Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aß42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2%. Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

MSC-derived exosomes mitigate cadmium-induced male reproductive injury by ameliorating DNA damage and autophagic flux.

Cadmium, an environmental toxicant, severely impairs male reproductive functions and currently lacks effective clinical treatments. Mesenchymal stem cell-derived exosomes (MSC-Exos) are increasingly recognized as a potential alternative to whole-cell therapy for tissue injury and regeneration. This study aims to investigate the protective effects of MSC-Exos against cadmium toxicity on male reproduction. Our findings reveal that MSC-Exos treatment significantly promotes spermatogenesis, improves sperm quality, and reduces germ cell apoptosis in cadmium-exposed mice. Mechanistically, MSC-Exos dramatically mitigate cadmium-induced cell apoptosis in a spermatogonia cell line (GC-1 spg) in vitro by reducing DNA damage and promoting autophagic flux. These results suggest that MSC-Exos have a protective effect on cadmium-induced germ cell apoptosis by ameliorating DNA damage and autophagy flux, demonstrating the therapeutic potential of MSC-Exos for cadmium toxicity on male reproduction.

Y chromosome microdeletions in Chinese men with infertility: prevalence, phenotypes, and intracytoplasmic sperm injection outcomes.

BACKGROUND: The incidence of Y chromosome microdeletions varies among men with infertility across regions and ethnicities worldwide. However, comprehensive epidemiological studies on Y chromosome microdeletions in Chinese men with infertility are lacking. We aimed to investigate Y chromosome microdeletions prevalence among Chinese men with infertility and its correlation with intracytoplasmic sperm injection (ICSI) outcomes. METHODS: This single-center retrospective study included 4,714 men with infertility who were evaluated at the Reproductive Center of the First Affiliated Hospital of Sun Yat-sen University between May 2017 and January 2021. Semen analysis and Y-chromosome microdeletion via multiplex polymerase chain reaction were conducted on the men. The study compared outcomes of 36 ICSI cycles from couples with male azoospermia factor (AZF)cd deletions with those of a control group, which included 72 ICSI cycles from couples without male Y chromosome microdeletions, during the same period. Both groups underwent ICSI treatment using ejaculated sperm. RESULTS: Among 4,714 Chinese men with infertility, 3.31% had Y chromosome microdeletions. The combined deletion of sY254 and sY255 in the AZFc region and sY152 in the AZFd region was the prevalent pattern of Y chromosome microdeletion, with 3.05% detection rate. The detection rates of AZF deletions in patients with normal total sperm count, mild oligozoospermia, severe oligozoospermia, cryptozoospermia, and azoospermia were 0.17%, 1.13%, 5.53%, 71.43%, and 7.54%, respectively. Compared with the control group, the AZFcd deletion group exhibited no significant difference in the laboratory results or pregnancy outcomes of ICSI cycles using ejaculated sperm. CONCLUSIONS: This is the largest epidemiological study on Y chromosome microdeletions in Chinese men with infertility. The study results underline the necessity for detecting Y chromosome microdeletion in men with infertility and severe sperm count abnormalities, especially those with cryptozoospermia. The combined deletion of sY254 and sY255 in the AZFc region and sY152 in the AZFd region was the most prevalent Y chromosome microdeletion pattern. Among patients with AZFcd deletion and ejaculated sperm, ICSI treatment can result in pregnancy outcomes, similar to those without AZFcd deletion.

Combination of High Ligation and Intraoperative Embolization using Polidocanol for Treatment of Varicoceles.

Varicoceles are dilated veins within the pampiniform plexus and are relatively common in the general male population. The spermatic vein has many branches in the scrotal segment and then gradually merges into 1-2 trunks after passing through the internal inguinal ring. The key to a successful varicocelectomy is to ligate all the spermatic veins while protecting the testicular arteries and spermatic lymphatic vessels from damage. The small veins, including the branches of spermatic veins and collateral veins, are easily missed for ligation during conventional high ligation of varicocele, which has been suggested as a major cause of postoperative recurrence. Although microsurgery effectively reduces the risk of missing ligation of the spermatic veins during surgery, it has several shortcomings, such as long operation time and a steep learning curve. More importantly, this technique is difficult to carry out in primary hospitals due to the requirement of specialized equipment. Therefore, an attempt to modify the traditional high ligation aiming to reduce the postoperative recurrence rate has been carried out here. The protocol here combines traditional high ligation with intraoperative embolization to seal off the branches of the spermatic vein and collateral veins. We rapidly injected foamed sclerosant into the internal spermatic vein under direct observation after separation of the spermatic vein and then ligated all the veins. The foamed sclerosant through the varicose vein hampers endothelial cell growth, promotes the growth of thrombus and fibrosis, and ultimately forms fibrous streaks that permanently fill the venous. The results showed a more satisfactory effect on reducing the postoperative recurrence rate compared with traditional high ligation. Since this protocol is simple to carry out and has better results in reducing the recurrence rate, this can be an alternative surgical method for the treatment of varicocele, especially in primary hospitals.

Altered small non-coding RNA expression profiles of extracellular vesicles in the prostatic fluid of patients with chronic pelvic pain syndrome.

Chronic pelvic pain syndrome (CPPS) and chronic prostatitis (CP) is difficult to distinguish from each other, herein termed CP/CPPS. The present study aimed at gaining further insight into the change in extracellular vesicles (EVs) in the prostatic fluid of males with CPPS. From December 2019 to November 2020, after clinical screening, 24 patients with CPPS without obvious urinary symptoms and 13 healthy male participants were included. EVs were isolated from expressed prostatic secretion (EPS) of all subjects. The small non-coding ribonucleic acid (sncRNA) expression of EVs was sequenced, analyzed, and validated by quantitative real-time polymerase chain reaction (qPCR) assays. The results showed that numerous sncRNAs were differentially expressed between the patients and healthy participants. Further qPCR assays validated that several chronic pain-related miRNAs, including miR-204-5p, let-7d-3p, let-7b-3p, let-7c-3p, miR-146a-5p, and miR-320a-5p, were differentially expressed. Series sncRNAs including several chronic pain-related miRNAs were altered in EVs in prostatic fluid of patients with CPPS, which may serve as diagnostic markers for CPPS.

Inhibiting Necroptosis of Spermatogonial Stem Cell as a Novel Strategy for Male Fertility Preservation.

Fertility preservation is a common concern for male cancer survivors of reproductive age. However, except for testicular tissue cryopreservation, which is not very effective, there is no feasible and precise therapy capable of protecting spermatogenesis for prepubertal boys before or during gonadotoxic treatment. This study aims to investigate the effects of inhibiting necroptosis of spermatogonial stem cell (SSC) in fertility preservation. Male mice 12 weeks of age were used to establish gonadotoxicity with two intraperitoneal injections of busulfan at a total dose of 40 mg kg-1. The mouse model and the primary cultured mouse SSCs were used to characterize the relationship between necroptosis of SSC and gonadotoxicity. Meanwhile, the effects of an inhibitor of necroptosis pathway, RIPA-56, were observed on day 36 in the mouse model of busulfan-induced gonadotoxicity. We found that the number of SSCs was decreased, but the level of necroptosis was upregulated on day 18 after busulfan treatment in testes from gonadotoxic mice. Further experiments in primary cultured cells showed that the necroptosis caused cell death in busulfan-treated SSCs and could be inhibited by RIPA-56. After suppressing the necroptosis of SSCs, the busulfan-induced mice had a decreased loss of spermatogenic cells as shown by histology and an increased Johnsen's score. Moreover, the quantities of SSCs and epididymal spermatozoa were restored after intervention with RIPA-56, indicating a series of beneficial effects by targeting the necroptosis of SSCs in mice undergoing busulfan treatment. In conclusion, our findings reveal that the necroptosis of SSCs plays a critical role in busulfan-induced gonadotoxicity and may be a potential target for male fertility preservation.

[Oxidative stress induces damage to epididymal epithelial tight junction protein ZO-1 and impairs epididymal function in varicocele rats].

OBJECTIVE: To investigate oxidative stress-mediated damage to the epididymal epithelial tight junction protein ZO-1 and its impact on epididymal function in varicocele rats. METHODS: We randomly divided 45 male adolescent SD rats into three groups of equal number: sham operation (left renal vein exposed and isolated), experimental (left renal vein constricted and collaterals of the left spermatic vein fully ligated), and treatment (60-day intragastric administration of vitamin E at 150 mg/kg/d after modeling). At 60 days after modeling, we observed the histological changes in the left epididymis, detected the expressions of ZO-1 and other tight junction-related proteins by real-time quantitative PCR, immunohistochemistry, immunofluorescence staining and Western blotting, determined sperm motility, and measured the levels of superoxide dismutase (SOD), total antioxidant capacity (T-AOC), methylene dioxyamphetamine (MDA) and α-glucosidase (α-Glu) in the epididymal tissue of the rats. RESULTS: Compared with the rats of the sham operation group, those of the experimental group showed disorganized epithelial structure and decreased number of epithelial cells in the left epididymis, with some epithelial cells desquamated into the lumen. The expression of ZO-1 was significantly lower in the experimental than in the sham operation group (P < 0.05) but markedly upregulated after VE treatment (P < 0.05). In comparison with the sham operation group, the animals in the experimental group exhibited remarkably increased content of MDA in the epididymal tissue (ï¼»0.41 ± 0.05ï¼½ vs ï¼»1.21 ± 0.18ï¼½ nmol/mg prot, P < 0.05) but decreased levels of SOD (ï¼»814.65 ± 73.64ï¼½ vs ï¼»298.62 ± 67.84ï¼½ U/mg prot, P < 0.05), T-AOC (ï¼»0.84 ± 0.07ï¼½ vs ï¼»0.24 ± 0.04ï¼½ nmol/mg prot, P < 0.05) and α-Glu (ï¼»11.72 ± 2.72ï¼½ vs ï¼»5.82 ± 1.24ï¼½ U/mg prot, P < 0.05). VE treatment, however, remarkably reduced the content of MDA (ï¼»0.69 ± 0.12ï¼½ nmol/mg prot) and elevated the levels of SOD (ï¼»497.73 ± 48.03ï¼½ U/mg prot), T-AOC (ï¼»0.42 ± 0.06ï¼½ nmol/mg prot) and α-Glu (ï¼»9.11 ± 1.91ï¼½ U/mg prot) as compared with those in the experimental group (all P < 0.05). The percentage of progressively motile sperm was significantly lower in the experimental than in the sham operation group (ï¼»31.33 ± 6.32ï¼½% vs ï¼»71.21 ± 5.21ï¼½%, P < 0.05), but markedly increased after VE treatment (ï¼»60.68 ± 5.31ï¼½%, P < 0.05). CONCLUSIONS: Varicocele reduces the expression of the EETJ protein ZO-1 and impairs epididymal function via oxidative stress, while vitamin E can effectively upregulate the ZO-1 expression and improve epididymal function by decreasing oxidative stress in the epididymis of varicocele rats.

Up-regulated TLR2 and TLR4 expressions in liver and spleen during acute murine T. gondii infection.

Toll-like receptors (TLRs) play a central role in the pathogen clearance and pathological processes. The liver is an important innate immune organ, in which Kupffer cells and hepatocytes are important innate immune cells. However, the role of TLR2 and TLR4 in the liver caused by Toxoplasma gondii infection remains less clear. In this study, mice were infected with T. gondii RH strain and the grades of liver and spleen injuries were histopathologically evaluated. TLR2+ and TLR4+ cells in the livers and spleens were detected by immunohistochemistry, and their messenger RNA (mRNA) expressions were detected using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The pathological severities in the livers and spleens were increased with time in T. gondii-infected mice. Compared with uninfected controls, obvious TLR2+ and TLR4+ cells were observed in the livers and spleens infected with T. gondii at 8 days post-infection, accompanied with significantly over-expressed mRNA levels of TLR2 and TLR4 in the livers and spleens after infection. Our data indicated that increased levels of TLR2 and TLR4 in the liver and spleen may play an important role during acute T. gondii infection.