 cm (sensitivity: 33.6%, specificity: 41.6%); and varicocele (p<0.001) were independent factors for overall sperm retrieval. The FSH cutoff of 7.45 mIU/mL (sensitivity: 31.3%, specificity: 37.7%, p<0,001); longest testicular axis length 3.85 cm (sensitivity: 76.7%, specificity: 65.4%, p<0.001); and varicocele (p<0.001) were independent factors for NOA diagnosis. Varicocele was the only clinical parameter that significantly predicted the success of sperm retrieval in patients with NOA.
CONCLUSIONS
FSH, LH, longest testicular axis, and varicocele are among the clinical parameters that are useful for predicting overall sperm retrieval success and NOA diagnosis. However, varicocele is the only clinical parameter that significantly predicts sperm retrieval success in patients with NOA. High-quality studies are required to assess the other predictors of sperm retrieval success.
Topics: Humans; Male; Azoospermia; Indonesia; Retrospective Studies; Sperm Retrieval; Varicocele; Semen; Follicle Stimulating Hormone
PubMed: 38434641
DOI: 10.12688/f1000research.141969.1 -
Cell Journal Jul 2023Testicular dysfunction, whether linked to varicocele, obesity, diabetes, aging, inflammation, or lifestyle or environmental issues, is frequently accompanied by an... (Review)
Review
Testicular dysfunction, whether linked to varicocele, obesity, diabetes, aging, inflammation, or lifestyle or environmental issues, is frequently accompanied by an accumulation of unfolded or misfolded proteins, indicating impaired endoplasmic reticulum (ER) function. In this review, we examined the Google Scholar, Scopus and PubMed databases (from 2011 to 2022) to support the association of ER stress with defective spermatogenesis in animal models and humans. ER stress, whether in its pro-survival or pro-apoptotic aspect, appears to be closely linked to each studied situation. Several studies have demonstrated a significant increase in oxidative stress (OS) levels in infertile men compared to fertile individuals, which is associated with poor spermatogenesis quality. OS is likely the result of the interplay between ER stress and spermatogenesis defects. These findings suggest that therapeutic strategies aimed at mitigating both ER stress and OS could be of interest in restoring male reproductive function.
PubMed: 37543856
DOI: 10.22074/cellj.2023.1983074.1205