Associations between cytokines and the risk of female and male infertility: A two-sample Mendelian randomization analysis.

PURPOSE: Observational studies have linked cytokines to the occurrence of female and male infertility. However, it is not clear how biomarkers of inflammation are causally related to infertility. To explore whether genetic variants in circulating cytokines are associated with the pathogenesis of infertility, we performed two-sample Mendelian randomization (MR) analysis. METHODS: A total of 31,112 individuals of European ancestry were included in a genome-wide association study (GWAS) of 47 circulating cytokines as instrumental variables (IVs). Outcome data were female infertility, including four different subtypes, and male infertility, from the FinnGen consortium. Five MR methods, including inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were employed to examine the genetic association between cytokines and the risk of female infertility and male infertility. The false discovery rate (FDR) was controlled using the Benjamini-Hochberg method. RESULTS: After FDR correction, cis-protein quantitative trait locus (cis-pQTL) instruments showed that the cytokines GROa and MCSF were positively associated with female infertility. In analyses of subtypes of female infertility, eotaxin and sICAM were inversely associated with ovulation-related infertility; MCP3 alone was positively associated with uterus-related infertility; GROa and MCSF were positively correlated with infertility of cervical, vaginal, and other or unspecified origin; and MIP1a was negatively correlated with tubal origin infertility. The cytokines HGF, IL-2ra, and RANTES were positively correlated with male infertility. Similar findings were obtained in sensitivity analyses. There was no evidence of pleiotropy or heterogeneity in the results. CONCLUSION: These findings contribute to current understanding of the role of cytokine biomarkers in the etiology of female and male infertility. Furthermore clinical experimental validation is required to evaluate the potential of these cytokines as biomarkers.

Association between semen parameters and recurrent pregnancy loss: An umbrella review of meta-analyses.

AIM: Recurrent pregnancy loss (RPL) is a common clinical reproductive problem. With research advancements, an increasing number of studies have suggested that male factors play an important role in RPL. However, the evaluation results of male sperm quality in published meta-analyses are inconsistent. We aimed to summarize the evidence of the association between semen factors and RPL and evaluate the level and validity of the evidence. METHODS: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases for systematic reviews or meta-analyses to evaluate the association between male semen parameters and RPL. The methodological quality of the included meta-analyses was assessed, and data and evidence were re-synthesized and stratified using a random-effects model. RESULTS: Seven meta-analyses and nine semen parameters were included in the final analysis. The methodological quality of all publications was considered low or very low. There was highly suggestive evidence for the association between sperm DNA fragmentation (SDF), sperm progressive motility rate, and RPL (class II). The evidence level for the association between sperm concentration, normal sperm morphology, sperm deformity rate, total motility, and RPL was suggestive evidence (class III). The evidence level for the association between sperm volume and sperm count and RPL was weak (class IV). There was no significant association between sperm pH and RPL (class NS). CONCLUSIONS: Our results suggest level II evidence for the association between male SDF and RPL, while the evidence level for the association between conventional semen routine parameters and RPL was low (classes III and IV).

Gastric Cancer Growth Modulated by circSNTB2/miR-6938-5p/G0S2 and PDCD4.

BACKGROUND: Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. Increasing studies have indicated that circular RNAs (circRNAs) play critical roles in cancer progression. However, the precise mechanism and functions of most circRNAs are still unknown in gastric cancer. METHODS: In the present study, we aim to uncover the mechanism by which circRNAs regulate gastric cancer tumorigenesis. By analyzing the microarray data, we screened differential expressed circRNAs in the gastric cancer group and identified a down-regulated circRNA, hsa_circ_0040039 (circSNTB2). Mechanically, circSNTB2 served as a sponge for the miR-6938-5p and up-regulated its expression. RESULTS: Meanwhile, G0/G1 switch gene 2 (G0S2) and programmed cell death gene 4 (PDCD4) were identified to be the aim genes of miR-6938-5p, constructing circSNTB2/miR-6938-5p/G0S2 and PDCD4 pathways. CONCLUSION: Taken together, our findings demonstrated that circSNTB2 plays an essential role in gastric cancer by regulating miR-6938-5p through G0S2 and PDCD4 genes. CircSNTB2 could be a promising biomarker for GC diagnosis and targeted therapy.

Complete genome sequencing of a Tequintavirus bacteriophage with a broad host range against Salmonella Abortus equi isolates from donkeys.

Salmonella enterica subspecies enterica serovar abortus equi (S. Abortus equi) is the most common cause of abortion in mares. It has recently been found to cause abortion in donkeys more frequently in China. A novel virulent bacteriophage vB_SabS_Sds2 (hereafter designated as Sds2) was isolated from the feces of donkeys using a S. Abortus equi strain as a host. Phage Sds2 had an isometric polyhedral head and an uncontracted long tail, belonging to the Tequintavirus, Markadamsvirinae, Demerecviridae, Caudovirales. The genome of phage Sds2 was 114,770 bp, with a GC content of 40.26%. The genome contained 160 open reading frames (ORFs), and no ORFs were associated with pathogenicity, drug resistance, or lysogenization by sequence analysis. Both genome annotation and phylogenetic analysis indicated that phage Sds2 was highly similar to T5-like bacteriophages. Phage Sds2 could lyse 100% (30/30) of S. Abortus equi strains, 25.3% (24/95) of other serotypes of Salmonella strains, and 27.6% (8/29) of Escherichia coli strains using the double-layer agar plate method. The in vitro test showed that phage Sds2 had high bactericidal activity against S. Abortus equi at a wide range of MOIs. The in vivo test indicated that phage Sds2 had an inhibitory effect on abortion in mice challenged with S. Abortus equi. In general, phage Sds2 is a novel lytic phage with a wide host range and has the potential to prevent abortion caused by S. Abortus equi.

Effects of Changes in Osmolarity on the Biological Activity of Human Normal Nucleus Pulposus Mesenchymal Stem Cells.

The expansion and maintenance of the NPMSC (nucleus pulposus mesenchymal stem cell) phenotype are considered as potential therapeutic tools for clinical applications in intervertebral disc tissue engineering and regenerative medicine. However, the harsh microenvironment within the intervertebral disc is the main limitation of its regeneration. The osmolarity of the intervertebral disc is higher than that of other tissues, which has an important influence on the biological characteristics of NPMSCs. In this study, we observed the effect of different osmolarities on the biological characteristics of human normal NPMSCs cultured in vitro and explored the role of osmolarity in intervertebral disc degeneration. Our data demonstrated that the change in osmotic pressure has an important effect on the biological activity of NPMSCs, and this effect may occur through the P16INK4A/Rb pathway. This study provides a theoretical basis for the future treatment of intervertebral disc degeneration.

Sa12b-Modified Functional Self-Assembling Peptide Hydrogel Enhances the Biological Activity of Nucleus Pulposus Mesenchymal Stem Cells by Inhibiting Acid-Sensing Ion Channels.

Various hydrogels have been studied for nucleus pulposus regeneration. However, they failed to overcome the changes in the acidic environment during intervertebral disc degeneration. Therefore, a new functionalized peptide RAD/SA1 was designed by conjugating Sa12b, an inhibitor of acid-sensing ion channels, onto the C-terminus of RADA16-I. Then, the material characteristics and biocompatibility of RAD/SA1, and the bioactivities and mechanisms of degenerated human nucleus pulposus mesenchymal stem cells (hNPMSCs) were evaluated. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) confirmed that RAD/SA1 self-assembling into three-dimensional (3D) nanofiber hydrogel scaffolds under acidic conditions. Analysis of the hNPMSCs cultured in the 3D scaffolds revealed that both RADA16-I and RAD/SA1 exhibited reliable attachment and extremely low cytotoxicity, which were verified by SEM and cytotoxicity assays, respectively. The results also showed that RAD/SA1 increased the proliferation of hNPMSCs compared to that in culture plates and pure RADA16-I. Quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting demonstrated that the expression of collagen I was downregulated, while collagen II, aggrecan, and SOX-9 were upregulated. Furthermore, Ca2+ concentration measurement and western blotting showed that RAD/SA1 inhibited the expression of p-ERK through Ca2+-dependent p-ERK signaling pathways. Therefore, the functional self-assembling peptide nanofiber hydrogel designed with the short motif of Sa12b could be used as an excellent scaffold for nucleus pulposus tissue engineering. Moreover, RAD/SA1 exhibits great potential applications in the regeneration of mildly degenerated nucleus pulposus.

Sa12b Improves Biological Activity of Human Degenerative Nucleus Pulposus Mesenchymal Stem Cells in a Severe Acid Environment by Inhibiting Acid-Sensitive Ion Channels.

Sa12b is a wasp peptide that can inhibit acid-sensitive ion channels (ASICs). The biological effects of nucleus pulposus mesenchymal stem cells (NP-MSCs) have not been investigated. Therefore, this study investigated the effect of Sa12b on the biological activity of NP-MSCs through ASICs in the acidic environment of intervertebral disc degeneration (IVDD). In this study, NP-MSCs were isolated from the nucleus pulposus (NP) in patients who underwent lumbar disc herniation surgery, identified by flow cytometry and tertiary differentiation, and cultured in vitro in an acidic environment model of IVDD with a pH of 6.2. Proliferation, and apoptosis were observed after different Sa12b concentrations were added to P2 generation NP-MSCs. The Ca2+ influx was detected using flow cytometry and laser confocal scanning microscopy, and qPCR was used to detect the relative expression of stem cell-associated genes (Oct4, Nanog, Jag1, and Notch1), the relative expression of extracellular matrix (ECM)-associated genes (collagen II, aggrecan, and SOX-9), and the relative expression of genes encoding ASICs (ASIC1, ASIC2, ASIC3, and ASIC4). Western blotting was used to detect the protein expression of collagen II and aggrecan in different treatment groups. Cells isolated and cultured from normal NP were spindle-shaped and adherent, and they exhibited expansion in vitro. Flow cytometry results showed that the cells exhibited high expression of CD73 (98.1%), CD90 (97.5%), and CD105 (98.3%) and low expression of HLA-DR (0.93%), CD34 (2.63%), and CD45 (0.33%). The cells differentiated into osteoblasts, adipocytes, and chondrocytes. According to the International Society for Cellular Therapy criteria, the isolated and cultured cells were NP-MSCs. With an increase in Sa12b concentration, the cell proliferation rate of NP-MSCs increased, and the apoptosis rate decreased significantly, reaching the optimal level when the concentration of Sa12b was 8 µg/µl. When the Sa12b concentration was 8 µg/µl and contained the ASIC non-specific inhibitor amiloride, the Ca2+ influx was the lowest, followed by that when the Sa12b concentration was 8 µg/µl. The Ca2+ influx was the highest in the untreated control group. qPCR results showed that as the concentration of Sa12b increased, the relative expression of Oct4, Nanog, Jag1, Notch1, collagen II, aggrecan, and SOX-9 increased, while that of ASIC1, ASIC2, ASIC3, and ASIC4 decreased. The difference was statistically significant (p < 0.05). In conclusion, Sa12b can improve the biological activity of NP-MSCs in severely acidic environments of the intervertebral disc by reducing Ca2+ influx via AISC inhibition and, probably, the Notch signaling pathway. This study provides a new approach for the biological treatment of IVDD. Inhibition of AISCs by Sa12b may delay IVDD and improve low back pain.

Verbascoside attenuates experimental varicocele-induced damage to testes and sperm levels through up-regulation of the hypothalamus-pituitary-gonadal (HPG) axis.

CONTEXT: Verbascoside (VB), which is found in many medicinal plant families, exhibits biological activities in various diseases. However, its effects on varicocele (VCL)-induced damage remain unknown. OBJECTIVE: To investigate the effects and mechanism of VB on experimental rats with varicocele (VCL)-induced damage. MATERIALS AND METHODS: Sixty sexually mature male Sprague-Dawley (SD) rats were divided into six groups (n = 10): control, control-sham, VCL-vehicle (normal saline), and VCL + VB groups (50, 100, and 200 mg/kg/day, intraperitoneally). After 4 weeks of VB treatment, all animals were sacrificed, and the body and testicular weight, sperm quality parameters, histopathology, antioxidant status, and hormone levels were tested. The levels of gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone in the hypothalamus were detected by western blot. RESULTS: Compared with the VCL-vehicle group (41.14%), administration of VB significantly increased the sperm viability (59.29, 65.45, 84.93%). VB groups showed higher Johnson's score (3.57 ± 0.15, 4.71 ± 0.26, 7.93 ± 0.37) than VCL-vehicle group (2.72 ± 0.24). Antioxidant status and hormone levels alterations were also observed. Meanwhile, the mean number of apoptotic tubules (8.15 ± 0.96, 6.61 ± 1.05, 2.17 ± 0.08) and apoptotic index showed a marked decrease. Compared with the VCL-vehicle group (0.21 ± 0.09), the VB groups (0.36 ± 0.07, 0.42 ± 0.06, 0.88 ± 0.10) showed considerable increases in GnRH. DISCUSSION AND CONCLUSIONS: VB has protective effects on reproductive organs and VB may be therapeutically useful in the treatment of varicocele through up-regulation of the HPG axis.