Physiological and transcriptomic changes of zebrafish (Danio rerio) in response to Isopropylate Triphenyl Phosphate (IPPP) exposure.

Isopropylate Triphenyl Phosphate (IPPP), a novel organophosphorus flame retardant, has become a widespread environmental pollutant. However, the toxic effects and mechanisms of IPPP remain unclear. In this study, we evaluated the neurodevelopmental toxicity effects of IPPP on zebrafish embryonic development, neurobehavior, and physiological and transcriptomic changes. The results showed that IPPP induced adverse developments such as low survival rates and hatching rates, decreased body length and eye distance, and also led to increased heart rates and embryonic malformation rates. The developmental defects mainly included typical pericardial edema, eye deformities, and a reduction in the number of newborn neurons. Mitochondrial energy metabolism disorders and apoptosis of cardiomyocytes may be responsible for heart malformation. Behavioral results showed that IPPP caused abnormal changes in swimming speed, total swimming distance and trajectory, and showed a low-dose effect. In addition, the decreased activity of neurotransmitters such as acetylcholinesterase (AchE) and dopamine (DA), and the changes in genes related to the central nervous system (CNS) and metabolism pathway may be the causes of neurodevelopmental toxicity of IPPP. Meanwhile, IPPP induced oxidative stress and apoptosis, and changed the ATPase activity of zebrafish larvae by altering nuclear factor erythroid2-related factor 2 (Nrf2) and mitochondrial signaling pathways, respectively. Transcriptome sequencing results indicated that Cytochrome P450 and drug metabolism, Energy metabolism-related pathways, Glutathione metabolism, Retinoid acid (RA) and REDOX signaling pathways were significantly enriched, and most of the genes in these pathways were up-regulated after IPPP treatment, which may be new targets for IPPP-induced neurodevelopment. In summary, the results of this study provide an important reference for a comprehensive assessment of the toxic effects and health risks of the new pollutant IPPP.

Association between heavy metals exposure and risk of attention deficit hyperactivity disorder (ADHD) in children: a systematic review and meta-analysis.

Heavy metals can negatively affect children's neurodevelopment, yet the relationship between heavy metals exposure and attention deficit hyperactivity disorder (ADHD) in children remains unclear. We aimed to examine associations between exposure to five common heavy metals (lead, arsenic, mercury, cadmium, and manganese) with neurodevelopmental toxicity and the risk of ADHD in children. Online databases of PubMed, Web of Science, and Embase were searched before February 29, 2024. A total of 31 studies involving 25,258 children were included in the final analysis. Our findings revealed that lead exposure was positively associated with ADHD risk in children (OR = 1.95, 95% CI: 1.57-2.41) overall, while the associations varied among different WHO regions, with the strongest in the Americas. Sensitivity analyses revealed significant associations between arsenic (OR = 1.53, 95% CI: 1.01-2.32) and manganese (OR = 1.79, 95% CI: 1.28-2.49) exposure and ADHD risk after omitting one study. Arsenic exposure was positively associated with ADHD risk in studies conducted in the Americas and adjusted for environmental smoke exposure. Positive associations between manganese exposure and ADHD risk were also found in several subgroup analyses. No significant associations were found for mercury and cadmium exposure. Dose-response meta-analysis suggested that children with higher blood lead levels exhibited a higher probability of ADHD diagnosis. Lead exposure consistently increases the risk of ADHD in children, while arsenic and manganese exposure may be associated with ADHD under different occasions. More research is required to understand heavy metals' impact on ADHD across varying exposure levels, particularly in less contaminated regions.

Visual toxicity in zebrafish larvae following exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), triphenyl phosphate (TPhP), and isopropyl phenyl diphenyl phosphate (IPPP).

TPhP and IPPP, alternatives to PBDEs as flame retardants, have been studied for their developmental toxicity, but their visual toxicities are less understood. In this study, zebrafish larvae were exploited to evaluate the potential ocular impairments following exposure to BDE-47, TPhP, and IPPP. The results revealed a range of ocular abnormalities, including malformation, vascular issues within the eyes, and histopathological changes in the retina. Notably, the visually mediated behavioral changes were primarily observed in IPPP and TPhP, indicating that they caused more severe eye malformations and vision impairment than BDE-47. Molecular docking and MD simulations showed stronger binding affinity of TPhP and IPPP to RAR and RBP receptors. Elevated ROS and T3 levels induced by these compounds led to apoptosis in larvae eyes, and increased GABA levels induced by TPhP and IPPP hindered retinal repair. In summary, our results indicate TPhP and IPPP exhibit severer visual toxicity than BDE-47, affecting eye development and visually guided behaviors. The underlying mechanism involves disruptions in RA signaling, retinal neurotransmitters imbalance, thyroid hormones up-regulation, and apoptosis in larvae eyes. This work highlights novel insights into the need for cautious use of these flame retardants due to their potential biological hazards, thereby offering valuable guidance for their safer applications.

Analysis of the effect of thermal treatment and catalyst introduction on electrode performance in vanadium redox flow battery.

All-vanadium redox flow batteries (VRFB) have the advantages of high safety and long life, and have broad application prospects in the field of large-scale power energy storage. Low energy density is the main factor restricting its development. In this study, the carbon felt used as the electrode was pretreated in various ways to improve the performance of the vanadium redox flow battery. The pretreatment conditions of carbon felt were compared to the performance of carbon felt after treatment at different temperatures and different times. The properties of the pretreated carbon felt were investigated and their effect on cell performance was tested.Next, by introducing a noble metal catalyst into the carbon felt, the characteristics of the carbon felt were studied and the effect on the performance of the vanadium redox flow battery was investigated. It was found that Carbon felt thermal-treated at 500 °C for 2 h showed the best characteristics and had the longest charge/discharge time and the lowest resistance. The results also show that Carbon felt with catalyst introduced without PTFE(Polytetrafluoroethylene) binder showed larger BET(Brunauer-Emmett-Teller) surface area and electrical conductivity compared to PTFE mixed, and cell performance was also excellent.

Corylin alleviated sepsis-associated cardiac dysfunction via attenuating inflammation through downregulation of microRNA-214-5p.

Background: Corylin, a natural flavonoid, is isolated from the fruit of Psoralea corylifolia L. Nevertheless, the effect of corylin on sepsis-associated cardiac dysfunction is still unclear. The purpose of this study is to determine the role and mechanism of corylin in sepsis related cardiac dysfunction. Methods: Experiments were carried out on mice with lipopolysaccharide (LPS) or sepsis induced by cecal ligation and puncture (CLP) or myocardial cell sepsis induced by LPS. Results: Administration of corylin improved cardiac dysfunction induced by LPS or CLP in mice. Corylin inhibited the increases of interleukin-1 (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α in the heart of mice with LPS or CLP. LPS elevated the levels of IL-1ß, IL-6 and TNF-α in cardiomyocytes, which were inhibited by corylin treatment. Corylin attenuated the increases of microRNA (miRNA)-214-5p in the heart of mice with LPS, CLP, LPS-treated NRCMs, H9c2 and AC16 cells. Administration of miRNA-214-5p agomiR reversed the improving effects of corylin on the damaged cardiac function and the increases of IL-1ß, IL-6 and TNF-α in mice treated with LPS. Conclusion: These outcomes indicated that corylin improved sepsis-associated cardiac dysfunction by inhibiting inflammation. And corylin inhibited inflammation of sepsis by decreasing miRNA-214-5p. Downregulation of miRNA-214-5p improved sepsis-associated cardiac dysfunction and inhibited inflammatory factors.

Association between parenting styles and dyslexia in primary school students: the mediating role of home literacy environment.

Background: Despite an increasing amount of research on the relationship between parenting styles and neurodevelopmental disorders, there has been minimal focus on how parenting styles impact children's reading abilities. The aim of this study was to investigate the potential mediating role of the home literacy environment in the connection between parenting styles and dyslexia. Methods: A total of 212 primary school students from grade 2-5 were recruited for this study. The Chinese Reading Ability Test was used to screen children with dyslexia. The home literacy environment was evaluated using a structured questionnaire that measured the frequency and quality of reading-related activities between parents and children. Egna Minnen Beträffande Uppfostran questionnaire was used to assess the parenting style, including emotional warmth, rejection, overprotection, and anxious rearing. It is a self-report tool filled out by the children themselves, used to assess their perceptions of their parents' parenting styles. The structural equation modeling was carried out to evaluate the direct, indirect, and total effects of parenting styles on dyslexia. Results: Compared to control group, male children with dyslexia had lower scores in parenting styles characterized by emotional warmth, overprotecting and anxious rearing (p < 0.05), while female children with dyslexia only showed lower scores in anxious rearing (p < 0.05). Children with dyslexia lacked regular reading time (OR = 2.69, 95%CI: 1.04-6.97, p < 0.05), and have higher homework pressure compared to normal children (OR = 7.41, 95%CI: 1.45-37.82, p < 0.05). Additionally, emotional warmth, paternal overprotection and anxious rearing were negatively associated with dyslexia in children (all p < 0.05). Our findings indicate a strong correlation between dyslexia, home literacy environment, and parenting styles. In a structural equation model, the home literacy environment was identified as an independent mediator between parenting styles and dyslexia. The total effect of parenting styles on dyslexia is 0.55, with an indirect effect of 0.68 mediated by the home literacy environment. Conclusion: The findings of this study indicate that home literacy environment serves as a mediator between parenting styles and dyslexia in children. This study highlights how parenting styles influence dyslexia, offering key insights for aiding dyslexic children and guiding effective interventions.

Gestational weight trajectory and risk of adverse pregnancy outcomes among women with gestational diabetes mellitus: A retrospective cohort study.

The aim of this study was to explore gestational weight gain (GWG) trajectories and their associations with adverse pregnancy outcomes. A retrospective cohort study including 11,064 women with gestational diabetes mellitus (GDM) was conducted between 2015 and 2019 in China. The latent class trajectory model was used to identify GWG trajectories, and logistic regression was performed to examine odds ratio (OR) of pregnancy outcomes. Three trajectories of GWG were identified in these 11,604 women with GDM. Trajectory 1: 64.02% of women had sustained moderate GWG throughout pregnancy; Trajectory 2: 17.75% of women showed a high initial GWG but followed by a low GWG from the third trimester until delivery; Trajectory 3: 18.23% had low initial GWG but followed by drastic GWG from the second trimester until delivery. Compared with pregnant women with Trajectory 1, women with Trajectory 2 had a higher risk of large for gestational age (adjusted odds ratio [AOR]: 1.29, 95% confidence interval [CI]: 1.12-1.48) but at a lower risk of having hypertensive disorders of pregnancy (AOR: 0.76, 95% CI: 0.57-0.96). Women in Trajectory 3 were more likely to develop small for gestational age (AOR: 2.12, 95% CI: 1.62-2.78), low birthweight (AOR: 1.49, 95% CI: 1.07-2.08), preterm birth (AOR: 1.28, 95% CI: 1.05-1.63), caesarean section (AOR: 1.26, 95% CI: 1.112-1.42) and hypertensive disorders of pregnancy (AOR: 2.24, 95% CI: 1.82-2.76). The association of GWG trajectory with adverse pregnancy outcomes differs across prepregnancy body mass index and GWG categories. Women with a slow initial GWG but followed by drastic GWG had higher risks of adverse pregnancy outcomes. Early clinical recognition of poor GWG trajectory will contribute to early intervention in high-risk groups to minimise adverse outcomes.

Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

Identification of Synonymous Pathogenic Variants in Monogenic Disorders by Integrating Exome with Transcriptome Sequencing.

Exome sequencing is becoming a first-tier clinical diagnostic test for Mendelian diseases, drastically reducing the time and cost of diagnostic odyssey and improving the diagnosis rate. Despite its success, exome sequencing faces practical challenges in assessing the pathogenicity of numerous intronic and synonymous variants, leaving a significant proportion of patients undiagnosed. In this study, a whole-blood transcriptome database was constructed that showed the expression profile of 2981 Online Mendelian Inheritance in Man disease genes in blood samples. Meanwhile, a workflow integrating exome sequencing, blood transcriptome sequencing, and in silico prediction tools to identify and validate splicing-altering intronic or synonymous variants was proposed. Following this pipeline, seven synonymous variants in eight patients were discovered. Of these, the functional evidence of c.981G>A (PIGN), c.1161A>G (ALPL), c.858G>A (ATP6AP2), and c.1011G>T (MTHFR) have not been reported previously. RNA sequencing validation confirmed that these variants induced aberrant splicing, expanding the disease-causing variant spectrum of these genes. Overall, this study shows the feasibility of combining multi-omics data to identify splicing-altering variants, especially the power of RNA sequencing. It also reveals that synonymous variants, which often are overlooked in standard diagnostic approaches, comprise an important portion of unresolved genetic diseases.

Sulfasalazine ameliorates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress and nuclear factor-kappaB pathways.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has a high mortality rate and incidence of complications. The pathophysiology of ALI/ARDS is still not fully understood. The lipopolysaccharide (LPS)-induced mouse model of ALI has been widely used to study human ALI/ARDS. Sulfasalazine (SASP) has antibacterial and anti-inflammatory effects and is used for treating inflammatory bowel and rheumatic diseases. However, the effect of SASP on LPS-induced ALI in mice has not yet been reported. Therefore, we aimed to investigate the effect of SASP on LPS-induced ALI in mice. Mice were intraperitoneally injected with SASP 2 h before or 4 h after LPS modeling. Pulmonary pathological damage was measured based on inflammatory factor expression (malondialdehyde and superoxide dismutase levels) in the lung tissue homogenate and alveolar lavage fluid. The production of inflammatory cytokines and occurrence of oxidative stress in the lungs induced by LPS were significantly mitigated after the prophylactic and long-term therapeutic administration of SASP, which ameliorated ALI caused by LPS. SASP reduced both the production of inflammatory cytokines and occurrence of oxidative stress in RAW264.7 cells, which respond to LPS. Moreover, its mechanism contributed to the suppression of NF-κB and nuclear translocation. In summary, SASP treatment ameliorates LPS-induced ALI by mediating anti-inflammatory and antioxidant effects, which may be attributed to the inhibition of NF-κB activation and promotion of antioxidant defenses. Thus, SASP may be a promising pharmacologic agent for ALI therapy.

Transcriptome analysis revealed that short-term stress in Blattella germanica to ß-cypermethrin can reshape the phenotype of resistance adaptation.

Previous studies on insect resistance have primarily focused on resistance monitoring and the molecular mechanisms involved, while overlooking the process of phenotype formation induced by insecticide stress. In this study, we compared the expression profiles of a beta-cypermethrin (ß-CYP) resistant strain (R) and a susceptible strain (S) of Blattella germanica after ß-CYP induction using transcriptome sequencing. In the short-term stress experiment, we identified a total of 792 and 622 differentially expressed genes (DEGs) in the S and R strains. Additionally, 893 DEGs were identified in the long-term adaptation experiment. To validate the RNA-Seq data, we performed qRT-PCR on eleven selected DEGs, and the results were consistent with the transcriptome sequencing data. These DEGs exhibited down-regulation in the short-term stress group and up-regulation in the long-term adaptation group. Among the validated DEGs, CUO8 and Cyp4g19 were identified and subjected to knockdown using RNA interference. Subsequent insecticide bioassays revealed that the mortality rate of cockroaches treated with ß-CYP increased by 69.3% and 66.7% after silencing the CUO8 and Cyp4g19 genes (P<0.05). Furthermore, the silencing of CUO8 resulted in a significant thinning of the cuticle by 59.3% and 53.4% (P<0.05), as observed through transmission electron microscopy and eosin staining, in the S and R strains, respectively. Overall, our findings demonstrate that the phenotypic plasticity in response to short-term stress can reshape the adaptive mechanisms of genetic variation during prolonged exposure to insecticides. And the identified resistance-related genes, CUO8 and Cyp4g19, could serve as potential targets for controlling these pest populations.

Safety evaluation of Staphylococcus and its application in soy sauce brewing.

The strain Staphylococcus PT-1 was isolated from soy sauce mash and whole genome sequencing revealed it didn't contain drug resistance genes and virulence genes. Salt tolerance test showed that PT-1 could withstand 20% NaCl. It was inoculated into a pork broth medium. Through volatile component detection, the content of pyrazine in the fermentation broth was 0.83% pyrazine and 1.36% 2, 5-dimethylpyrazine. When the strain was applied to the brewing process of soy sauce, the contents of total nitrogen and amino acid nitrogen in the resulting product were higher than those in the control group; the contents of ammonium salt and NaCl were lower than those in the control group; the total acid content was similar. Solid phase microextraction-gas chromatography-mass spectrometry was used to detect the volatile components of two finished soy sauce products. Compared to soy sauce fermented by typical means, that added with PT-1 contained unique components, such as 2,5-dimethylpyrazine (1.8027%), 2-methylpyrazine (0.0158%), 3-ethyl-2,5-dimethylpyrazine (0.5809%), and 4-ethyl guaiacol (8.7477%). Sensory evaluation showed that the total score of PT-1-fermented soy sauce was higher than that of the control group and was characterized by full and rich flavor. These results provide new insights for improving the quality of soy sauce by using novel strains for fermentation.

Home reading environment, sociometric and demographic factors associated with dyslexia in primary school students in China: A case-control study.

Background: Developmental dyslexia (DD) has been generally recognized as a multifactorial psychological disorder in recent decades. However, studies on reading and learning environment, social and demographic factors affecting Chinese developmental dyslexia (DD) are still scarce in China. This study aims to explore multidimensional home influencing factors associated with DD before and after birth. Methods: A total of 60 dyslexic and 252 normal elementary school students graded 2-5 were recruited in Shantou, China. The Least Absolute Shrinkage and Selection Operator (LASSO) regression model was used for the social and demographic variables screening. Odds ratios (ORs) with 95 % confidence intervals (CIs) for associations between DD and related factors were estimated by multivariate logistic regression models. Results: Through LASSO regression, we ultimately identified 13 key variables, including maternal education level and family monthly income, among others. The logistic regression analyses showed that the risk of DD was higher in children with lower maternal education levels. Divergent parenting styles may be a risk factor for developing DD as opposed to consistent parenting styles (OR = 4.93, 95%CI: 1.11-21.91). Children whose mothers suffered from malnutrition during pregnancy were more likely to develop DD (OR = 10.31, 95%CI: 1.84-37.86), as well as exposure to second-hand smoking at home every day (OR = 5.33, 95%CI: 1.52-18.66). Interestingly, children's active reading (OR = 0.26, 95%CI: 0.08-0.84; OR = 0.17, 95%CI: 0.04-0.76 for "sometimes" and "often" compared to none, respectively), children having extracurricular reading fairy tale books (OR = 0.37, 95%CI: 0.15-0.90), and children having extracurricular reading composition books (OR = 0.25, 95%CI: 0.09-0.69) were significant protective factors for DD. Conclusions: Home reading environment, several educational, sociometric and demographic factors may influence the development of dyslexia. We should pay attention to these factors on the development of dyslexia, so as to provide the well social and familial environment to ensure the healthy development of children.

Industrial air pollution and low birth weight in New Mexico, USA.

In recent decades, the low birth weight (LBW) rate in New Mexico has consistently exceeded the Unites States average. Maternal exposure to air pollution during pregnancy may be a significant contributor to LBW in offspring. This study investigated the links between maternal residential exposure to air pollution from industrial sources and the risk of LBW in offspring. The analysis included 22,375 LBW cases and 233,340 controls. It focused on 14 common chemicals listed in the Toxic Release Inventory (TRI) and monitoring datasets, which have abundant monitoring samples. The Emission Weighted Proximity Model (EWPM) was used to calculate maternal air pollution exposure intensity. Adjusted odds ratios (adjORs) were calculated using binary logistic regressions to examine the association between maternal residential air pollution exposure and LBW, while controlling for potential confounders, such as the maternal age, race/ethnicity, gestational age, prenatal care, education level, consumption of alcohol during pregnancy, public health regions, child's sex, and the year of birth. Multiple comparison correction was applied using the False Discovery Rate approach. The results showed that maternal residential exposure to 1,2,4-trimethylbenzene, benzene, chlorine, ethylbenzene, and styrene had significant positive associations with LBW in offspring, with adjusted odds ratios ranging from 1.10 to 1.13. These five chemicals remained as significant risk factors after dividing the estimated exposure intensities into four categories. In addition, significant linear trends were found between LBW and maternal exposure to each of the five identified chemicals. Furthermore, 1,2,4-trimethylbenzene was identified as a risk factor to LBW for the first time. The findings of this study should be confirmed through additional epidemiological, biological, and toxicological studies.

A pruned feed-forward neural network (pruned-FNN) approach to measure air pollution exposure.

Environmental epidemiology studies require accurate estimations of exposure intensities to air pollution. The process from air pollutant emission to individual exposure is however complex and nonlinear, which poses significant modeling challenges. This study aims to develop an exposure assessment model that can strike a balance between accuracy, complexity, and usability. In this regard, neural networks offer one possible approach. This study employed a custom-designed pruned feed-forward neural network (pruned-FNN) approach to calculate the air pollution exposure index based on emission time and rates, terrain factors, meteorological conditions, and proximity measurements. The model's performance was evaluated by cross-validating the estimated exposure indexes with ground-based monitoring records. The pruned FNN can predict pollution exposure indexes (PEIs) that are highly and stably correlated with the monitored air pollutant concentrations (Spearman's rank correlation coefficients for tenfold cross-validation (mean ± standard deviation: 0.906 ± 0.028) and for random cross-validation (0.913 ± 0.024)). The predicted values are also close to the ground truth in most cases (95.5% of the predicted PEIs have relative errors smaller than 10%) when the training datasets are sufficiently large and well-covered. The pruned-FNN method can make accurate exposure estimations using a flexible number of variables and less extensive data in a less money/time-consuming manner. Compared to other exposure assessment models, the pruned FNN is an appropriate and effective approach for exposure assessment that covers a large geographic area over a long period of time.

Maternal exposure to metal components of PM2.5 and low birth weight in New Mexico, USA.

Infants with low birth weight (LBW) are more likely to have health problems than normal weight infants. In studies examining the associations between particulate matter (PM) exposures and LBW, there is a tendency to focus on PM2.5 as a whole. However, insufficient information is available regarding the effects of different components of PM2.5 on birth weight. This study identified the associations between maternal exposure to 10 metal components of PM2.5 and LBW in offspring based on small area (divided by population size) level data in New Mexico, USA, from 2012 to 2016. This study used a pruned feed-forward neural network (pruned-FNN) approach to estimate the annual average exposure index to each metal component in each small area. The linear regression model was employed to examine the association between maternal PM2.5 metal exposures and LBW rate in small areas, adjusting for the female percentage and race/ethnicity compositions, marriage status, and educational level in the population. An interquartile range increase in maternal exposure to mercury and chromium of PM2.5 increased LBW rate by 0.43% (95% confidence interval (CI): 0.18-0.68%) and 0.63% (95% CI: 0.15-1.12%), respectively. These findings suggest that maternal exposure to metal components of air pollutants may increase the risk of LBW in offspring. With no similar studies in New Mexico, this study also posed great importance because of a higher LBW rate in New Mexico than the national average. These findings provide critical information to inform further epidemiological, biological, and toxicological studies.

NMDA receptor activation induces damage of alveolar type II cells and lung fibrogenesis through ferroptosis.

Ferroptosis, a newly discovered type of regulated cell death, has been implicated in numerous human diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with poor prognosis and limited treatment options. Emerging evidence has linked ferroptosis and glutamate-determined cell fate which is considered a new light on the etiology of pulmonary fibrosis. Here, we observed that N-methyl d-aspartate receptor (NMDAR) activation promoted cell damage and iron deposition in MLE-12 cells in a dose-, time-, and receptor-dependent manner. This mediated substantial Ca2+ influx, upregulated the expression levels of nNOS and IRP1, and affected intracellular iron homeostasis by regulating the expression of iron transport-related proteins (i.e., TFR1, DMT1, and FPN). Excessive iron load promoted the continuous accumulation of total intracellular and mitochondrial reactive oxygen species, which ultimately led to ferroptosis. NMDAR inhibition reduced lung injury and pulmonary fibrosis in bleomycin-induced mice. Bleomycin stimulation upregulated the expression of NMDAR1, nNOS, and IRP1 in mouse lung tissues, which ultimately led to iron deposition via regulation of the expression of various iron metabolism-related genes. NMDAR activation initiated the pulmonary fibrosis process by inducing iron deposition in lung tissues and ferroptosis of alveolar type II cells. Our data suggest that NMDAR activation regulates the expression of iron metabolism-related genes by promoting calcium influx, increasing nNOS and IRP1 expression, and increasing iron deposition by affecting cellular iron homeostasis, ultimately leading to mitochondrial damage, mitochondrial dysfunction, and ferroptosis. NMDAR activation-induced ferroptosis of alveolar type II cells might be a key event to the initiation of pulmonary fibrosis.

Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections.

BACKGROUND: Early studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear. METHODS: 142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air-liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses. RESULTS: In this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial-mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-ß signaling. CONCLUSIONS: Our findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.

Differences in tissue-associated bacteria between metastatic and non-metastatic colorectal cancer.

Background and aims: Accumulated evidence indicates that the intestinal microbiota plays crucial roles in the initiation and progression of colorectal cancer (CRC). However, the effects of the tissue-associated microbiota on CRC metastasis are poorly defined. The aim of this study was to explore the differences in bacteria between metastatic and non-metastatic CRC tissues and identify potential bacterial species that associate with CRC metastasis. Methods: 16S rDNA amplicon high-throughput sequencing was used to test the intestinal tissue-associated microbiota in patients with metastatic CRC (n = 48) and non-metastatic CRC (n = 44). The microbial diversity and differential species were analysed by standard microbiological methods, and then the differential bacteria were confirmed by qPCR. Receiver operating characteristic (ROC) curves were plotted to evaluate the ability of the differential bacteria in predicting the metastasis of CRC. In addition, the microbial compositions of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were analysed. Results: The α- or ß-diversity of microbial community between the metastatic and non-metastatic CRC groups did not exhibit significant differences. However, some bacterial abundances between two groups showed significant differences. At the phylum level, Bacteroidota and Desulfobacterota were significantly higher in the metastatic group than in the non-metastatic group, while Proteobacteria was significantly decreased in the metastatic group. At the genus level, Bacteroides (mainly composed of Bacteroides fragilis and Bacteroides uniformis) was significantly higher in the metastatic group than in the non-metastatic group, while Streptococcus and Escherichia-Shigella were significantly decreased. The ROC curves of the selected bacteria showed area under the curve (AUC) values ranging from 0.598 to 0.69; when CEA and the selected bacteria were combined, the AUC values increased from 0.678 to 0.705. In addition, the bacterial composition of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were also different, and the differential bacteria were consistent with those between metastatic and non-metastatic CRC tumor tissues. Conclusion: The bacterial composition of tumor and tumor adjacent tissue from the metastatic CRC group was different from that of the non-metastatic CRC group; in particular, Bacteroides was increased, and Streptococcus was decreased. These findings are helpful to further reveal the mechanism of CRC metastasis and provide new ideas for the clinical diagnosis and treatment of CRC metastasis.