Inflammatory cytokines may mediate the causal relationship between gut microbiota and male infertility: a bidirectional, mediating, multivariate Mendelian randomization study.

Introduction: Studies have shown that the gut microbiota is associated with male infertility (MI). However, their causal relationship and potential mediators need more evidence to prove. We aimed to investigate the causal relationship between the gut microbiome and MI and the potential mediating role of inflammatory cytokines from a genetic perspective through a Mendelian randomization approach. Methods: This study used data from genome-wide association studies of gut microbes (Mibiogen, n = 18, 340), inflammatory cytokines (NFBC1966, FYPCRS, FINRISK 1997 and 2002, n=13, 365), and male infertility (Finngen, n=120, 706) to perform two-way Mendelian randomization (MR), mediated MR, and multivariate MR(MVMR) analyses. In this study, the inverse variance weighting method was used as the primary analysis method, and other methods were used as supplementary analysis methods. Results: In the present study, two gut microbes and two inflammatory cytokines were found to have a potential causal relationship with MI. Of the two gut microorganisms causally associated with male infertility, Anaerotruncus increased the risk of male infertility (odds ratio = 1.81, 95% confidence interval = 1.18-2.77, P = 0.0062), and Bacteroides decreased the risk of male infertility (odds ratio = 0.57, 95% confidence interval = 0.33-0.96, P = 0.0363). In addition, of the two inflammatory cytokines identified, hepatocyte growth factor(HGF) reduced the risk of male infertility (odds ratio = 0.50, 95% confidence interval = 0.35-0.71, P = 0.0001), Monocyte chemotactic protein 3 (MCP-3) increased the risk of male infertility (odds ratio = 1.28, 95% confidence interval = 1.03-1.61, P = 0.0039). Mediated MR analysis showed that HGF mediated the causal effect of Bacteroides on MI (mediated percentage 38.9%). Multivariate MR analyses suggest that HGF may be one of the pathways through which Bacteroides affects MI, with other unexplored pathways. Conclusion: The present study suggests a causal relationship between specific gut microbiota, inflammatory cytokines, and MI. In addition, HGF may mediate the relationship between Bacteroides and MI.

High Dietary Inflammatory Index increases the risk of female infertility: An analysis of NHANES 2013-2018.

Diet-related inflammation, which can be evaluated using the dietary inflammatory index (DII), is increasingly related to female infertility. However, studies on the association between DII and infertility are limited. In this study, we aim to explore the association between DII and infertility and its dose-effect relationship among women aged 20 to 45 years through a cross-sectional analysis of the National Health and Nutrition Examination Survey 2013-2018. A total of 2613 women aged 20 to 45 years were included and analyzed. The DII was calculated using the first 24-hour dietary recall interview data and divided into quartiles. Weighted multivariable logistic regression and restricted cubic spline analysis were used to explore the relationship between DII and infertility. The odds ratio (OR) (95% confidence interval [CI]) for the association between DII and infertility was 1.06 (0.96-1.19) after multivariable adjustment. Compared with the first quartile (anti-inflammatory diet), the fourth quartile of DII (pro-inflammatory diet) was more strongly associated with an increased risk of infertility, with an OR of 1.61 (95% CI, 1.05-2.47). Restricted cubic splines showed a J-shaped nonlinear association between DII and infertility (P for nonlinear = .003), with a cutoff point of 2.45. When DII was higher than 2.45, the OR for infertility was 1.95 (95% CI, 1.49-2.54). Similar results were observed among the subgroup analyses. In conclusion, this study found high DII (pro-inflammatory diet) increases the risk of female infertility. DII had a J-shaped nonlinear relationship with female infertility, whose cut point is 2.45. Controlling the intake of pro-inflammatory food may be beneficial for female infertility.

Inflammatory markers are associated with infertility prevalence: a cross-sectional analysis of the NHANES 2013-2020.

BACKGROUND: Inflammation exerts a critical role in the pathogenesis of infertility. The relationship between inflammatory parameters from peripheral blood and infertility remains unclear. Aim of this study was to investigate the association between inflammatory markers and infertility among women of reproductive age in the United States. METHODS: Women aged 20-45 were included from the National Health and Nutrition Examination Survey (NHANES) 2013-2020 for the present cross-sectional study. Data of reproductive status was collected from the Reproductive Health Questionnaire. Six inflammatory markers, systemic immune inflammation index (SII), lymphocyte count (LC), product of platelet and neutrophil count (PPN), platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) were calculated from complete blood counts in mobile examination center. Survey-weighted multivariable logistic regression was employed to assess the association between inflammatory markers and infertility in four different models, then restricted cubic spline (RCS) plot was used to explore non-linearity association between inflammatory markers and infertility. Subgroup analyses were performed to further clarify effects of other covariates on association between inflammatory markers and infertility. RESULTS: A total of 3,105 women aged 20-45 was included in the final analysis, with 431 (13.88%) self-reported infertility. A negative association was found between log2-SII, log2-PLR and infertility, with an OR of 0.95 (95% CI: 0.78,1.15; p = 0.60), 0.80 (95% CI:0.60,1.05; p = 0.10), respectively. The results were similar in model 1, model 2, and model 3. Compared with the lowest quartile (Q1), the third quartile (Q3) of log2-SII was negatively correlation with infertility, with an OR (95% CI) of 0.56 (95% CI: 0.37,0.85; p = 0.01) in model 3. Similarly, the third quartile (Q3) of log2-PLR was negatively correlation with infertility, with an OR (95% CI) of 0.61 (95% CI: 0.43,0.88; p = 0.01) in model 3. No significant association was observed between log2-LC, log2-PPN, log2-NLR, log2-LMR and infertility in model 3. A similar U-shaped relationship between log2-SII and infertility was found (p for non-linear < 0.05). The results of subgroup analyses revealed that associations between the third quartile (Q3) of log2-SII, log2-PLR and infertility were nearly consistent. CONCLUSION: The findings showed that SII and PLR were negatively associated with infertility. Further studies are needed to explore their association better and the underlying mechanisms.

The involvement of MALAT1-ALKBH5 signaling axis into proliferation and metastasis of human papillomavirus-positive cervical cancer.

Infection with high-risk human papillomavirus (HPV), for example, with types 16 and 18, is closely associated with cervical cancer development, which continues to threaten women's health globally. Although HPV oncogenes have been recognized as the main cause of transformation of normal cervical epithelial cells, non-coding RNA could also be involved in the initiation and promotion of cervical cancer development. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-documented long non-coding RNA (lncRNA), has been previously reported to exert roles in HPV-positive cervical cancer; however, the detailed underlying mechanism has yet to be investigated. In the present study, high expression levels of MALAT1 in HPV-Positive Cervical Cancer cells were confirmed, and silencing MALAT1 resulted in decreased rates of cell proliferation, migration, and invasion, both in vitro and in a zebrafish xenograft tumor model. Moreover, the results obtained showed that silencing MALAT1 led to down-regulation of the N6-methyladenosine (m6A) demethylase ALKBH5 via regulating miR-141-3p expression, which caused a decrease in the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 expression, thereby suppressing cell migration and invasion. Taken together, the results obtained have suggested that the MALAT-ALKBH5 signaling axis may be activated in HPV-positive cervical cancer cells, which could contribute to cell proliferation and metastasis through the regulation of key genes, such as MMP2 or MMP9. The findings of the present study should both help to improve our understanding of the underlying tumorigenic mechanisms of HPV-positive cervical cancer and be of further use in the development of potential therapeutic drugs.

Effect of magnetic field on electroosmotic flow of viscoelastic fluids in a microchannel.

Electroosmotic flow is an efficient transportation technology driven by applying an external electric field across the microchannel, which has a great potential for future application. This work is presented to study the unsteady electroosmotic flow of viscoelastic fluids combined with a constant pressure gradient and a vertical magnetic field through a parallel plate microchannel. For the reason that the upper and bottom walls of the parallel plate microchannel in microfluidic devices can be made of different materials, this leads to different hydrophobic properties, asymmetric zeta wall potentials, and different slip boundary conditions. The Navier slip model with different slip coefficients at walls is considered. The generalized Maxwell fluid with fractional derivative is adopted for the constitutive equation of the fluid. The analytical and numerical solutions of velocity are derived by employing the integral transform method and finite difference method, respectively. Excellent agreement is found between the numerical solutions and analytical solutions. Finally, the effects of fractional parameter α , relaxation time λ , slip coefficients a and b , the ratio of wall zeta potentials Rξ , Hartmann number Ha , and electrical field strength parameter S on velocity profiles are interpreted graphically in detail.

Numerical study of electroosmotic slip flow of fractional Oldroyd-B fluids at high zeta potentials.

In this paper, an investigation of the electroosmotic flow of fractional Oldroyd-B fluids in a narrow circular tube with high zeta potential is presented. The Navier linear slip law at the walls is considered. The potential field is applied along the walls described by the nonlinear Poisson-Boltzmann equation. It's worth noting here that the linear Debye-Hückel approximation can't be used at the condition of high zeta potential and the exact solution of potential in cylindrical coordinates can't be obtained. Therefore, the Matlab bvp4c solver method and the finite difference method are employed to numerically solve the nonlinear Poisson-Boltzmann equation and the governing equations of the velocity distribution, respectively. To verify the validity of our numerical approach, a comparison has been made with the previous work in the case of low zeta potential and the excellent agreement between the solutions is clear. Then, in view of the obtained numerical solution for the velocity distribution, the numerical solutions of the flow rate and the shear stress are derived. Furthermore, based on numerical analysis, the influence of pertinent parameters on the potential distribution and the generation of flow is presented graphically.