m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation.

Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.

The relationship among pregnancy-related anxiety, perceived social support, family function and resilience in Chinese pregnant women: a structural equation modeling analysis.

BACKGROUND: Accumulating evidence suggests that pregnancy-related anxiety (PRA) has adverse impacts on maternity health and infant development. A substantial body of literature has documented the important influence of family function, perceived social support and resilience on PRA. However, research identifying the mediating mechanisms underlying this relationship in China are still lacking. Therefore, the current study aimed to investigate the prevalence of PRA under the three-child policy in China, and also explore the interrelationships among perceived social support, family function, resilience, and PRA. METHODS: In this cross-sectional study, a convenient sampling method was used to select 579 pregnant women who underwent prenatal examination at the maternity outpatient departments of the First Affiliated Hospital of Chongqing Medical University in China from December 2021 to April 2022. Participants were required to complete the following questionnaires: the demographic form, the Chinese Pregnancy-related Anxiety scale, the 10-item Connor-Davidson Resilience Scale, the APGAR Family Care Index Scale, and Multidimensional Scale of Perceived Social Support. Pearson correlation analysis was utilized to examine the rudimentary relationship among the study variables. Bootstrapping analyses in the structural equation modeling were applied to identify the significance of indirect effects. RESULTS: There were 41.4% of pregnant Chinese women indicating PRA. Correlational analyses indicated that perceived social support, family function and resilience were negatively associated with PRA (r = - 0.47, P < 0.01; r = - 0.43, P < 0.01; r = - 0.37, P < 0.01, respectively). The results of bootstrapping analyses demonstrated significant indirect effects of perceived social support (ß = - 0.098, 95% CI [- 0.184, - 0.021]) and family function (ß = - 0.049, 95% CI [- 0.103, - 0.011]) on PRA via resilience. CONCLUSIONS: Chinese pregnant women are suffering from high levels of PRA. Better family function and perceived social support might reduce the occurrence of PRA, as well as by the mediating effects of resilience. Healthcare providers must be concerned about PRA and perform corresponding actions to reduce it. By strengthening social support and improving family function, antenatal care providers could effectively reduce or prevent PRA. And more importantly, implementing resilience-promoting measures are also essential to relieve anxiety and support mental health in pregnant women.

The Angiotensin-Converting Enzyme Inhibitory State Promotes the Transformation of Non-Small Cell Lung Cancer Blood Supply Pattern Toward Vasculogenic Mimicry Formation.

Tumor microenvironment plays an important role in tumor proliferation, metastasis, and angiogenesis. Local RAS is a key factor to tumor proliferation and metastasis in NSCLC microenvironment, but its role on angiogenesis and VM formation remains unclear. Although overwhelming majority of previous studies suggested that VM is well established in aggressive tumor and facilitates tumor growth and metastasis, we put forward different views from another angle. We proved that status of tumor blood supply patterns, including VM channels and endothelial vessels, can dynamically exchange with each other along with local RAS fluctuations in microenvironment. Quantitatively, ACE2/ACEI promotes VM formation via Nodal/Notch4 activation; while structurally, ACE2/ACEI leads to a strong and solid structure of VM via inhibition of VE-cadherin internalization. These changes induced by ACE2/ACEI relate to relatively low metastasis rate and comforting prognoses of NSCLC patients.