Gestational and Postpartum Exposure to PM2.5 Components and Glucose Metabolism in Chinese Women: A Prospective Cohort Study.

Pregnant women are physiologically prone to glucose intolerance, while the puerperium represents a critical phase for recovery. However, how air pollution disrupts glucose homeostasis during the gestational and early postpartum periods remains unclear. This prospective cohort study conducted an oral glucose tolerance test and measured the insulin levels of 834 pregnant women in Guangzhou, with a follow-up for 443 puerperae at 6-8 weeks postpartum. Residential PM2.5 and five chemical components were estimated by an established spatiotemporal model. The adjusted linear model showed that an IQR increase in gestational PM2.5 exposure was associated with an increase of 0.17 mmol/L (95% CI: 0.06, 0.28) in fasting plasma glucose (FPG) and 0.24 (95% CI: 0.05, 0.42) in the insulin resistance index. Postpartum PM2.5 exposure was linked to a 0.17 mmol/L (95% CI: 0.05, 0.28) elevation in FPG per IQR, with a strengthened association found in women with gestational diabetes (Pinteraction = 0.003). In the quantile-based g-computation model, NO3- consistently contributed to the combined effect of PM2.5 components on gestational and postpartum FPG. This study was the first to suggest that PM2.5 components were associated with exacerbated gestational insulin resistance and elevated postpartum FPG. Targeted interventions reducing the emissions of toxic PM2.5 components are essential to improving maternal glucose metabolism.

Development of an Automated Morphometric Approach to Assess Vascular Outcomes following Exposure to Environmental Chemicals in Zebrafish.

BACKGROUND: Disruptions in vascular formation attributable to chemical insults is a pivotal risk factor or potential etiology of developmental defects and various disease settings. Among the thousands of chemicals threatening human health, the highly concerning groups prevalent in the environment and detected in biological monitoring in the general population ought to be prioritized because of their high exposure risks. However, the impacts of a large number of environmental chemicals on vasculature are far from understood. The angioarchitecture complexity and technical limitations make it challenging to analyze the entire vasculature efficiently and identify subtle changes through a high-throughput in vivo assay. OBJECTIVES: We aimed to develop an automated morphometric approach for the vascular profile and assess the vascular morphology of health-concerning environmental chemicals. METHODS: High-resolution images of the entire vasculature in Tg(fli1a:eGFP) zebrafish were collected using a high-content imaging platform. We established a deep learning-based quantitative framework, ECA-ResXUnet, combined with MATLAB to segment the vascular networks and extract features. Vessel scores based on the rates of morphological changes were calculated to rank vascular toxicity. Potential biomarkers were identified by vessel-endothelium-gene-disease integrative analysis. RESULTS: Whole-trunk blood vessels and the cerebral vasculature in larvae exposed to 150 representative chemicals were automatically segmented as comparable to human-level accuracy, with sensitivity and specificity of 95.56% and 95.81%, respectively. Chemical treatments led to heterogeneous vascular patterns manifested by 31 architecture indexes, and the common cardinal vein (CCV) was the most affected vessel. The antipsychotic medicine haloperidol, flame retardant 2,2-bis(chloromethyl)trimethylenebis[bis(2-chloroethyl) phosphate], and tert-butylphenyl diphenyl phosphate ranked as the top three in vessel scores. Pesticides accounted for the largest group, with a vessel score of ≥1, characterized by a remarkable inhibition of subintestinal venous plexus and delayed development of CCV. Multiple-concentration evaluation of nine per- and polyfluoroalkyl substances (PFAS) indicated a low-concentration effect on vascular impairment and a positive association between carbon chain length and benchmark concentration. Target vessel-directed single-cell RNA sequencing of fli1a+ cells from larvae treated with λ-cyhalothrin, perfluorohexanesulfonic acid, or benzylbutyl phthalate, along with vessel-endothelium-gene-disease integrative analysis, uncovered potential associations with vascular disorders and identified biomarker candidates. DISCUSSION: This study provides a novel paradigm for phenotype-driven screenings of vascular-disrupting chemicals by converging morphological and transcriptomic profiles at a high-resolution level, serving as a powerful tool for large-scale toxicity tests. Our approach and the high-quality morphometric data facilitate the precise evaluation of vascular effects caused by environmental chemicals. https://doi.org/10.1289/EHP13214.

Environmentally Relevant Concentrations of Tetrabromobisphenol A Exposure Impends Neurovascular Formation through Perturbing Mitochondrial Metabolism in Zebrafish Embryos and Human Primary Endothelial Cells.

Tetrabromobisphenol A (TBBPA), the most extensively utilized brominated flame retardant, has raised growing concerns regarding its environmental and health risks. Neurovascular formation is essential for metabolically supporting neuronal networks. However, previous studies primarily concerned the neuronal injuries of TBBPA, its impact on the neurovascularture, and molecular mechanism, which are yet to be elucidated. In this study, 5, 30, 100, 300 µg/L of TBBPA were administered to Tg (fli1a: eGFP) zebrafish larvae at 2-72 h postfertilization (hpf). The findings revealed that TBBPA impaired cerebral and ocular angiogenesis in zebrafish. Metabolomics analysis showed that TBBPA-treated neuroendothelial cells exhibited disruption of the TCA cycle and the Warburg effect pathway. TBBPA induced a significant reduction in glycolysis and mitochondrial ATP production rates, accompanied by mitochondrial fragmentation and an increase in mitochondrial reactive oxygen species (mitoROS) production in neuroendothelial cells. The supplementation of alpha-ketoglutaric acid, a key metabolite of the TCA cycle, mitigated TBBPA-induced mitochondrial damage, reduced mitoROS production, and restored angiogenesis in zebrafish larvae. Our results suggested that TBBPA exposure impeded neurovascular injury via mitochondrial metabolic perturbation mediated by mitoROS signaling, providing novel insight into the neurovascular toxicity and mode of action of TBBPA.

High Dose of Estrogen Protects the Lungs from Ischemia-Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway.

We explored the sex difference in lung ischemia-reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.

Investigating the Nexus of NLRP3 Inflammasomes and COVID-19 Pathogenesis: Unraveling Molecular Triggers and Therapeutic Strategies.

The coronavirus disease 2019 (COVID-19) global pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been marked by severe cases demonstrating a "cytokine storm", an upsurge of pro-inflammatory cytokines in the bloodstream. NLRP3 inflammasomes, integral to the innate immune system, are speculated to be activated by SARS-CoV-2 within host cells. This review investigates the potential correlation between NLRP3 inflammasomes and COVID-19, exploring the cellular and molecular mechanisms through which SARS-CoV-2 triggers their activation. Furthermore, promising strategies targeting NLRP3 inflammasomes are proposed to mitigate the excessive inflammatory response provoked by SARS-CoV-2 infection. By synthesizing existing studies, this paper offers insights into NLRP3 as a therapeutic target, elucidating the interplay between COVID-19 and its pathophysiology. It serves as a valuable reference for future clinical approaches in addressing COVID-19 by targeting NLRP3, thus providing potential avenues for therapeutic intervention.

Mapping the Landscape of Obesity Effects on Male Reproductive Function: A Bibliometric Study.

BACKGROUND: Due to changes in lifestyle and dietary habits, the global population with obesity is increasing gradually, resulting in a significant rise in the number of individuals having obesity. Obesity is caused by an imbalance between energy intake and consumption, leading to excessive fat accumulation, which interferes with normal human metabolism. It is also associated with cardiovascular disease, metabolic syndrome, male reproductive endocrine regulation disorders, systemic and local inflammatory reactions, excessive oxidative stress, and apoptosis. All these factors can damage the internal environment for sperm generation and maturation, resulting in male sexual dysfunction, a decline in sperm quality, and lower fertility. This study analyzes the trends and priorities of the effects of obesity on male reproductive disorders from a bibliometric perspective. METHODS: This study uses the Web of Science as the statistical source, covering all time spans. Tools like Web of Science, VOSviewer, and CiteSpace are used to analyze countries, institutions, authors, journals, and keywords in the field. Total publications, total citations, and average number of citations are selected for statistics. RESULTS: The results show that the research on the impact of obesity on male reproductive function can be roughly divided into three stages: the initial stage, the slow development stage, and the rapid development stage. Our statistical scope includes 463 highly relevant articles that we have screened. We found that the journal with the most publications in this field is Andrologia, and the institution with the highest total citations is the University of Utah. The most influential countries, institutions, and authors in this field are the United States, the University of Utah, and Carrell, Douglas. Currently, research related to the impact of obesity on male reproduction focuses mainly on three aspects: biochemistry, molecular biology, and reproductive biology. The keyword explosion results indicate that sperm, obesity, and male reproduction are at the forefront and trends of future research in this field. There has been a shift from basic biochemical and molecular research to research on molecular mechanisms relying on omics technologies. However, we have observed that the number of papers published in 2022 is lower than in 2021, indicating a growth interruption during this period. Considering that this deviation may be due to the impact of the COVID-19 pandemic, it may hinder the progress of certain experiments in 2022. In recent years, China has rapidly developed research in this field. However, the average citation rate is relatively low, indicating the need for Chinese scholars to improve the quality of their articles further. Based on our research and in the context of global obesity, men are at risk of increased infertility. Addressing this issue relies on our continued research into the mechanisms of obesity-related male reproductive disorders. Over the past forty-three years, with the contributions of scientists worldwide, research in this field has flourished. CONCLUSION: The impact of obesity on male reproductive disorders has been extensively studied. Currently, research in this field primarily focuses on male sperm function, sperm quality, and the effects or mechanisms of cells on male reproduction. Future trends in this field should concentrate on the relationship between male fertility and energy metabolism, as well as the endocrine function of adipose tissue. This study comprehensively analyzes the current research status and global trends in obesity and male reproductive disorders. We also discuss the future developments in this field, making it easier for researchers to understand its developmental history, current status, and trends, providing valuable reference for effective exploration in this area.

Prickle1-driven basement membrane deposition of the iPSC-derived embryoid bodies is separable from the establishment of apicobasal polarity.

Basement membrane (BM) component deposition is closely linked to the establishment of cell polarity. Previously, we showed that Prickle1 is crucial for BM deposition and cell polarity events in tear duct elongation. To gain a deeper understanding of the intimate relationship between BM formation and cell polarity, we generated induced pluripotent stem cells (iPSCs)-derived embryoid bodies (EBs) with a basement membrane separating the visceral endoderm (VE) and inner EB cell mass. We found that Prickle1 was highly expressed in VE of the normal EBs, and the Prickle1 mutant EBs displayed severely impaired BM. Notably, the formation of the basement membrane appeared to rely on the proper microtubule network of the VE cells, which was disrupted in the Prickle1 mutant EBs. Moreover, disruption of vesicle trafficking in the VE hindered BM secretion. Furthermore, reintroducing Prickle1 in the mutant EBs completely rescued BM formation but not the apicobasal cell polarity of the VE. Our data, in conjunction with studies by others, highlight the conserved role of Prickle1 in directing the secretion of BM components of the VE cells during embryonic germ layer differentiation, even in the absence of established general polarity machinery. Our study introduces a novel system based on iPSCs-derived EBs for investigating cellular and molecular events associated with cell polarity.

Efficacy of antioxidant supplementation in improving endocrine, hormonal, inflammatory, and metabolic statuses of PCOS: a meta-analysis and systematic review.

Background and aim: A large number of recent studies have reported on the use of antioxidants in patients with polycystic ovary syndrome (PCOS). This study aimed to evaluate the antioxidant effects on PCOS. Methods: We searched PubMed, Embase, Web of Science, and The Cochrane Library to identify randomized controlled trials investigating the use of antioxidants in treating PCOS. Statistical analysis was performed using Review Manager 5.4. Stata17.0 software was used to conduct sensitivity analyses. Results: This meta-analysis included 49 articles and 62 studies. The sample comprised 1657 patients with PCOS from the antioxidant group and 1619 with PCOS from the placebo group. The meta-analysis revealed that the fasting blood glucose levels [standardized mean difference (SMD): -0.31, 95% confidence interval (CI): -0.39 to -0.22, P < 0.00001], the homeostatic model assessment of insulin resistance (SMD: -0.68, 95% CI: -0.87 to -0.50], P < 0.00001), and insulin levels (SMD: -0.68, 95% CI: -0.79 to -0.58, P < 0.00001) were significantly lower in patients with PCOS taking antioxidants than those in the placebo group. Further, total cholesterol levels (SMD: -0.38, 95% CI: -0.56 to -0.20, P < 0.001), low-density lipoprotein cholesterol levels (SMD: -0.24, 95% CI: -0.37 to -0.10, P = 0.0008), and very low-density lipoprotein levels (SMD: -0.53, 95% CI: -0.65 to -0.41, P < 0.00001) were lower in patients with PCOS taking antioxidant supplements compared with the placebo group. Total testosterone (TT) level (SMD: -0.78, 95% CI: -1.15 to -0.42, P < 0.0001), dehydroepiandrosterone level (SMD: -0.42, 95% CI: -0.58 to -0.25, P < 0.00001), and mean standard deviation modified Ferriman-Gallway (MF-G scores) (SMD: -0.63, 95% CI: -0.98 to -0.28, P = 0.0004) were lower in patients taking antioxidant supplements. C-reactive protein (CRP) levels (SMD: -0.48, 95% CI: -0.63 to -0.34, P < 0.000001), body mass index [mean difference (MD): -0.27, 95% CI: -0.50 to -0.03, P = 0.03], weight (MD: -0.73, 95% CI: -1.35 to -0.11, P = 0.02), and diastolic blood pressure (MD: -3.78, 95% CI: -6.30 to -1.26, P = 0.003) were significantly lower. Moreover, the levels of sex hormone-binding protein (SMD: 0.23, 95% CI: 0.07-0.38, P = 0.004), high-density lipoprotein cholesterol (SMD: 0.11, 95% CI: 0.01-0.20, P = 0.03), total antioxidant capacity (SMD: 0.59, 95% CI: 0.31-0.87, P < 0.0001), and quantitative insulin sensitivity index (SMD: 0.01, 95% CI: 0.01-0.02, P < 0.00001) were higher in patients with PCOS who took antioxidant supplements compared with the placebo group. Antioxidant supplements did not affect other analyzed parameters in these patients, including follicle-stimulating hormone, free androgen index, nitric oxide, glutathione, malondialdehyde, and diastolic blood pressure. Conclusions: Antioxidants are beneficial in treating PCOS. Our study might provide a new treatment strategy for patients with clinical PCOS. We hope that more high-quality studies evaluating the effects of antioxidants on patients with PCOS will be conducted in the future. Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023448088.

Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115.

STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1-/- mice and STINGN153S/WT bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1-/- mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

Recent Advances in Enterovirus A71 Infection and Antiviral Agents.

Enterovirus A71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease (HFMD) that majorly affects children. Most of the time, HFMD is a mild disease but can progress to severe complications, such as meningitis, brain stem encephalitis, acute flaccid paralysis, and even death. HFMD caused by EV-A71 has emerged as an acutely infectious disease of highly pathogenic potential in the Asia-Pacific region. In this review, we introduced the properties and life cycle of EV-A71, and the pathogenesis and the pathophysiology of EV-A71 infection, including tissue tropism and host range of virus infection, the diseases caused by the virus, as well as the genes and host cell immune mechanisms of major diseases caused by enterovirus 71 (EV-A71) infection, such as encephalitis and neurologic pulmonary edema. At the same time, clinicopathologic characteristics of EV-A71 infection were introduced. There is currently no specific medication for EV-A71 infection, highlighting the urgency and significance of developing suitable anti-EV-A71 agents. This overview also summarizes the targets of existing anti-EV-A71 agents, including virus entry, translation, polyprotein processing, replication, assembly and release; interferons; interleukins; the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase B signaling pathways; the oxidative stress pathway; the ubiquitin-proteasome system; and so on. Furthermore, it overviews the effects of natural products, monoclonal antibodies, and RNA interference against EV-A71. It also discusses issues limiting the research of antiviral drugs. This review is a systematic and comprehensive summary of the mechanism and pathological characteristics of EV-A71 infection, the latest progress of existing anti-EV-A71 agents. It would provide better understanding and guidance for the research and application of EV-A71 infection and antiviral inhibitors.

Age and light damage influence Fzd5 regulation of ocular growth-related genes.

Genetic and environmental factors can independently or coordinatively drive ocular axis growth. Mutations in FRIZZLED5 (FZD5) have been associated with microphthalmia, coloboma, and, more recently, high myopia. The molecular mechanism of how Fzd5 participates in ocular growth remains unknown. In this study, we compiled a list of human genes associated with ocular growth abnormalities based on public databases and a literature search. We identified a set of ocular growth-related genes from the list that was altered in the Fzd5 mutant mice by RNAseq analysis at different time points. The Fzd5 regulation of this set of genes appeared to be impacted by age and light damage. Further bioinformatical analysis indicated that these genes are extracellular matrix (ECM)-related; and meanwhile an altered Wnt signaling was detected. Altogether, the data suggest that Fzd5 may regulate ocular growth through regulating ECM remodeling, hinting at a genetic-environmental interaction in gene regulation of ocular axis control.

Maternal exposure to nano-titanium dioxide impedes fetal development via endothelial-to-mesenchymal transition in the placental labyrinth in mice.

BACKGROUND: Extensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal-fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5-16.5. RESULTS: TiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-ß (TGF-ß) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes. CONCLUSION: Our study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.

Bacterial diversity in primary infected root canals of a Chinese cohort: analysis of 16 S rDNA sequencing.

PURPOSE: To characterize the bacterial community in the primarily infected root canals. METHODS: A total of 13 samples were collected from the primarily infected root canals. 16 S rDNA sequencing was performed to define bacterial community. Taxonomic annotation, bacterial hierarchical structures, community richness and diversity, and inter-subject variability of the bacterial community in the root canal samples were analyzed. Gender, age, and duration of the toothache-specific bacterial community associated with the patient groups were analyzed. RESULTS: A total of 359 Species were annotated and identified in the whole study cohort. The Alpha diversity analysis showed that the species diversity and detection rate of the 13 samples were high, which reflected the authenticity of sequencing results. The Beta diversity analysis was used to compare the degree of difference between different root canal samples. The 13 samples were divided into two groups according to the results, group A was samples I1-I12, and group B was samples I13. The bacterial species of group A samples were analyzed with the clinical characteristics of patients, and it was found that gender, and duration specific differences in bacterial species, and there was no significant difference in species types among different ages of patients. CONCLUSION: There were a wide diversity and inter-subject variability in the bacterial community in the primary infected root canals. While Porphyromonas gingivalis was the most abundant species, Fusobacterium nucleatum was the most variable species in the bacterial community of the root canal. The bacterial community at different taxonomic levels varied from sample to sample, despite consistent disease diagnoses. There was gender, duration-specific differences in the bacterial species in the primary infected root canals.

Pyrroloquinoline quinone inhibits PCSK9-NLRP3 mediated pyroptosis of Leydig cells in obese mice.

Abnormal lipid metabolism and chronic low-grade inflammation are the main traits of obesity. Especially, the molecular mechanism of concomitant deficiency in steroidogenesis-associated enzymes related to testosterone (T) synthesis of obesity dominated a decline in male fertility is still poorly understood. Here, we found that in vivo, supplementation of pyrroloquinoline quinone (PQQ) efficaciously ameliorated the abnormal lipid metabolism and testicular spermatogenic function from high-fat-diet (HFD)-induced obese mice. Moreover, the transcriptome analysis of the liver and testicular showed that PQQ supplementation not only inhibited the high expression of proprotein convertase subtilisin/Kexin type 9 (PCSK9) but also weakened the NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis, which both played a negative role in T synthesis of Leydig Cells (LCs). Eventually, the function and the pyroptosis of LCs cultured with palmitic acid in vitro were simultaneously benefited by suppressing the expression of NLRP3 or PCSK9 respectively, as well the parallel effects of PQQ were affirmed. Collectively, our data revealed that PQQ supplementation is a feasible approach to protect T synthesis from PCSK9-NLRP3 crosstalk-induced LCs' pyroptosis in obese men.

Parental Exposure to Environmentally Relevant Concentrations of Bisphenol-A Bis(diphenyl phosphate) Impairs Vascular Development in Offspring through DNA/RNA Methylation-Dependent Transmission.

Bisphenol-A bis(diphenyl phosphate) (BDP) has been increasingly detected in indoor environmental and human samples. Little is known about its developmental toxicity, particularly the intergenerational effects of parental exposure. In this study, adult zebrafish were exposed to BDP at 30-30,000 ng/L for 28 days, with results showing that exposure did not cause a transfer of BDP or its metabolites to offspring. Vascular morphometric profiling revealed that parental exposure to BDP at 30 and 300 ng/L exerted significant effects on the vascular development of offspring, encompassing diverse alterations in multiple types of blood vessels. N6-Methyladenosine (m6A) methylated RNA immunoprecipitation sequencing of larvae in the 300 ng/L group revealed 378 hypomethylated and 350 hypermethylated m6A peaks that were identified in mRNA transcripts of genes crucial for vascular development, including the Notch/Vegf signaling pathway. Concomitant changes in 5 methylcytosine (m5C) DNA methylation and gene expression of m6A modulators (alkbh5, kiaa1429, and ythdf1) were observed in both parental gonads and offspring exposed to BDP. These results reveal that parental exposure to low concentrations of BDP caused offspring vascular disorders by interfering with DNA and RNA methylation, uncovering a unique DNA-RNA modification pattern in the intergenerational transmission of BDP's developmental toxicity.

Nicotinamide Mononucleotide Improves Spermatogenic Disorders in Aluminum-Exposed Rats by Modulating the Glycolytic Pathway.

This study aimed to investigate the protective effect of nicotinamide mononucleotide (NMN) on testicular spermatogenesis in aluminum chloride (AlCl3)-exposed rats and to elucidate the potential underlying mechanism. The results indicated that AlCl3-induced testicular damage, leading to reduced sperm quality, increased apoptosis, decreased cell proliferation, and impaired Sertoli cell function in rats. Additionally, glycolytic metabolism was observed to be hindered. However, after NMN treatment, there was a noticeable improvement in testicular damage among the rats, marked by increased sperm quality, reduced apoptosis, enhanced cell proliferation, improved Sertoli cell function, and an activated glycolytic metabolism. The findings of this study suggest that NMN alleviates testicular spermatogenesis impairment induced by AlCl3 exposure through the inhibition of spermatogenic cell apoptosis, promotion of spermatogenic cell proliferation, and activation of glycolytic pathways. The study contributes an experimental foundation for potential future clinical applications of NMN in cases of AlCl3-exposed spermatogenic dysfunction.

A pancancer analysis of the oncogenic role of cyclin B1 (CCNB1) in human tumors.

Aberrant levels of the G2/M cyclin cyclin B1 (gene CCNB1) have been associated with multiple cancers; however, the literature lacks a focused and comprehensive analysis of the regulation of this important regulator of cell proliferation in cancer. Through this work, we performed a pancancer analysis of the levels of CCNB1 and dissected aspects of regulation and how this correlates with cancer prognosis. We comprehensively evaluated the expression and promoter methylation of CCNB1 across 38 cancers based on RNA sequencing data obtained from the Cancer Genome Atlas (TCGA). The correlation of CCNB1 with prognosis and the tumor microenvironment was explored. Using lung adenocarcinoma data, we studied the potential upstream noncoding RNAs involved in the regulation of CCNB1 and validated the protein levels and prognostic value of CCNB1 for this disease site. CCNB1 was highly expressed, and promoter methylation was reduced in most cancers. Gene expression of CCNB1 correlated positively with poor prognosis of tumor patients, and these results were confirmed at the protein level using lung adenocarcinoma. CCNB1 expression was associated with the infiltration of T helper cells, and this further correlated with poor prognosis for certain cancers, including renal clear cell carcinoma and lung adenocarcinoma. Subsequently, we identified a specific upstream noncoding RNA contributing to CCNB1 overexpression in lung adenocarcinoma through correlation analysis, expression analysis and survival analysis. This study provides a comprehensive analysis of the expression and methylation status of CCNB1 across several forms of cancer and provides further insight into the mechanistic pathways regulating Cyclin B1 in the tumorigenesis process.

Glucose metabolism profile recorded by flash glucose monitoring system in patients with hypopituitarism during prednisone replacement.

BACKGROUND: Commonly used glucocorticoids replacement regimens in patients with hypopituitarism have difficulty mimicking physiological cortisol rhythms and are usually accompanied by risks of over-treatment, with adverse effects on glucose metabolism. Disorders associated with glucose metabolism are established risk factors of cardiovascular events, one of the life-threatening ramifications. AIM: To investigate the glycometabolism profile in patients with hypopituitarism receiving prednisone (Pred) replacement, and to clarify the impacts of different Pred doses on glycometabolism and consequent adverse cardiovascular outcomes. METHODS: Twenty patients with hypopituitarism receiving Pred replacement [patient group (PG)] and 20 normal controls (NCs) were recruited. A flash glucose monitoring system was used to record continuous glucose levels during the day, which provided information on glucose-target-rate, glucose variability (GV), period glucose level, and hypoglycemia occurrence at certain periods. Islet ß-cell function was also assessed. Based on the administered Pred dose per day, the PG was then regrouped into Pred > 5 mg/d and Pred ≤ 5 mg/d subgroups. Comparative analysis was carried out between the PG and NCs. RESULTS: Significantly altered glucose metabolism profiles were identified in the PG. This includes significant reductions in glucose-target-rate and nocturnal glucose level, along with elevations in GV, hypoglycemia occurrence and postprandial glucose level, when compared with those in NCs. Subgroup analysis indicated more significant glucose metabolism impairment in the Pred > 5 mg/d group, including significantly decreased glucose-target-rate and nocturnal glucose level, along with increased GV, hypoglycemia occurrence, and postprandial glucose level. With regard to islet ß-cell function, PG showed significant difference in homeostasis model assessment (HOMA)-ß compared with that of NCs; a notable difference in HOMA-ß was identified in Pred > 5 mg/d group when compared with those of NCs; as for Pred ≤ 5 mg/d group, significant differences were found in HOMA-ß, and fasting glucose/insulin ratio when compared with NCs. CONCLUSION: Our results demonstrated that Pred replacement disrupted glycometabolic homeostasis in patients with hypopituitarism. A Pred dose of > 5 mg/d seemed to cause more adverse effects on glycometabolism than a dose of ≤ 5 mg/d. Comprehensive and accurate evaluation is necessary to consider a suitable Pred replacement regimen, wherein, flash glucose monitoring system is a kind of promising and reliable assessment device. The present data allows us to thoroughly examine our modern treatment standards, especially in difficult cases such as hormonal replacement mimicking delicate natural cycles, in conditions such as diabetes mellitus that are rapidly growing in worldwide prevalence.

Environmentally relevant concentrations of fipronil selectively disrupt venous vessel development in zebrafish embryos/larvae.

The pesticide fipronil is widely dispersed in aquatic environments and frequently detected in the general population. Although the adverse effects on embryonic growth by fipronil exposure have been extensively documented, the early responses for its developmental toxicity are largely unknown. In the present study, we explored the sensitive targets of fipronil, focusing on vascular injury using zebrafish embryos/larvae and cultured human endothelial cells. Exposure to 5-500 µg/L fipronil at the early stage impeded the growth of sub-intestinal venous plexus (SIVP), caudal vein plexus (CVP), and common cardinal veins (CCV). The damages on venous vessels occurred at exposure to the environmentally relevant concentration as low as 5 µg/L fipronil, whereas no significant change was observed in general toxicity indexes. In contrast, vascular development of the dorsal aorta (DA) or intersegmental artery (ISA) was not affected. In addition, the mRNA levels of vascular markers and vessel type-specific function genes exhibited significant decreases in venous genes, including nr2f2, ephb4a, and flt4, but no appreciable change in arterial genes. Likewise, the more pronounced changes in cell death and cytoskeleton disruption were shown in human umbilical vein endothelial cells as compared with human aortic endothelial cells. Furthermore, molecular docking supported a stronger affinity of fipronil and its metabolites to the proteins correlated with venous development, such as BMPR2 and SMARCA4. These results reveal the heterogeneity in developing vasculature responsive to fipronil's exposure. The preferential impacts on the veins confer higher sensitivity, allowing them to be appropriate targets for monitoring fipronil's developmental toxicity.

Inflammasomes during SARS-CoV-2 infection and development of their corresponding inhibitors.

Corona Virus Disease 2019 (COVID-19) continues to be a burden for human health since its outbreak in Wuhan, China in December 2019. Recently, the emergence of new variants of concerns (VOCs) is challenging for vaccines and drugs efficiency. In severe cases, SARS-CoV-2 provokes inappropriate hyperinflammatory immune responses leading to acute respiratory distress syndrome (ARDS) and even death. This process is regulated by inflammasomes which are activated after binding of the viral spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) receptor and triggers innate immune responses. Therefore, the formation of "cytokines storm" leads to tissue damage and organ failure. NOD-like receptor family pyrin domain containing 3 (NLRP3) is the best studied inflammasome known to be activated during SARS-CoV-2 infection. However, some studies suggest that SARS-CoV-2 infection is associated with other inflammasomes as well; such as NLRP1, absent in melanoma-2 (AIM-2), caspase-4 and -8 which were mostly found during dsRNA virus or bacteria infection. Multiple inflammasome inhibitors that exist for other non-infectious diseases have the potential to be used to treat severe SARS-CoV-2 complications. Some of them have showed quite encouraging results during pre- and clinical trials. Nevertheless, further studies are in need for the understanding and targeting of SARS-Cov-2-induced inflammasomes; mostly an update of its role during the new VOCs infection is necessary. Hence, this review highlights all reported inflammasomes involved in SARS-CoV-2 infection and their potential inhibitors including NLRP3- and Gasdermin D (GSDMD)-inhibitors. Further strategies such as immunomodulators and siRNA are also discussed. As highly related to COVID-19 severe cases, developing inflammasome inhibitors holds a promise to treat severe COVID-19 syndrome effectively and reduce mortality.