Where do obesity and male infertility collide?

The parallel rise in obesity and male infertility in modern societies necessitates the identification of susceptibility genes underlying these interconnected health issues. In our study, we conducted a comprehensive search in the OMIM database to identify genes commonly associated with male infertility and obesity. Subsequently, we performed an insilico analysis using the REVEL algorithm to detect pathogenic single nucleotide polymorphisms (SNPs) in the coding region of these candidate genes. To validate our findings in vivo, we conducted a comprehensive analysis of SNPs and gene expression of candidate genes in 200 obese infertile subjects and 240 obese fertile individuals using ARMS-PCR. Additionally, we analyzed 20 fertile and 22 infertile obese individuals using Realtime-qPCR. By removing duplicated queries, we obtained 197 obesity-related genes and 102 male infertility-related genes from the OMIM database. Interestingly, the APOB gene was found in common between the two datasets. REVEL identified the rs13306194 variant as potentially pathogenic with a calculated score of 0.524. The study identified a significant association between the AA (P value = 0.001) genotype and A allele (P value = 0.003) of the APOB rs13306194 variant and infertility in obese men. APOB expression levels were significantly lower in obese infertile men compared to obese fertile controls (p < 0.01). Moreover, the AA genotype of rs13306194 APOB was associated with a significant decrease in APOB gene expression in obese infertile men (p = 0.05). There is a significant association between the Waist-to-Hip Ratio (WHR) and LH with infertility in the obese infertile group. These results are likely to contribute to a better understanding of the causes of male infertility and its association with obesity.

Biomarker Profile of Colorectal Cancer: Current Findings and Future Perspective.

OBJECTIVE: Breakthroughs in omics technology have led to a deeper understanding of the fundamental molecular changes that play a critical role in the development and progression of cancer. This review delves into the hidden molecular drivers of colorectal cancer (CRC), offering potential for clinical translation through novel biomarkers and personalized therapies. METHODS: We summarizes recent studies utilizing various omics approaches, including genomics, transcriptomics, proteomics, epigenomics, metabolomics and data integration with computational algorithms, to investigate CRC. RESULTS: Integrating multi-omics data in colorectal cancer research unlocks hidden biological insights, revealing new pathways and mechanisms. This powerful approach not only identifies potential biomarkers for personalized prognosis, diagnosis, and treatment, but also predicts patient response to specific therapies, while computational tools illuminate the landscape by deciphering complex datasets. CONCLUSIONS: Future research should prioritize validating promising biomarkers and seamlessly translating them into clinical practice, ultimately propelling personalized CRC management to new heights.

Circular RNAs in renal cell carcinoma: from mechanistic to clinical perspective.

CircRNAs, a special type of noncoding RNAs characterized by their stable structure and unique abilities to form backsplicing loops, have recently attracted the interest of scientists. These RNAs are abundant throughout the body and play important roles such as microRNA sponges, templates for transcription, and regulation of protein translation and RNA-binding proteins. Renal cancer development is highly correlated with abnormal circRNA expression in vivo. CircRNAs are currently considered promising targets for novel therapeutic approaches as well as possible biomarkers for prognosis and diagnosis of various malignancies. Despite our growing understanding of circRNA, numerous questions remain unanswered. Here, we address the characteristics of circRNAs and their function, focusing in particular on their impact on drug resistance, metabolic processes, metastasis, cell growth, and programmed cell death in renal cancer. In addition, the application of circRNAs as prognostic and diagnostic biomarkers will be discussed.

Association of miR-146a and miR196a2 genotype with susceptibility to idiopathic recurrent pregnancy loss in Iranian women: A case-control study.

BACKGROUND: Recurrent pregnancy loss (RPL) is the most common complaint of pregnancy in females with a prevalence of 5%. Numerous documents have shown that single nucleotide polymorphisms are able to change miRNA transcription and/or maturation, which may alter the incidence of disorders such as RPL. OBJECTIVE: To assess the relationship of miR-146aC > G (rs2910164) and miR-196a2T > C (rs11614913) with RPL susceptibility in Iranian women. MATERIALS AND METHODS: Blood samples were collected from 214 women who had experienced at least two consecutive spontaneous miscarriages (case) and 147 normal individuals without a history of miscarriage (control). MiR-146aC > G and miR-196a2T > C genotypes were evaluated via the restriction fragment length polymorphism technique. RESULTS: The genotypes incidence did not show a significant difference in pre-miR-146aC > G polymorphism CC vs CG + GG (p = 0.854; OR = 0.933; 95% CI) and CC + CG vs GG (p = 0.282; OR = 1.454; 95% CI). Also, no significant difference was observed between pre-miR-196a2T > C polymorphism TT vs TC + CC (p = 0.862; OR = 0.938; 95% CI) and TT + TC vs CC and (p = 0.291; OR = 1.462; 95% CI) in both the case and control groups. CONCLUSION: The results showed that although the distribution of miR-146aC > G and miR-196a2T > C was different between the unknown RPL and control groups, these variances were not statistically significant.

Fertility preservation in women with ovarian cancer: Finding new pathways: A case-control study.

BACKGROUND: Surgery and chemotherapy are the two most common treatments for cancers, including ovarian cancer. Although most ovarian cancers occur over the age of 45 yr, it may involve younger women and affect their reproductive ability. OBJECTIVE: To assess the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), Forkhead Box O1 (FOXO1), and miR-340 genes in the ovarian cancer tissues as well as ovarian cancer cell lines. MATERIALS AND METHODS: In this case-control study, 30 ovarian cancer samples (with the average age of 37 ± 2.5 years) coupled with their non-tumor marginal tissue (as a control) were collected. Proliferated cell lines were treated with several concentrations of cisplatin, and the half maximal inhibitory concentration (IC50) of cisplatin was quantified by MTT-assay. After RNA extraction, cDNA synthesis and qRT-PCR were done. Finally, the results were analyzed. RESULTS: While the expression levels of miR-340 and FOXO1 genes in tumor samples displayed a significant reduction (p ≤ 0.001), the LGR5 gene presented a significant increase in expression (p ≤ 0.0001). However, conversely, the expression levels of miR-340 and FOXO1 genes in cisplatin-sensitive cell lines, after 24, 48, and 72 hr of cisplatin treatment, indicated a significant increase (p ≤ 0.001) while the expression of LGR5 gene showed a significant decrease in the cisplatin-sensitive cell line (p < 0.05). CONCLUSION: The LGR5, FOXO1, and miR-340 genes can be targeted for early diagnosis and more accurate treatment of ovarian cancer and may prevent some of the ovarian cancer complications such as infertility.

Genomics and Transcriptomics: The Powerful Technologies in Precision Medicine.

In a clinical trial, people with the same disease can show different responses after treatment with the same drug and exactly under the same conditions. Some of them may improve, some may not show any response, and occasionally side effects may be observed. In other words, people with the same disease process under the same therapeutic conditions may have different responses. Today, some diseases are resistant to conventional (standard) treatment procedures. Why do people with the same disease show different responses to the treatment with the same drug? This is primarily due to differences in molecular pathways (especially genetic variations) associated with the disease. On the other hand, designing and delivery of a new drug is a time-consuming and costly process, so any mistake in any stage of this process can have irreparable consequences for pharmaceutical companies and consumer patients. Therefore, we can achieve more accurate and reliable treatments by acquiring precise insight into different aspects of precision medicine including genomics and transcriptomics. The aim of this paper is to address the role of genomics and transcriptomics in precision medicine.

Evaluation of miR-181b and miR-126-5p expression levels in T2DM patients compared to healthy individuals: Relationship with NF-KappaB gene expression / Evaluación de los niveles de expresión de miR-181b y miR-126-5p en pacientes con DMT2 comparados con personas sanas: relación con la expresión del gen NF- kappaB

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder whose prevalence is rising very fast across the world. Diagnosis of this disease in early stages (pre-diabetic stage) plays an important role in reducing mortality associated with this disorder. miRNAs, as key players in the pathogenesis of T2DM, have been investigated in several studies. Furthermore, their expression profile changes in the early stages of diabetes mellitus in body fluids such as serum, peripheral blood, and peripheral blood mononuclear cell (PBMC) have been studied. Due to their high stability and the presence of non-invasive sensitive methods for their measurement, such as real-time PCR, they can be used for early diagnosis of T2DM as a biomarker. In this experimental study, the expression levels of miR-181b, miR-126-5p, and NF-KappaB were measured in patients with T2DM, pre-diabetic subjects, and healthy controls in a Yazd population. MATERIAL AND METHOD: Ninety asymptomatic subjects including 30 T2DM, 30 pre-diabetic, and 30 healthy subjects (diagnosis based on WHO criteria) were included in this study. Real-time PCR was used to measure the expression levels of miR-181b and miR-126-5p. Moreover, the NF-KappaB expression level was also measured to determine its relationship with these two microRNAs. RESULT: In this study, the expression level of miR-181b and miR-126-p decreased gradually in pre-diabetic as well as T2DM subjects compared to healthy controls. Furthermore, our study showed a significant negative correlation between these two miRNAs and NF-KappaB for the first time. CONCLUSION: These results introduce these anti-inflammatory miRNAs as powerful tools for early diagnosis of T2DM

ANTECEDENTES: La diabetes mellitus tipo 2 (DMT2) es un trastorno metabólico progresivo cuya prevalencia aumenta muy rápidamente en todo el mundo. El diagnóstico de esta enfermedad en estadios iniciales (fase prediabética) tiene un papel importante para reducir la mortalidad asociada con este trastorno. Los miARN, como elementos clave en la patogenia de la DMT2, se han investigado en varios estudios. Además, se han estudiado los cambios de su perfil de expresión en los estadios iniciales de la diabetes mellitus en líquidos corporales como el suero, la sangre periférica y las células mononucleares de sangre periférica (CMSP). Gracias a su elevada estabilidad y a la existencia de métodos sensibles no invasivos para medirlos, como la RCP en tiempo real, pueden utilizarse como biomarcadores para el diagnóstico precoz de la DMT2. En este estudio experimental se determinaron los niveles de expresión de miR-181b, miR-126-5p y NF-kappaB en pacientes con DMT2, sujetos prediabéticos y controles sanos de una población de la ciudad de Yazd. MATERIAL Y MÉTODO: Se incluyeron en este estudio a 90 sujetos asintomáticos, incluidos 30 con DMT2, 30 prediabéticos y 30 sanos (el diagnóstico se basó en los criterios de la OMS). Se utilizó RCP en tiempo real para determinar los niveles de expresión de miR-181b y miR-126-5p. Se midió también el nivel de expresión de NF-kappaB para determinar su relación con estos 2 micro-ARN. RESULTADOS: En este estudio, el nivel de expresión de miR-181b y miR-126-5p descendió gradualmente en los sujetos prediabéticos y con DMT2 comparados con los controles sanos. Además, nuestro estudio mostró por primera vez una correlación negativa importante entre estos 2 miARN y NF-kappaB. CONCLUSIÓN: Estos resultados sugieren que estos miARN antiinflamatorios son herramientas potentes para el diagnóstico precoz de la DMT2

Deficient Expression of DGCR8 in Human Testis is Related to Spermatogenesis Dysfunction, Especially in Meiosis I.

INTRODUCTION: DiGeorge syndrome critical region gene 8 (DGCR8) contributes to miRNA biogenesis, and defects in its expression could lead to defects in spermatogenesis. METHODS: Here, we assess gene and protein expression levels of DGCR8 in the testicular biopsy specimens obtained from men with obstructive azoospermia (OA, n = 19) and various types of non-obstructive azoospermia (NOA) including maturation arrest (MA, n = 17), Sertoli cell-only syndrome (SCOS, n = 20) and hypospermatogenesis (HYPO, 18). Also, samples of men with NOA were divided into two groups based on successful and unsuccessful sperm recovery, NOA+ in 21 patients and NOA- in 34 patients. RESULTS: Examinations disclosed a severe decrease in DGCR8 in samples with MA and SCOS in comparison to OA samples (P < 0.001). Also, the results showed DGCR8 has significantly lower expression in testis tissues of NOA- group in comparison to NOA+ group (p<0.05). Western blot analysis confirmed that the DGCR8 protein was not expressed in SCOS samples and had a very low expression in MA and HYPO samples. DISCUSSION: The results of this survey showed that DGCR8 is an important gene for the entire spermatogenesis pathway. Moreover, DGCR8 gene plays an important role in the diagnosis of NOA subgroups, and also the expression changes in it might contribute to SCOS or MA phenotypes. This gene with considering other related genes can also be a predictor of sperm retrieval.

Major miRNA Involved in Insulin Secretion and Production in Beta-Cells.

Insulin is implicated as a leading factor in glucose homeostasis and an important theme in diabetes mellitus (DM). Numerous proteins are involved in insulin signaling pathway and their dysregulation contributes to DM. microRNAs (miRNAs) as single-strand molecules have a critical effect on gene expression at post-transcriptional levels. Intensive investigation done by DM researchers disclosed that miRNAs have a significant role in insulin secretion by direct targeting numerous proteins engaged in insulin signaling pathway; so, their dysregulation contributes to DM. In this review, we presented some major miRNAs engaged in the insulin production and secretion.

Upregulation of the RNF8 gene can predict the presence of sperm in azoospermic individuals.

OBJECTIVE: In this study, specimens from testicular biopsies of men with nonobstructive azoospermia (NOA) were used to investigate whether RNF8 gene could serve as a biomarker to predict the presence of sperm in these patients. METHODS: Testicular biopsy specimens from 47 patients were classified according to the presence of sperm (positive vs. negative groups) and investigated for the expression of RNF8. The level of RNF8 gene expression in the testes was compared between these groups using reverse-transcription polymerase chain reaction. RESULTS: The expression level of RNF8 was significantly higher in testicular samples from the positive group than in those from the negative group. Moreover, the area under the curve of RNF8 expression for the entire study population was 0.84, showing the discriminatory power of RNF8 expression in differentiating between the positive and negative groups of men with NOA. A receiver operating characteristic curve analysis showed that RNF8 expression had a sensitivity of 81% and a specificity of 84%, with a cutoff level of 1.76. CONCLUSION: This study points out a significant association between the expression of RNF8 and the presence of sperm in NOA patients, which suggests that quantified RNF8 expression in testicular biopsy samples may be a valuable biomarker for predicting the presence of spermatozoa in biopsy samples.

Some of the Factors Involved in Male Infertility: A Prospective Review.

Infertility is defined as the inability of couples to have a baby after one year of regular unprotected intercourse, affecting 10 to 15% of couples. According to the latest WHO statistics, approximately 50-80 million people worldwide sufer from infertility, and male factors are responsible for approximately 20-30% of all infertility cases. The diagnosis of infertility in men is mainly based on semen analysis. The main parameters of semen include: concentration, appearance and motility of sperm. Causes of infertility in men include a variety of things including hormonal disorders, physical problems, lifestyle problems, psychological issues, sex problems, chromosomal abnormalities and single-gene defects. Despite numerous efforts by researchers to identify the underlying causes of male infertility, about 70% of cases remain unknown. These statistics show a lack of understanding of the mechanisms involved in male infertility. This article focuses on the histology of testicular tissue samples, the male reproductive structure, factors affecting male infertility, strategies available to find genes involved in infertility, existing therapeutic methods for male infertility, and sperm recovery in infertile men.

Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia.

BACKGROUND: Tudor domain-containing proteins (TDRDs) play a critical role in piRNA biogenesis and germ cell development. piRNAs, small regulatory RNAs, act by silencing of transposons during germline development and it has recently been shown in animal model studies that defects in TDRD genes can lead to sterility in males. METHODS: Here we evaluate gene and protein expression levels of four key TDRDs (TDRD1, TDRD5, TDRD9 and TDRD12) in testicular biopsy samples obtained from men with obstructive azoospermia (OA, n = 29), as controls, and various types of non-obstructive azoospermia containing hypospermatogenesis (HP, 28), maturation arrest (MA, n = 30), and Sertoli cell-only syndrome (SCOS, n = 32) as cases. One-way ANOVA test followed by Dunnett's multiple comparison post-test was used to determine inter-group differences in TDRD gene expression among cases and controls. RESULTS: The results showed very low expression of TDRD genes in SCOS specimens. Also, the expression of TDRD1 and TDRD9 genes were lower in MA samples compared to OA samples. The expression of TDRD5 significantly reduced in SCOS, MA and HP specimens than the OA specimens. Indeed, TDRD12 exhibited a very low expression in HP specimens in comparison to OA specimens. All these results were confirmed by Western blot technique. CONCLUSION: TDRDs could be very important in male infertility, which should be express in certain stages of spermatogenesis.

Evaluation of miR-181b and miR-126-5p expression levels in T2DM patients compared to healthy individuals: Relationship with NF-κB gene expression.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder whose prevalence is rising very fast across the world. Diagnosis of this disease in early stages (pre-diabetic stage) plays an important role in reducing mortality associated with this disorder. miRNAs, as key players in the pathogenesis of T2DM, have been investigated in several studies. Furthermore, their expression profile changes in the early stages of diabetes mellitus in body fluids such as serum, peripheral blood, and peripheral blood mononuclear cell (PBMC) have been studied. Due to their high stability and the presence of non-invasive sensitive methods for their measurement, such as real-time PCR, they can be used for early diagnosis of T2DM as a biomarker. In this experimental study, the expression levels of miR-181b, miR-126-5p, and NF-κB were measured in patients with T2DM, pre-diabetic subjects, and healthy controls in a Yazd population. MATERIAL AND METHOD: Ninety asymptomatic subjects including 30 T2DM, 30 pre-diabetic, and 30 healthy subjects (diagnosis based on WHO criteria) were included in this study. Real-time PCR was used to measure the expression levels of miR-181b and miR-126-5p. Moreover, the NF-κB expression level was also measured to determine its relationship with these two microRNAs. RESULT: In this study, the expression level of miR-181b and miR-126-p decreased gradually in pre-diabetic as well as T2DM subjects compared to healthy controls. Furthermore, our study showed a significant negative correlation between these two miRNAs and NF-κB for the first time. CONCLUSION: These results introduce these anti-inflammatory miRNAs as powerful tools for early diagnosis of T2DM.