Quercetin Mitigates Lysophosphatidylcholine (LPC)-Induced Neutrophil Extracellular Traps (NETs) Formation through Inhibiting the P2X7R/P38MAPK/NOX2 Pathway.

Neutrophil extracellular traps (NETs) are three-dimensional reticular structures that release chromatin and cellular contents extracellularly upon neutrophil activation. As a novel effector mechanism of neutrophils, NETs possess the capacity to amplify localized inflammation and have been demonstrated to contribute to the exacerbation of various inflammatory diseases, including cardiovascular diseases and tumors. It is suggested that lysophosphatidylcholine (LPC), as the primary active component of oxidized low-density lipoprotein, represents a significant risk factor for various inflammatory diseases, such as cardiovascular diseases and neurodegenerative diseases. However, the specific mechanism of NETs formation induced by LPC remains unclear. Quercetin has garnered considerable attention due to its anti-inflammatory properties, serving as a prevalent flavonoid in daily diet. However, little is currently known about the underlying mechanisms by which quercetin inhibits NETs formation and alleviates associated diseases. In our study, we utilized LPC-treated primary rat neutrophils to establish an in vitro model of NETs formation, which was subsequently subjected to treatment with a combination of quercetin or relevant inhibitors/activators. Compared to the control group, the markers of NETs and the expression of P2X7R/P38MAPK/NOX2 pathway-associated proteins were significantly increased in cells treated with LPC alone. Quercetin intervention decreased the LPC-induced upregulation of the P2X7R/P38MAPK/NOX2 pathway and effectively reduced the expression of NETs markers. The results obtained using a P2X7R antagonist/activator and P38MAPK inhibitor/activator support these findings. In summary, quercetin reversed the upregulation of the LPC-induced P2X7R/P38MAPK/NOX2 pathway, further mitigating NETs formation. Our study investigated the potential mechanism of LPC-induced NETs formation, elucidated the inhibitory effect of quercetin on NETs formation, and offered new insights into the anti-inflammatory properties of quercetin.

Identification of dietary factors that impact the gut microbiota associated with vitiligo: A Mendelian randomization study and meta-analysis.

Previous observational studies have suggested that gut microbiota might be associated with vitiligo. However, owing to the limitations in observational studies of reverse causality and confounders, it remains unclear that whether and how the causal relationships exist. The results suggested that pylum.Bacteroidetes, family.BacteroidalesS24.7, genus.LachnospiraceaeND3007, genus.Marvinbryantia are protective factors for vitiligo. Conversely, family.Lachnospiraceae, order.Burkholderiales, genus.Adlercreutzia, genus.Catenibacterium and genus.Lachnospira are risk factors for vitiligo. In addition, the causative connection between dietary factors and the gut microbiota associated with vitiligo was also investigated. The results revealed that 'alcohol intake versus 10 years pervious' results in a reduction in the abundance of genus.Lachnospiraceae ND3007 and family.BacteroidalesS24.7, bread intake leads to a reduction of genus.Marvinbryantia, 'average weekly red wine intake' is linked to a decrease in the abundance of order.Burkholderiales, tea intake is associated with an augmentation in the abundance of genus.Catenibacterium, salad/raw vegetable intake elevates the abundance of order.Burkholderiales. In summary, this Mendelian randomization study substantiates potential causal effects of gut microbiota on vitiligo. Modulating the gut microbiota through regulating dietary composition may be a novel strategy for preventing vitiligo.

Alternative splicing of CsbHLH133 regulates geraniol biosynthesis in tea plants.

Geraniol is one of the most abundant aromatic compounds in fresh tea leaves and contributes to the pleasant odor of tea products. Additionally, it functions as an airborne signal that interacts with other members of the ecosystem. To date, the regulation of the geraniol biosynthesis in tea plants remains to be investigated. In this study, a correlation test of the content of geraniol and its glycosides with gene expression data revealed that nudix hydrolase, CsNudix26, and its transcription factor, CsbHLH133 are involved in geraniol biosynthesis. In vitro enzyme assays and metabolic analyses of genetically modified tea plants confirmed that CsNudix26 is responsible for the formation of geraniol. Yeast one-hybrid, dual-luciferase reporter, and EMSA assays were used to verify the binding of CsbHLH133 to the CsNudix26 promoter. Overexpression of CsbHLH133 in tea leaves enhanced CsNudix26 expression and geraniol accumulation, whereas CsbHLH133 silencing reduced CsNudix26 transcript levels and geraniol content. Interestingly, CsbHLH133-AS, produced by alternative splicing, was discovered and proved to be the primary transcript expressed in response to various environmental stresses. Furthermore, geraniol release was found to be affected by various factors that alter the expression patterns of CsbHLH133 and CsbHLH133-AS. Our findings indicate that distinct transcript splicing patterns of CsbHLH133 regulate geraniol biosynthesis in tea plants in response to different regulatory factors.

Bridging Neurobiological Insights and Clinical Biomarkers in Postpartum Depression: A Narrative Review.

Postpartum depression (PPD) affects 174 million women worldwide and is characterized by profound sadness, anxiety, irritability, and debilitating fatigue, which disrupt maternal caregiving and the mother-infant relationship. Limited pharmacological interventions are currently available. Our understanding of the neurobiological pathophysiology of PPD remains incomplete, potentially hindering the development of novel treatment strategies. Recent hypotheses suggest that PPD is driven by a complex interplay of hormonal changes, neurotransmitter imbalances, inflammation, genetic factors, psychosocial stressors, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This narrative review examines recent clinical studies on PPD within the past 15 years, emphasizing advancements in neuroimaging findings and blood biomarker detection. Additionally, we summarize recent laboratory work using animal models to mimic PPD, focusing on hormone withdrawal, HPA axis dysfunction, and perinatal stress theories. We also revisit neurobiological results from several brain regions associated with negative emotions, such as the amygdala, prefrontal cortex, hippocampus, and striatum. These insights aim to improve our understanding of PPD's neurobiological mechanisms, guiding future research for better early detection, prevention, and personalized treatment strategies for women affected by PPD and their families.

Polycyclic aromatic hydrocarbons exposure associated with increased risk of psoriasis.

Psoriasis is considered to be multifactorial, with both genetic and environmental factors contributing to its development. Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment, originating from sources such as cigarette smoke, exhaust emissions, grilled foods, smoked foods and urban air. Researchs have established a link between PAHs exposure and autoimmune disorders; however, specific effects of PAHs on psoriasis remain underexplored. This study aims to evaluate the correlation between PAHs exposure and susceptibility to psoriasis. We analysed eight monohydroxy PAHs (1-Hydroxynaphthalene (1-NAP), 2-Hydroxynaphthalene (2-NAP), 3-Hydroxyfluorene (3-FLU), 2-Hydroxyfluorene (2-FLU), 1-Hydroxyphenanthrene (1-PHE), 1-Hydroxypyrene (1-PYR), 2-Hydroxyphenanthrene (2-PHE) and 3-Hydroxyphenanthrene (3-PHE)) in 5996 participants from the National Health and Nutrition Examination Survey (NHANES). We employed multivariate logistic regression, trend analysis, weighted quantile sum (WQS) regression and restricted cubic spline (RCS) analysis to investigate the relationship between PAHs exposure and psoriasis risk. Multivariate logistic regression and trend analysis revealed that monohydroxy PAHs, including 2-NAP, 3-FLU, 2-FLU and the mixture of 2-PHE and 3-PHE, are associated with an increased risk of psoriasis. Additionally, WQS regression showed a significant positive correlation between combined exposure to monohydroxy PAHs and psoriasis risk, with the mixture of 2-PHE and 3-PHE (47.3%) being the most influential factor. RCS regression further corroborated these findings. Specifically, 2-FLU can increase the expression of psoriasis-related inflammatory factors in HaCaT cells. In conclusion, PAHs exposure increases the risk of developing psoriasis. Efforts to reduce PAHs levels in the environment and minimise exposure are crucial for public health strategies aimed at preventing psoriasis.

Response of comammox Nitrospira clades A and B communities to long-term fertilization and rhizosphere effects and their relative contribution to nitrification in a subtropical paddy field of China.

The recently discovered complete ammonia oxidation (comammox Nitrospira) containing clade A and clade B has further complemented our understanding of nitrification process. Nevertheless, understanding the community feature of comammox Nitrospira clades A and B and their relative contribution to nitrification in paddy rhizosphere are still in its infancy. In this study, we assessed the community diversity and structure of comammox Nitrospira clades A and B in paddy rhizosphere and bulk soils under thirty years of different fertilization strategies, i.e., non-fertilization control (CK), chemical fertilizers application (NPK), and NPK plus swine manure (NPKM), respectively. NPKM significantly increased the a-diversity (Chao1 and Shannon indices) of comammox Nitrospira clade A and altered the community structure (P < 0.05) but had little effect on clade B. A two-way analysis of variance (ANOVA) showed that the effect of long-term fertilization on soil comammox Nitrospira community and nitrification potential rate (PNR) was much greater than that of rhizosphere. Compared with NPK, soil PNR was greatly increased by 51.0% under the NPKM treatment in the rhizosphere (P < 0.05). Phylogenetic analysis showed that NPKM improved the relative abundances of sub-clade A.2.1 and sub-clade A.3.2 of the comammox clade A community, with an average increase of 212.2 and 210.4% in both rhizosphere and bulk soils relative to the NPK treatment. Soil organic matter, NH4+-N, and pH were significant soil drivers of comammox Nitrospira clades A and B community. Furthermore, linear regression and structural equation modeling clearly showed that comammox Nitrospira clade A a-diversity were significantly associated with soil PNR (P < 0.05). Our results suggest (i) that comammox Nitrospira clade A are sensitive to the organic fertilization; and (ii) that comammox Nitrospira clade A contribute more to nitrification than clade B under the long-term organic fertilized paddy soil.

Quercetin Attenuates KLF4-Mediated Phenotypic Switch of VSMCs to Macrophage-like Cells in Atherosclerosis: A Critical Role for the JAK2/STAT3 Pathway.

The objective of this study was to elucidate the protective role of quercetin in atherosclerosis by examining its effect on the phenotypic switch of vascular smooth muscle cells (VSMCs) to macrophage-like cells and the underlying regulatory pathways. Aorta tissues from apolipoprotein E-deficient (ApoE KO) mice fed a high-fat diet (HFD), treated with or without 100 mg/kg/day quercetin, were analyzed for histopathological changes and molecular mechanisms. Quercetin was found to decrease the size of atherosclerotic lesions and mitigate lipid accumulation induced by HFD. Fluorescence co-localization analysis revealed a higher presence of macrophage-like vascular smooth muscle cells (VSMCs) co-localizing with phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 3 (p-STAT3), and Krüppel-like factor 4 (KLF4) in regions of foam cell aggregation within aortic plaques. However, this co-localization was reduced following treatment with quercetin. Quercetin treatment effectively inhibited the KLF4-mediated phenotypic switch in oxidized low-density lipoprotein (ox-LDL)-loaded mouse aortic vascular smooth muscle cells (MOVAS), as indicated by decreased expressions of KLF4, LGALS3, CD68, and F4/80, increased expression of alpha smooth muscle actin (α-SMA), reduced intracellular fluorescence Dil-ox-LDL uptake, and decreased lipid accumulation. In contrast, APTO-253, a KLF4 activator, was found to reverse the effects of quercetin. Furthermore, AG490, a JAK2 inhibitor, effectively counteracted the ox-LDL-induced JAK2/STAT3 pathway-dependent switch to a macrophage-like phenotype and lipid accumulation in MOVAS cells. These effects were significantly mitigated by quercetin but exacerbated by coumermycin A1, a JAK2 activator. Our research illustrates that quercetin inhibits the KLF4-mediated phenotypic switch of VSMCs to macrophage-like cells and reduces atherosclerosis by suppressing the JAK2/STAT3 pathway.

BCL7A inhibits the progression and drug-resistance in acute myeloid leukemia.

AIMS: This study aimed to elucidate the biological roles and regulatory mechanisms of B-cell lymphoma 7 protein family member A (BCL7A) in acute myeloid leukemia (AML), particularly its interaction with polypyrimidine tract binding protein 1 (PTBP1) and the effects on cancer progression and drug resistance. METHODS: BCL7A expression levels were analyzed in AML tissues and cell lines, focusing on associations with promoter hypermethylation. Interaction with PTBP1 and effects of differential expression of BCL7A were examined in vitro and in vivo. The impacts on cell proliferation, cycle progression, apoptosis, and differentiation were studied. Additionally, the regulatory roles of BCL7A on interferon regulatory factor 7 (IRF7) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were assessed. RESULTS: BCL7A was downregulated in AML due to promoter hypermethylation and negatively regulated by PTBP1. Upregulation of BCL7A impeded AML cell growth, induced apoptosis, promoted cell differentiation, and decreased cell infiltration into lymph nodes, enhancing survival in mouse models. Overexpression of BCL7A upregulated IRF7 and downregulated HMGCS1, linking to reduced AML cell malignancy and decreased resistance to cytarabine. CONCLUSIONS: BCL7A acts as a tumor suppressor in AML, inhibiting malignant progression and enhancing drug sensitivity through the IRF7/HMGCS1 pathway. These findings suggest potential therapeutic targets for improving AML treatment outcomes.

Multi-isotopes (δD, δ18Owater, 87Sr/86Sr, δ34S and δ18Osulfate) as indicators for groundwater salinization genesis and evolution of a large agricultural drainage lake basin in Inner Mongolia, Northwest China.

Groundwater salinization, a major eco-environmental problem in arid and semi-arid areas, can accelerate soil salinization, reducing crop productivity and imbalances in ecosystem diversity. This study classified water samples collected from the Ulansuhai Lake basin into five clusters using self-organizing maps (SOM). On this basis, multiple isotopes (δ18Owater, δD, 87Sr/86Sr, δ18Osulfate and δ34S) and isotopic models (Rayleigh fractionation and Bayesian isotope mixing models) were used to identify and quantify the genesis and evolution of groundwater salinization. The results showed that the samples were brackish or saline water, and the hydrochemical types were dominated by Na + K-Cl (SO4). It has been proved that the processes associated with groundwater salinization in the Ulansuhai Lake basin were dominated by water-rock interaction and human inputs. Among them, evaporite dissolution contributed substantially to groundwater salinity. Furthermore, salt inputs from human activities cannot be negligible. Based on the model calculations, evaporite dissolution accounted for the most significant proportion of all sources, with a mean value of 53 %. In addition, human inputs from regular agricultural activities (28 % from sewage and manure and 8 % from fertilizers) constituted another vital source of groundwater salinization associated with extensive agricultural activities in the study area. This study's results can deepen our understanding of the genesis of groundwater salinization and the evolution of the agricultural drainage lake basin. This knowledge will assist the Environmental Protection Department in developing effective policies for groundwater management in the Yellow River Basin.

The potential of bacterial anti-phagocytic proteins in suppressing the clearance of extracellular vesicles mediated by host phagocytosis.

Extracellular vesicles (EVs), characterized by low immunogenicity, high biocompatibility and targeting specificity along with excellent blood-brain barrier permeability, are increasingly recognized as promising drug delivery vehicles for treating a variety of diseases, such as cancer, inflammation and viral infection. However, recent findings demonstrate that the intracellular delivery efficiency of EVs fall short of expectations due to phagocytic clearance mediated by the host mononuclear phagocyte system through Fcγ receptors, complement receptors as well as non-opsonic phagocytic receptors. In this text, we investigate a range of bacterial virulence proteins that antagonize host phagocytic machinery, aiming to explore their potential in engineering EVs to counteract phagocytosis. Special emphasis is placed on IdeS secreted by Group A Streptococcus and ImpA secreted by Pseudomonas aeruginosa, as they not only counteract phagocytosis but also bind to highly upregulated surface biomarkers αVß3 on cancer cells or cleave the tumor growth and metastasis-promoting factor CD44, respectively. This suggests that bacterial anti-phagocytic proteins, after decorated onto EVs using pre-loading or post-loading strategies, can not only improve EV-based drug delivery efficiency by evading host phagocytosis and thus achieve better therapeutic outcomes but also further enable an innovative synergistic EV-based cancer therapy approach by integrating both phagocytosis antagonism and cancer targeting or deactivation.