The vacuolar-type H+-translocating ATPase (V-ATPase) plays a pivotal role in cellular homeostasis by acidifying endosomes and lysosomes, regulating key processes such as autophagy and membrane trafficking. While the importance of V-ATPase in these functions is well-established, the methodologies for studying its assembly and function remain varied and under-characterized. In this study, we systematically validated and compared methodologies for assessing V-ATPase assembly and endo/lysosomal acidification under physiological and high-fat conditions, both in vitro and in vivo. Various techniques, including fractionation, immunoprecipitation, immunofluorescence microscopy, and proximity ligation assays, were evaluated using cardiomyocyte cell lines, rat models of lipid overload, and two heart-specific V-ATPase-knockout mouse models (V-ATPase subunits ATP6V1G1 and ATP6V0D2). High palmitate (HP) and bafilomycin A1 (BafA) were used to manipulate v-ATPase function, while a colorimetric assay assessed proton-pumping activity. Results consistently showed that HP and BafA induced V-ATPase disassembly and inhibited proton-pumping activity, leading to impaired endo/lysosomal acidification and autophagy inhibition upon fusion of autophagosomes with lysosomes. Similar findings were observed in vivo, where a high-fat diet (HFD) reproduced the effects of HP on cardiac tissue. The methodologies were further validated in two heart-specific V-ATPase-knockout mouse models, demonstrating consistent outcomes across different experimental approaches. This study establishes a robust framework for evaluating V-ATPase assembly and function. The validated methodologies reveal that lipid overload inhibits autophagy and contributes to insulin resistance by inducing V-ATPase disassembly and subsequent lysosomal dysfunction. These findings offer insights into the molecular mechanisms underlying metabolic diseases and provide valuable tools for further research.

Acute lung injury (ALI) and its severe phenotype, acute respiratory distress syndrome (ARDS), represent devastating and highly lethal respiratory disorders. Hallmarked by unrestrained pulmonary inflammation predominantly driven by myeloid cells, these conditions ultimately culminate in profound disruption of the alveolar-capillary barrier. The reciprocal crosstalk between autophagy and inflammation and its molecular underpinnings in ALI pathogenesis remain incompletely defined. The role of myeloid Becn1 in maintaining pulmonary homeostasis and modulating susceptibility to lipopolysaccharide (LPS)-induced ALI was defined, and the potential link between intestinal barrier integrity, gut microbiota, and ALI severity was further interrogated. The expression of BECN1 in bronchoalveolar lavage fluid (BALF) cells from patients with ARDS and in lung tissues of mice with LPS-induced ALI was detected by western blot and immunofluorescence respectively. Myeloid cell-specific Becn1 conditional knockout (cKO) mice were generated. Parallel analyses were performed in both steady-state and LPS-challenged mice, including quantitative lung histopathological analysis, inflammatory cytokine profiling of BALF, bulk RNA sequencing of lung tissue, histological assessment of intestinal architecture and intestinal tight junction integrity, and 16S rRNA gene sequencing of fecal microbiota. Myeloid Becn1 deficiency alone was sufficient to disrupt pulmonary homeostasis, leading to spontaneous lung injury characterized by increased alveolar-capillary permeability, inflammatory cell infiltration, and aberrant activation of immune-inflammatory pathways. When challenged with LPS, these pre-existing inflammatory priming effects translated to exacerbated pulmonary pathology and exaggerated cytokine storm. Beyond the lung, Becn1 cKO mice developed spontaneous intestinal barrier dysfunction and gut microbiota dysbiosis at steady state, including blunted intestinal villi, reduced goblet cells, impaired tight junction integrity, increased mast cell infiltration, and a characteristic microbial shift with depleted Actinobacteria and expanded Alistipes. All these intestinal and microbial perturbations were likely further amplified by LPS challenge, consistent with a potential association between intestinal-microbial dysregulation and exacerbated pulmonary injury. Myeloid Becn1 governs pulmonary-intestinal immune homeostasis, and its deficiency drives spontaneous lung injury, hyperinflammation, impaired gut-lung crosstalk, and exacerbated acute lung injury, establishing myeloid Becn1 as a critical determinant of acute lung injury severity.

Inhalation exposure to plastic particles has raised widespread concern for lung health. This study aimed to systematically evaluate the effects of inhaled polystyrene nanoparticles (PS-NPs, 50 nm) and polystyrene microparticles (PS-MPs, 1 μm) on pulmonary inflammation and lung function in healthy mice, and further investigate the superimposed effects of prior particle exposure on the severity of acute lung injury (ALI). Healthy mice underwent inhalation exposure to PS-NPs or PS-MPs (15 mg/kg, once daily for 14 days). Both types of particles induced mild pulmonary inflammatory infiltration (increased bronchoalveolar lavage fluid inflammatory cells, lung tissue CD68+ cell infiltration, mild alveolar septal thickening, and pulmonary interstitial inflammatory cell infiltration). Pulmonary function testing revealed that PS-NPs induced compensatory ventilatory enhancement, significantly reduced lung compliance, and impaired parenchymal elasticity, whereas PS-MPs primarily caused large airway obstructive dysfunction and elevated small airway resistance, with overall lung function impairment being more severe than that induced by PS-NPs. Using an LPS-induced ALI mouse model to assess the superimposed effects of prior exposure, the results showed that PS-MPs pre-exposure significantly exacerbated LPS-induced inflammatory cell infiltration, upregulation of pro-inflammatory cytokines (Il1β, Il6, and Tnfa), and destruction of lung tissue structure, while synergistically aggravating comprehensive pulmonary dysfunction across baseline ventilation, static lung volume, lung elasticity, and both large and small airway function. In contrast, PS-NPs pre-exposure exhibited weaker superimposed effects compared to PS-MPs. These findings highlight the need for a deeper understanding of the size-dependent toxicity of inhalable plastic particles and warn of the health risks.

The gut-lung axis is involved in acute lung injury (ALI) and its fatal sequela, acute respiratory distress syndrome (ARDS), yet the molecular mechanisms governing this crosstalk remain poorly defined. Untargeted metabolomics of plasma revealed significant dysregulation of tryptophan metabolism in ARDS patients compared to healthy controls. Murine dietary interventions demonstrated that high tryptophan intake alleviated ALI severity, whereas deficiency exacerbated injury, with protection being gut microbiota dependent. 16S ribosomal RNA (16S rRNA) gene sequencing revealed marked depletion of a functionally central bacterium Lactobacillus johnsonii (L. johnsonii) during ALI. Supplementation with L. johnsonii or its encapsulated form attenuated ALI, but this required dietary tryptophan sufficiency. Mechanistically, L. johnsonii converts tryptophan into oxindole, which enters pulmonary macrophages, promotes the aryl hydrocarbon receptor-RelA binding, and thereby suppresses RelA-mediated transcriptional activation of C-X-C motif chemokine 13 (CXCL13). Both genetic ablation and pharmacological inhibition of CXCL13 ameliorated ALI symptoms. Importantly, oxindole and CXCL13 levels correlated with ARDS severity in patients, suggesting their clinical relevance. Collectively, these findings define a protective microbiota-dependent gut-lung axis in ALI/ARDS that is mediated by dietary tryptophan-derived oxindole, which acts at least partially through CXCL13 suppression to underscore targetable diet-microbe-metabolite therapeutic paradigms.

Air pollution (AP), intensified by industrialization and urbanization, is a key environmental factor linked to rheumatoid arthritis (RA). However, its molecular and immunological impact on RA remains unclear. This study integrates epidemiological data, bioinformatics, single-cell transcriptomics, and animal models to investigate how AP contributes to the development of RA. Global epidemiological analysis shows rising RA prevalence in over 95% of countries. Mendelian randomization analysis indicated a positive correlation between PM10 exposure and the risk of RA. Machine learning identifies Formin Binding Protein 1 (FNBP1) as a key air pollution-related gene (APRG), with decreasing expression in RA patients and strong correlation with disease activity. PM10 exposure may impair natural killer (NK) cell differentiation and cytotoxicity by suppressing FNBP1 expression, ultimately weakening immune surveillance and exacerbating inflammatory responses. Furthermore, by integrating single-cell sequencing, animal models, and human-derived cell experiments, we demonstrated that PM10 exposure aggravates inflammation and joint damage in a collagen-induced arthritis (CIA) model. Mechanistically, PM10 likely impairs the cytotoxic function of CD56dim NK cells through the modulation of FNBP1. Taken together, our research results have unveiled a completely novel mechanistic hypothesis regarding the onset and development of RA, the "PM10-FNBP1-NK cells" axis.

IntroductionThe gut-lung axis plays a critical role in the pathogenesis of acute lung injury (ALI). While intestinal microbiota, particularly Akkermansia muciniphila (AKK), has been linked to the regulation of ALI in adult murine model, its impact on juvenile hosts, who exhibit heightened susceptibility to lipopolysaccharide (LPS)-induced ALI, remains poorly understood. Moreover, despite microencapsulation enhancing the probiotic gastrointestinal survival and colonization of probiotics, the therapeutic potential of microencapsulated AKK (AKK-MC) in juvenile murine ALI has not been explored.MethodsIn this study, juvenile mice were orally gavaged with live AKK or AKK-MC for 14 days, with LPS-induced ALI established on day 11. Lung tissues were analyzed for morphological changes and inflammatory cytokine analysis. Bronchoalveolar lavage fluid (BALF) was collected for total cell counts and protein concentration. Macrophages and neutrophils infiltration in the lungs was quantified via immunofluorescence staining. Four segments of the intestinal tract (jejunum, ileum, cecum, and colon) were harvested for histological analysis using hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (AB-PAS), and toluidine blue (TBO) staining. These evaluations included measurements of villus height to crypt depth, intestinal injury scoring, and counts of goblet and mast cells.ResultsAKK-MC treatment resulted in higher fecal abundance of AKK compared to AKK group. AKK treatment attenuated LPS-induced weight loss and mitigated lung damage. This was evidenced by reduced protein concentration and cell counts in BALF, downregulation of Tnf-α and Il-1β expression, improved lung histology, and decreased macrophage infiltration and neutrophil extracellular traps formation. In the intestine, AKK treatment restored mucosal architecture, increased villus height to crypt depth ratios, maintained goblet cell populations, and reduced mast cell infiltration across intestinal segments.ConclusionThese results demonstrate that microencapsulation enhances AKK’s efficacy in ameliorating LPS-induced ALI in juvenile mice through gut microbiota modulation. This study provides a crucial foundation for the development of probiotic-based interventions in pediatric ALI.

Pulmonary inhalation of zinc oxide nanoparticles (ZnONPs) triggers metal fume fever in humans and acute lung injury (ALI) in animal experiments. Previous evidence suggests that autophagy is involved in the pathogenesis of ZnONPs-induced ALI, with BECN1/Beclin1-dependent autophagy and mitophagy playing a central role. In the present study, heterozygous-deficient (Becn1+/-) mice exhibit significantly exacerbated ALI compared to Becn1+/+ controls following ZnONPs exposure. Immunoprecipitation-mass spectrometry analysis revealed that ZnONPs remodel the BECN1 protein interactome, enriching pathways related to autophagy, mitophagy, and mitochondrial quality control. Furthermore, Becn1 haploinsufficiency disrupted autophagic progression, causing accumulation of dysfunctional mitochondria within mitophagosomes. Notably, administration of Tat-Beclin1, a cell-permeable autophagy-inducing peptide, effectively ameliorated ZnONPs-induced ALI in both Becn1+/+ and Becn1+/- mice exposed to ZnONPs. Crucially, macrophage-specific Becn1 knockout mice recapitulated the exacerbated injury phenotype, identifying myeloid BECN1 as the critical cellular protector. Mechanistically, Tat-Beclin1 restored autophagic progression and facilitated mitochondrial degradation, thereby attenuating ROS production and inflammatory cascades. These findings demonstrate that pharmacological restoration of BECN1 via Tat-Beclin1 offers a viable strategy for treating nanoparticle-induced metal fume fever and ALI.

Ferroptotic trigger waves (FTWs) mediate the long-distance propagation of transient cell-death signals across tissues, resulting in spatially correlated, large-scale cellular dysfunction and programmed demise. Blocking of FTWs represents a promising therapeutic strategy for iron accumulation-related pathologies. Based on spatial characteristics of FTWs, this study developed a nanocoupled system (Mg/Ce-MOF@MUFA-PLs) integrating "intracellular-membrane-cell population" multi-physical level to block FTWs, aiming to efficiently block FTWs through precise cellular targeting, resistance of target cell membrane lipid peroxidation, and intracellular Fe2+-Mg2+ displacement. This study employed coordination chemistry synthesis combined with short-range electrostatic interactions to prepare Mg/Ce-MOF with toxic oxygen radical scavenging enzyme activity and Fe2+-Mg2+ displacement capability; subsequently, the composite nanoparticles were coated with monounsaturated fatty acid phospholipids (MUFA-PLs) to endow them with capabilities of precise targeting and cell membranes MUFA-PLs ratio enhancing. In vitro and in vivo experiments confirmed that Mg/Ce-MOF@MUFA-PLs achieving near 100% equimolar Fe2+-Mg2+ displacement within 4 h, significantly increasing MUFA-PLs of target cell membrane and enabling efficient Mg/Ce-MOF delivery, over threefold improvement in ferroptosis resistance and redox systems compared to controls, and efficient bone mass enhancement with rapid defect healing in ovariectomized (OVX) mice/rats over 8 weeks. This FTWs-blocking strategy provides a paradigm for treating iron accumulation-related diseases.

As vital healing cells, inappropriate differentiation of tendon stem cells (TSCs) in persistent inflammation wound cause injured tendons to difficult healing, eventually developing into tendinopathy. The key inflammation cytokines Prostaglandin E2 (PGE2) and Interleukin-(IL-)6 are increased in injured tendons and the SMAD signaling pathways play key role in regulating stem cell activity. However the combined effects of PGE2 and IL-6 on TSC differentiation and the molecular mechanism in it have not been unexplored. In the current study, we found that PGE2 combined with IL-6 promote osteogenic, chondrogenic, and adipogenic differentiation of TSCs, inhibited tenogenic differentiation of TSCs, and activated the SMAD1/5/8 and SMAD2/3 signaling, while the SMAD inhibitors LDN 193,189 combined with SB431542 reversed those effects. SB431542 inhibited IL-6-induced SMAD2/3 signaling and up-regulated the phosphorylation level of SMAD1/5/8 induced by PGE2, which was consistent with the results that IL-6 inhibited PGE2-induced adipogenic differentiation of TSC. In vivo, LDN 193,189 combined with SB431542 prevented tendon injury induced by treadmill running in mice, and suppressed the expression of non-tenogenic differentiation markers and enhanced the tenogenic marker expression in injured tendons. Collectively, the present study demonstrated that PGE2 combined with IL-6 promoted non-tenogenic differentiation and inhibited tenogenic differentiation of TSCs via the SMAD1/5/8 and SMAD2/3 pathway. Additionally, we confirmed the positive effects of the SMAD inhibitors LDN193189 and SB431542 in preventing tendon injury in vivo and provide a novel strategy for preventing and treating tendon injuries.

While the pulmonary microenvironment is a complex ecosystem comprising lung epithelial cells, immune cells, interstitial cells, and blood vessels, this study specifically focuses on the epithelium-centric niche to investigate the specific effects of SiNPs. This targeted microenvironment, centered on the interaction between epithelial components and their immediate surroundings, is intricately linked to the early progression and progression of lung cancer. Due to the prominent advances in nanotechnology recently, the interactions between nanoparticles and humans are inevitable. However, the role and precise mechanism of nano-bio interactions in PEM and their contributions to lung cancer are yet to be elucidated. In this study, we unexpectedly discovered that pulmonary exposure to silicon nanoparticles (SiNPs), a significant inhaled pollutant nanoparticle which was previously involved in inflammatory and fibrosis responses in the lung, intriguingly inhibited the early progression and metastasis of lung cancer in both in vitro and in vivo models. Mechanistically, SiNPs disrupted lysosomal function in lung epithelial cells, impaired the autophagosome-lysosome degradation pathway, and reduced Extracellular vesicles (EVs)-mediated communication between lung epithelial cells and lung cancer cells. An obvious decrease in EVs and their cargo, particularly miR-296-3p, within the tumor microenvironment heightened the susceptibility of lung cancer cells to ferroptosis. Our findings suggest that pulmonary exposure to SiNPs inhibits lung cancer early progression and metastasis, with the Atg5/EVs/miR-296-3p axis playing a critical role in this process. This study offers new insights into the mechanisms linking nano-bio interaction reshaped pulmonary epithelial microenvironment and lung cancer progression.

Acute respiratory distress syndrome (ARDS) is a devastating lung condition in which injury to the alveolar epithelium and loss of mitochondrial fitness are central. The zinc transporter SLC39A1 is known to engage with mitochondria and modulate intraorganellar zinc levels. How this interaction translates into functional organelle protection, however, has not been resolved. Using an in vitro model of LPS-induced alveolar epithelial injury, we combined high-resolution imaging, biochemical assays, and mitochondrial functional analyses to investigate this relationship. These findings were extended in vivo using a murine model of LPS-induced lung injury. We found that inflammatory stress selectively recruits SLC39A1 to mitochondria. Functional studies demonstrated that SLC39A1 overexpression preserves mitochondrial integrity by maintaining ultrastructure, membrane potential, and ATP synthesis while mitigating oxidative stress. This cytoprotective role of SLC39A1 was further substantiated in an in vivo model of acute lung injury. Conversely, SLC39A1 depletion exacerbates LPS-induced damage. Mechanistically, we show that SLC39A1 is responsible for stress-triggered zinc accumulation within mitochondria. This zinc flux correlates with enhanced PINK1 protein stability, linking it to a PINK1-associated quality control mechanism. Our study thus reveals an organelle-specific defense mechanism in which inflammation-induced translocation of SLC39A1 to mitochondria facilitates zinc delivery, thereby engaging a PINK1-mediated quality control program that promotes cell survival. These insights extend our understanding of cellular adaptation in ARDS and nominate zinc transport as a potential target for mitochondrial therapy.

Vitamin B12 deficiency during pregnancy and lactation is common, yet its mechanistic impact on reproductive outcomes and offspring health remains poorly understood. Here, we show that maternal dietary vitamin B12 deprivation not only impairs maternal glucose metabolism and reproductive outcomes but also exacerbates high-fat-diet-induced obesity in offspring. These effects are mediated by gut microbiota and associated with a marked reduction of Bifidobacterium pseudolongum (B. pseudolongum) in both dams and their offspring. Maternal vitamin B12 deprivation limits early-life acquisition of B. pseudolongum in offspring during lactation, subsequently intensifying obesity and metabolic dysregulation. Early-life restoration of B. pseudolongum or its key metabolite, acetate, effectively ameliorates this aggravated obesity. Mechanistically, acetate acts through the Ffar2 receptor to upregulate Ehhadh expression. Together, these data establish that perinatal nutrition imprints long-term metabolic phenotypes in offspring via early-life acquisition of the gut microbiota, with a critical window during lactation.

Zinc transporters regulate intracellular zinc homeostasis, but their role in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remains underexplored. Here, we show that the zinc transporter SLC39A1 is highly upregulated in alveolar type II (AT2) cells from male murine ALI models and patients with ARDS. AT2-specific Slc39a1 deletion or zinc chelation exacerbates lung injury, whereas overexpression or zinc supplementation attenuates it. Notably, zinc supplementation fails to rescue Slc39a1-deficient mice, indicating SLC39A1 governs zinc uptake to control ALI. Zinc likely directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis in AT2 cells. Lc3b- or Tfe3-deficient mice show heightened lung injury, which remain unmitigated by zinc supplementation. Importantly, administration of AAV-shLc3b to AT2 Slc39a1-deficient mice did not further aggravate lung injury beyond that caused by either intervention alone. This epistatic relationship places SLC39A1 upstream of autophagy activation within a linear pathway. Collectively, we define an essential role for epithelial SLC39A1 in host defense against ALI/ARDS, which is mediated by a protective zinc-autophagy axis.

Acute lung injury (ALI) triggered by inhaled nanoparticles represents a growing clinical concern, yet the molecular mechanisms governing pulmonary vascular endothelial injury remain poorly defined. Here, we investigate the role of the MiT/TFE transcription factor family, the master regulators of autophagy-lysosomal biogenesis, in orchestrating endothelial adaptive responses to copper oxide nanoparticles (CuONPs). In human umbilical vein endothelial cells (HUVECs), CuONPs exposure induced lysosomal membrane permeabilization and oxidative stress, which triggered robust nuclear translocation of MiT/TFE factors, particularly TFE3. This activation drove a transcriptional program of autophagy-lysosomal biogenesis, promoting the clearance of damaged lysosomes and mitigating CuONPs-induced cell death. Notably, genetic silencing of TFE3 abrogated this adaptive response, exacerbating oxidative damage and cytotoxicity, while overexpression of TFE3 conferred significant protection. In a mouse model of intratracheal CuONPs instillation, pulmonary exposure activated the TFE3 pathway in vivo. Genetic ablation of Tfe3 in mice resulted in exacerbated pulmonary vascular barrier disruption, heightened inflammation, and aggravated lung injury. Conversely, pharmacological activation of autophagy-lysosomal biogenesis with the mTOR inhibitor Torin1 alleviated CuONPs-induced endothelial damage and lung inflammation, recapitulating the protective effect of TFE3 signaling. Collectively, our findings identify TFE3 as a critical regulator of endothelial homeostasis against nanoparticle-induced injury, acting through the transcriptional control of autophagy-lysosomal homeostasis. Targeting this pathway may represent a novel therapeutic strategy for nanoparticle-associated ALI.

Background:Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, with distant organ metastasis accounting for the majority of fatal outcomes. Epithelial-mesenchymal transition (EMT) plays a central role in enabling tumor cells to acquire migratory and tissue-invasive competence. Within this context, the IκB kinase β (IKKβ)/nuclear factor-kappa B (NF-κB)/Snail signaling cascade has emerged as a key regulatory hub orchestrating EMT-associated gene programs. Curcumin, a plant-derived polyphenolic compound, displays pleiotropic antitumor properties; however, the molecular basis of its capacity to restrain CRC cell motility requires further clarification. Methods:This investigation evaluated the migration-suppressive capacity of curcumin using HCT116 and SW620 CRC cell lines. Half maximal inhibitory concentration (IC50) values were derived from MTT-based cytotoxicity measurements after 48 hours of drug exposure. Cell cycle progression was characterized by flow cytometry, long-term proliferative potential was gauged through clonogenic assays, and motility was quantified using scratch wound and Transwell chamber approaches. Protein-level alterations in EMT-associated molecules [E-cadherin, N-cadherin, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF)] and constituents of the IKKβ/NF-κB/Snail signaling network were examined by immunoblotting. Results:Following 48-h curcumin exposure, IC50 values of 11.8 µM (HCT116) and 19.5 µM (SW620) were obtained. Uniform working concentrations (0, 6, 12 µM for HCT116; 0, 10, 20 µM for SW620) were applied throughout all downstream assays. Curcumin provoked cell cycle arrest and concentration-dependently reduced proliferative capacity, clonogenic survival, and migratory potential. At the protein level, E-cadherin abundance increased while N-cadherin, MMP-2, and VEGF levels declined in a dose-responsive fashion. Mechanistically, curcumin lowered IKKβ expression, attenuated NF-κB p65 phosphorylation, and down-regulated Snail protein. Conclusions:Collectively, these results indicate that curcumin curtails CRC cell migration, at least in part, through suppression of the IKKβ/NF-κB/Snail-driven EMT program, thereby providing a mechanistic rationale for its further preclinical and clinical evaluation as an adjunctive anti-metastatic approach in CRC.

Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut-brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut-brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.

Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and frequent chemoresistance. Yanghe Decoction (YHD), a traditional Chinese medicine formula, has demonstrated anti-tumor potential, but its mechanisms in OS remain unclear. In this study, we employed a network pharmacology approach to identify 67 active components and 101 OS-related targets of YHD, with core targets including AKT1, TP53, MAPK14, and CASP3, mainly enriched in the PI3K/AKT and MAPK signaling pathways. Molecular docking confirmed strong binding affinities between representative compounds and these targets. Functional experiments revealed that YHD inhibited OS cell proliferation, migration, and invasion, and promoted apoptosis by elevating intracellular reactive oxygen species levels and inducing mitochondrial dysfunction. Mechanistically, YHD suppressed the PI3K/AKT pathway while activating p38 MAPK signaling. Importantly, YHD enhanced the sensitivity of OS cells to cisplatin, demonstrating a synergistic inhibitory effect in vitro and in an orthotopic OS mouse model. These findings suggest that YHD exerts its anti-osteosarcoma effects via reactive oxygen species-mediated mitochondrial disruption and pathway modulation, and may serve as a promising adjuvant to conventional chemotherapy.

BACKGROUND:Nirmatrelvir/ritonavir, commonly known as Paxlovid, is one of the main drugs used to treat COVID-19. Neurological disorders are among the adverse drug reactions (ADRs) linked to Paxlovid, yet comprehensive data-mining studies based on real-world neurological adverse events induced by Paxlovid are lacking. METHODS:It is an observational study, to reduce the risk of bias affected by COVID-19 disease, our study included only patients with COVID-19 disease. In this case, disproportionate analysis is performed using the Report Odds Ratio (ROR) and its 95% Confidence Interval (CI). RESULTS:We screened and compared all medications associated with COVID-19 (N = 439) and found that 22 of these were linked to neurological adverse reactions. Paxlovid was associated with a threefold greater number of neurological adverse events compared to all other drugs combined (N = 11,792), with a strong signal value (ROR = 2.27). CONCLUSIONS:Compared to all other COVID-19-related drugs, Paxlovid has the highest number and stronger signal value for neurologic-related adverse reactions. Clinicians should pay special attention to female patients taking Paxlovid within the first 30 days, monitoring for symptoms such as dysgeusia, ageusia, headache, and anosmia. In addition, headache and anosmia are not uncommon occurrences as mentioned in the instructions and should be noted.