Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with renal fibrosis as its core pathological hallmark. A central driver of this fibrosis is epithelial-mesenchymal transition (EMT), during which renal tubular epithelial cells transform into matrix-producing myofibroblasts. Endothelial-mesenchymal transition (EndMT) has also emerged as a critical contributor, and together with EMT, accounts for the progressive accumulation of myofibroblasts and extracellular matrix. A major clinical challenge in halting DKD progression is "metabolic memory", a phenomenon whereby renal injury persists and EMT/EndMT remain activated even after glycemic control is achieved. The molecular basis underlying this sustained activation remains incompletely understood. Emerging evidence indicates that metabolic memory is largely mediated by epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNA dysregulation. These stable epigenetic imprints maintain the persistent activation of key pro-fibrotic signaling pathways, especially TGF-β, thereby continuously driving EMT, EndMT, and excessive extracellular matrix deposition. Although targeting epigenetic regulators has shown promising anti-fibrotic effects, a systematic review that integrates how metabolic memory orchestrates both EMT and EndMT through a multi-layered epigenetic network remains lacking. This review comprehensively summarizes the epigenetic mechanisms by which metabolic memory sustains EMT and EndMT in DKD, highlights key therapeutic targets, and discusses their translational and clinical implications.

BACKGROUND: Isopimpinellin (ISOP), derived from Toddalia asiatica (L.) Lam, is thought to possess anti-inflammatory potential. However, the effects of ISOP on rheumatoid arthritis (RA) and corresponding mechanisms remain unclear. METHODS: We evaluated the therapeutic effect of ISOP on RA using the collagen-induced arthritis (CIA) rat model. Subsequently, we determined the potential mechanisms of ISOP by combining single-cell RNA sequencing of rat synovial tissue in vivo with transcriptome analysis of macrophages in vitro. Molecular docking, thermal proteome profiling, cellular thermal shift assays, and drug affinity responsive target stability were then employed to identify the molecular targets of ISOP. Finally, we validated this target and explored the interaction between macrophages and RA-fibroblast-like synoviocytes (FLS) in vitro. RESULTS: We found that ISOP improved pathological changes in CIA rats. Mechanistically, ISOP inhibited macrophage migration and M1 macrophage polarization, and downregulated Spp1 expression. Furthermore, ISOP restrained the RAS/ERK pathway in M1 macrophages. Importantly, PLCG1 is a direct target of ISOP. Silencing PLCG1 reduced the related inhibitory effects of ISOP on M1 macrophage polarization. In addition, the supernatant of macrophages treated with ISOP reduced the proliferation and activation of RA-FLS. Silencing PLCG1 eliminated the regulatory effects of ISOP in the macrophage-RA-FLS co-culture system. CONCLUSIONS: ISOP exerts its anti-RA effects by targeting PLCG1 to inhibit the production of SPP1 in M1 macrophages.

Age-related diseases (ARDs) have brought substantial ageing burdens and posed severe health challenges. However, evidence on the disease burden and risk factors of ARDs in Southeast Asia, East Asia, and Oceania is still insufficient over a long period. Data on the 310 diseases and injuries were retrieved and obtained from the Global Burden of Disease Study 2023. Based on the regional incidence or prevalence rates among individuals aged 25 years and older, a two-step regression framework was applied to identify ARDs. The disease burden and risk factors of ARDs were measured. 53 were identified as ARDs, and 42 were non-communicable diseases (NCDs). Among 33 countries and territories, China exhibited the lowest disease burden of ARDs, whereas Nauru (Naoero) showed the highest disease burden. Ischemic heart disease, intracerebral hemorrhage, ischemic stroke, chronic obstructive pulmonary disease, and Alzheimer’s disease and other dementias were the top five ARDs for disease burden. High systolic blood pressure, ambient particulate matter pollution, smoking, high LDL cholesterol, and lead exposure were the top five risks for total risk-ARD burden. Implementing healthy ageing policies and developing regional tailored interventions can mitigate disease burden and promote early prevention and disease management, especially in age-related NCDs and modifiable risk factors.

Acute lung injury (ALI) remains a major public health challenge. Although Ophiopogonin D (OPD) possesses well-documented anti-inflammatory activity, its therapeutic efficacy and mechanisms in ALI remain elusive. In this study, we established an ALI model via lipopolysaccharide (LPS) challenge and treated mice with OPD. OPD significantly ameliorated multiple indices of lung injury. Using single-cell RNA sequencing (scRNA-seq), we identified the key cell types and pathways mediating OPD's protective effects. scRNA-seq revealed that OPD primarily corrected the M1/M2 macrophage imbalance. Both in vitro and in vivo, OPD suppressed M1 polarization and, more prominently, promoted the differentiation of Plet1+ macrophage, an M2-like subset. Mechanistically, OPD activated peroxisome proliferator-activated receptor gamma (PPARγ) to upregulate placenta-expressed transcript 1 (PLET1) expression; this effect was abolished by PPARγ inhibition. Thermal proteome profiling (TPP) coupled with subsequent validation identified nuclear receptor corepressor 1 (NCOR1) as a direct target of OPD. OPD disrupted the NCOR1-PPARγ interaction. Ncor1 knockdown phenocopied OPD's promotion of Plet1+ macrophage differentiation, whereas Ncor1 overexpression completely abrogated these effects. Collectively, OPD directly binds NCOR1 and disrupts the NCOR1-PPARγ interaction, thereby activating PPARγ and inducing Plet1+ macrophage differentiation to ameliorate LPS-induced ALI.

Background Ulcerative colitis (UC) is a chronic inflammatory disease that seriously endangers human health. Shaoyao Decoction (SYD) has been widely used in clinical practice to treat UC; however, its active components and molecular mechanisms remain unclear. Objective To elucidate the pharmacological mechanisms by which SYD and its active constituents ameliorate UC using single-cell RNA sequencing (scRNA-seq). Methods We first assessed the therapeutic efficacy of SYD in a dextran sulfate sodium (DSS)-induced UC mouse model. We then applied scRNA-seq to identify the potential cell populations and molecular pathways involved in SYD-mediated protection. Guided by these findings, we verified the inferred mechanisms in vivo and screened potential active compounds from SYD. We further examined their inhibitory effects on formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil migration and their protective effects on DSS-induced Caco-2 cell injury in vitro. Finally, we validated the underlying mechanisms using inhibitors, agonists, gene silencing, and overexpression approaches in vitro. Results SYD markedly alleviated weight loss, reduced disease activity index (DAI) scores, and mitigated colon shortening and histopathological damage in mice with UC. The scRNA-seq analysis revealed alterations in neutrophils and intestinal epithelial cells. Functional pathway analysis indicated that neutrophil migration, epithelial tight junction regulation, and apoptosis were key processes modulated by SYD. In vivo, SYD decreased neutrophil infiltration and downregulated the expression of RAC1, RAC2, S100A8, and S100A9. Concurrently, SYD upregulated the tight junction proteins TJP1 and OCLN and suppressed epithelial apoptosis. In vitro, Ferulic acid emerged as the potential compound responsible for suppressing neutrophil migration. RAC1 inhibition and Ferulic acid treatment produced comparable suppressive effects on neutrophil migration, whereas RAC1 activation effectively antagonized the inhibitory effect of Ferulic acid. Chrysin-7-O-glucuronide was identified as the potential component enhancing tight junction integrity and suppressing apoptosis in intestinal epithelial cells; silencing KLF4 eliminated these protective effects of Chrysin-7-O-glucuronide. Conversely, KLF4 overexpression exerted protective effects comparable to those of Chrysin-7-O-glucuronide treatment. Conclusion SYD exerts potent therapeutic effects against UC. Mechanistically, Ferulic acid in SYD suppresses RAC1-mediated neutrophil migration, while Chrysin-7-O-glucuronide enhances tight junction integrity and suppresses apoptosis in intestinal epithelial cells through a KLF4-dependent mechanism.

Objective In lupus nephritis (LN), renal tubular epithelial cells (RTECs) can acquire an abnormal MHC-II antigen-presenting cell-like phenotype and thereby amplify local immune responses. This study aimed to evaluate the therapeutic effects of the Uyghur medicine Fufang Muniziqi Granules (FMG) in LN, determine whether FMG acts by suppressing aberrant MHC-II expression in RTECs, and identify its potential targets and molecular mechanisms. Methods We treated spontaneous LN MRL/lpr mice with different doses of FMG. We assessed systemic immune activation by measuring the spleen index, autoantibodies, and inflammatory cytokines. We evaluated renal function and histopathology using renal function indicators, H&E staining, PAS staining, and Masson staining. We performed scRNA-seq and untargeted metabolomics analyses to examine changes in renal cell populations and metabolic status. In vitro, we used IFN-γ to induce an immune phenotype in HK-2 cells and then assessed CD74 expression, mitochondrial function, and PPARγ activity. Candidate active components of FMG were identified, and CETSA, molecular docking, and DARTS assays were subsequently used to validate their targets. Finally, we examined the effect of RTEC immune phenotype modulation on T cell activation using an HK-2 and Jurkat co-culture system. Results FMG markedly alleviated systemic inflammation and renal injury in MRL/lpr mice. It reduced spleen index, autoantibody levels, and inflammatory cytokines, and decreased Scr, BUN, and albumin-to-creatinine ratio (ACR), while improving renal histopathology. scRNA-seq analysis showed that FMG primarily targeted RTECs, where it downregulated MHC-II and IFN-γ-related gene sets and restored PPARγ-mediated antioxidative capacity. Non-targeted metabolomics analysis suggested that FMG could promote fatty acid oxidation in renal tissue. In vitro, Schisandrol A, identified as a candidate active component of FMG, suppressed IFN-γ-induced CD74 expression in HK-2 cells, improved mitochondrial function, and enhanced PPARγ transcriptional activity; these effects were attenuated by PPARγ inhibition. STUB1 was identified as a potential target through which Schisandrol A regulates PPARγ. Schisandrol A blocked the interaction between STUB1 and PPARγ, and inhibited STUB1-induced PPARγ ubiquitination. STUB1 silencing increased PPARγ activity and reduced MHC-II expression, mimicking the effect of Schisandrol A. Co-culture of HK-2 and Jurkat cells showed that Schisandrol A indirectly suppressed T cell activation (IL-2 level) via RTECs, with minimal direct effects on T cells. Conclusion FMG exerts therapeutic effects in LN by modulating the MHC-II antigen-presenting-like phenotype of RTECs. Mechanistically, Schisandrol A was identified as a candidate active component of FMG that may contribute to this effect by disrupting the interaction between STUB1 and PPARγ and suppressing MHC-II-associated immune activation in RTECs.

Furong Tongmai capsule (FRTM) is a traditional Chinese medicine formula with reported lipid-lowering and anti-inflammatory activities, but its mechanisms in atherosclerosis (AS) remain unclear. In ApoE-/- mice fed a high-fat diet, FRTM administration improved serum lipid profiles by reducing total cholesterol, triglycerides and low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol. FRTM also attenuated aortic lesion formation, reduced pro-inflammatory cytokines (IL-6, IL-1β and TNF-α), and improved oxidative stress indices. 16S rRNA sequencing showed that FRTM reshaped the gut microbiota, increasing beneficial taxa such as Lactobacillus and Bifidobacterium while decreasing Turicibacter. Functional prediction and untargeted serum metabolomics both suggested that arachidonic acid metabolism was a key pathway affected by FRTM. Furthermore, FRTM was associated with increased p-PPARγ and EP4 expression, decreased p-P65, and increased p-STAT3/STAT3, accompanied by downregulation of M1 markers (iNOS/Nos2) and upregulation of M2 markers (CD206 and ARG1). Faecal microbiota transplantation from FRTM-treated donors partially recapitulated the anti-atherosclerotic and anti-inflammatory effects. Overall, these findings suggest that FRTM may ameliorate AS in a murine model by modulating gut microbiota, arachidonic acid metabolism and macrophage polarization; however, further functional studies are needed to establish causality and assess translational relevance.

AIM:The aim of this study is to investigate the precise mechanisms by which Polydatin (PD) ameliorates cerebral ischemia-reperfusion injury (CIRI). METHODS:We first established a rat model of CIRI to evaluate PD's therapeutic effects. Transcriptomic analysis was used to explore PD's impact on gene expression in ischemic brain tissue of CIRI rats. OGD/R-induced microglial activation experiments validated that PD inhibits microglial activation by targeting the CXCL3/CXCR2 axis. RESULTS:PD intervention improved neurological function scores of CIRI rats, reduced infarct area, alleviated pathological damage, and preserved Nissl bodies in brain tissue. It also modulated oxidative stress levels. Transcriptomic analysis showed enrichment of the Cytokine-cytokine receptor interaction pathway and several inflammatory pathways after PD intervention, with downregulation of CXCL3 and CXCR2. PD decreased pro-inflammatory cytokine levels and CXCL3/CXCR2 protein expression in ischemic brain tissue of CIRI rats, and reduced positive expression areas of IBA1+CXCL3+, IBA1+CXCR2+, and MPO+CXCR2+. In vitro experiments demonstrated that PD reduced pro-inflammatory cytokine levels in BV2 cell supernatants treated with OGD/R and inhibited BV2 cell migration. However, these effects were abolished when treated with CXCL3 neutralizing antibody and SiCXCR2. CONCLUSION:Our findings suggest that PD can inhibit microglial migration and activation by acting on the CXCL3/CXCR2 axis, thereby alleviating the inflammatory response in CIRI.

Aging frequently correlates with the progressive decline in skeletal muscle mass and function, a condition termed sarcopenia. Epigenetic modifications, including DNA methylation, histone alterations, and microRNA regulation, critically influence gene expression changes throughout aging. This review elucidates molecular mechanisms underlying epigenetic alterations in aging skeletal muscle and their functional consequences. We elucidate how shifts in DNA methylation, histone modifications, and microRNA profiles contribute to muscle atrophy and dysfunction. Furthermore, we examine emerging therapeutic strategies targeting epigenetic pathways to mitigate age-related muscle deterioration. A deeper understanding of these epigenetic processes could facilitate the development of interventions to promote healthier aging and improve muscle function in older adults. A comprehensive understanding of these processes will guide therapeutic strategies aimed at improving elderly muscle health.

OBJECTIVE:Macrophages, as participants of innate and cellular immunity, play an important role in RA disease. However, whether Saussurea involucrata injection (SII) can regulate the polarization of macrophages and influence the development of RA remains unclear. METHOD:The cells of M0, M1, M1SII, M2, and M2SII groups were analyzed by transcriptome and untargeted metabolic sequencing. Differentially expressed mRNAs(DE-mRNAs), and differential metabolites were screened. GO and KEGG enrichment analysis of DE-mRNAs and differential metabolites was performed. RESULTS:We first screened 3836 DE-mRNAs and 100 metabolites in the M0 and M1 groups. A total of 4588 DE-mRNAs and 30 metabolites were screened in the M1 and M2 groups. Besides, a total of 1529 DE-mRNAs and 38 metabolites were screened in the M1 and M1SII groups. DE-mRNAs enriched GO and KEGG entries between M0 and M1 groups showed TNF signaling pathway, ECM-receptor interaction and PI3K-Akt signaling pathway, etc. The pathways of differentially enriched metabolites include Tryptophan metabolism, Secondary bile acid biosynthesis, etc. DE-mRNAs enriched GO and KEGG entries between M1 and M2 groups showed positive regulation of cell adhesion, JAK-STAT signaling pathway, and Chemokine signaling pathways. Differential metabolites are enriched in Metabolic pathways, Bile secretion, and Tryptophan metabolism. DE-mRNAs enriched GO and KEGG entries between M1 and M1 SII groups include cell adhesion molecule binding, ECM-receptor interaction and PI3K-Akt signaling pathway. Differential metabolite enrichment pathways include Neuroactive ligand-receptor interaction and dicarboxylate metabolism, etc. CONCLUSION: Through transcriptome and untargeted metabolomics sequencing analysis, we found that the mechanism of action of SII in the treatment of RA disease may be related to the regulation of macrophages. Importantly, it was found that the TGF-β signaling pathway, PI3K-Akt signaling pathway, Glyoxylate and dicarboxylate metabolism may be closely related to SII regulation of M1 macrophages for RA treatment.

Our previous research demonstrated that curcumin suppresses mouse colorectal cancer (CRC) cell CT26 migration and invasion by inhibiting heparanase (HPSE) mRNA expression. To further elucidate the mechanism of curcumin in human CRC treatment, we hypothesized that HPSE plays a pivotal role in human CRC metastasis and that curcumin inhibits this process by downregulating HPSE expression through epigenetic regulation mediated by non-coding RNAs. For further research, human CRC cells were infected with lentivirus to establish overexpression of HPSE cell lines and corresponding negative control cell lines. In vitro and in vivo experiments showed that curcumin inhibited the proliferation, migration, and metastasis of CRC cancer by inhibiting HPSE expression. In the tumor microenvironment, HPSE played an important role in activating the IL-6/STAT5 axis signaling pathway by destructing the extracellular matrix and releasing large number of cytokines, while changing the tumor microenvironment and EMT process, thus promoting tumor metastasis. RNA-seq analysis combined with qRT-PCR results showed that curcumin's inhibition of HPSE expression involved the regulation of non-coding RNAs. Taken together, our results suggested that HPSE promotes CRC metastasis by activating the IL-6/STAT5 signaling axis, disrupting the ECM, releasing cytokines, and altering the tumor microenvironment to facilitate EMT. Curcumin significantly inhibits CRC cell proliferation, migration, and metastasis by downregulating HPSE expression via non-coding RNAs, which related to IL-6/STAT5 axis signal pathways. This research provides a comprehensive understanding of the molecular mechanisms underlying curcumin's anti-CRC effects, emphasizing the role of HPSE and non-coding RNAs in tumor metastasis. These findings pave the way for the development of novel therapeutic strategies targeting HPSE and its regulatory pathways in CRC.

Colorectal cancer(CRC) is one of the most common malignant tumors worldwide, primarily originating from recurrent inflammatory bowel disease(IBD). Therefore, blocking the inflammation-cancer transformation in the colon has become a focus in the early prevention and treatment of CRC. The inflammation-cancer transformation in the colon involves multiple types of cells and complex pathological processes, including inflammatory responses and tumorigenesis. In this complex pathological process, immune cells(including non-specific and specific immune cells) and non-immune cells(such as tumor cells and fibroblasts) interact with each other, collectively promoting the progression of the disease. In traditional Chinese medicine(TCM), inflammation-cancer transformation in the colon belongs to the categories of dysentery and diarrhea, with the main pathogenesis being cold and heat in complexity. This paper first elaborates on the complex molecular mechanisms involved in the inflammation-cancer transformation process in the colon from the perspectives of inflammation, cancer, and their mutual influences. Subsequently, by comparing the pathogenic characteristics and clinical manifestations between inflammation-cancer transformation and the TCM pathogenesis of cold and heat in complexity, this paper explores the intrinsic connections between the two. Furthermore, based on the correlation between inflammation-cancer transformation in the colon and the TCM pathogenesis, this paper delves into the importance of the interaction between inflammation and cancer. Finally, it summarizes and discusses the clinical and basic research progress in the TCM intervention in the inflammation-cancer transformation process, providing a theoretical basis and treatment strategy for the treatment of CRC with integrated traditional Chinese and Western medicine.

This study investigated the regulatory potential of salidroside(SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation(Ch IP) assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL) is the downstream target gene of HIF-1α in osteoblasts. The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium(CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1α pathway. Hypoxic condition-induced overexpression of HIF-1α upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1α by downregulating the expression of RANKL, vascular endothelial growth factor(VEGF), interleukin 6(IL-6), and angiopoietin-like 4(ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1α in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL, VEGF, IL-6, and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.

BackgroundThe neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are peripheral serum markers commonly utilized as cost-effective indicators of inflammation. However, their efficacy as predictors of clinical disease activity in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), remains uncertain. To address this ambiguity, we conducted a meta-analysis to evaluate the clinical significance of NLR, PLR, and LMR in patients with IBD.MethodsA comprehensive search was conducted in the PubMed, Embase, Web of Science, and Cochrane databases, with the last search date being October 2024. Baseline values of NLR, PLR, and LMR during active and remission phases, as well as moderate and severe conditions, were analyzed as primary endpoints in patients with IBD compared to healthy populations, using risk ratios (WMD) and corresponding 95% confidence interval (CI) estimates.ResultsTwenty-three cohort studies involving 3550 IBD patients and 1010 healthy people were finally included in this meta-analysis. The results of the meta-analysis showed that peripheral serum NLR and PLR were significantly higher in IBD patients than in the healthy population NLR [WMD=1.57,95%CI(1.14,2.01),P<0.001], PLR [WMD=60.66,95%CI(51.68,69.64),P<0.001]; NLR in active versus remission stage of IBD, PLR, LMR had significant differences NLR [WMD=1.50,95%CI(1.23,1.78),P<0.001], PLR [WMD=69.02,95%CI(39.66,98.39,P<0.001], LMR [WMD=-1.14,95%CI(-1.43,-0.86,P<0.001]; IBD active period and remission period NLR, PLR and LMR had significant differences. 0.001]; there were significant differences in NLR and PLR between moderate and severe IBD NLR [WMD=-1.41,95%CI(-2.13,-0.69),P<0.001], PLR [WMD=-112.03,95%CI(-143.87,-80.19),P<0.001]; the diagnostic accuracy of markers in predicting the clinical activity of IBD was relatively good. The diagnostic accuracy of markers in predicting IBD clinical activity was more favorable AUC [ES=0.72,95%CI(0.69,0.75),P<0.001].ConclusionIn patients with IBD, elevated NLR and PLR are associated with increased disease activity and severity in UC and CD. Conversely, an elevated LMR is linked to reduced disease activity in IBD. Based on diagnostic accuracy results, inflammatory markers NLR and PLR serve as effective biomarkers for assessing IBD activity, thereby providing valuable insights for treatment decisions in IBD patients. However, LMR may not be a reliable independent marker due to conflicting or non-significant results. We anticipate that further high-quality prospective studies will validate our findings in the future.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024608118.

Fine particulate matter (PM2.5) air pollution constitutes a significant hazard to the well-being and survival of children everywhere, posing particularly dire risks to neonates. However, the neonatal disease burden attributable to PM2.5 pollution remains unclear worldwide. Data on neonatal diseases attributable to PM2.5 pollution were obtained and collected from the Global Burden of Disease Study (GBD) 2021. The main outcome was the age-standardized disability-adjusted life-years (DALYs) rate (ASDR) and age-standardized mortality rate (ASMR) per 100 000 population of neonatal diseases caused by PM2.5 pollution. These metrics were stratified by sex, region, country, and disease. The correlations, trends, and projections of the burden were also analyzed. Globally, there were approximately 497.0 thousand deaths and 44737.3 thousand DALYs from neonatal diseases caused by PM2.5 pollution in 2021. From 1990 to 2021, the overall ASDR (1120.4 to 723.1) and ASMR (12.5 to 8.0) showed a downward trend. However, the ASDR of neonatal diseases attributable to PM2.5 pollution was high in Sub-Saharan Africa (1717.1 to 1235.8) and South Asia (2010.4 to 1148.1), especially regarding household PM2.5 pollution. The higher ASDR attributable to PM2.5 pollution was observed in neonatal encephalopathy due to birth asphyxia and trauma and neonatal preterm birth. By 2050, the ASDR of neonatal disease impacts from household PM2.5 pollution remain persistently high. Neonatal disease burden attributable to PM2.5 pollution remains a crucial health issue in children. Targeted strategies to improve PM2.5 air quality and neonatal disease burden are essential.

IntroductionThe purpose of this study is to compare the relative effectiveness and safety of non-pharmacological interventions for the treatment of functional constipation (FC).MethodsWe searched Pubmed, Embase, Cochrane, and Web of Science databases for randomized controlled trials published from 2010 to November 2024. The quality of the included studies was evaluated using the Cochrane bias risk tool and Review Manager 5.4, and the evidence was graded using GRADEPro. A network meta-analysis (NMA) was conducted using R Studio, and the surface under the cumulative ranking curve (SUCRA) was used to rank the included drugs for each outcome measure to compare the clinical efficacy of different treatment methods for chronic functional constipation.ResultsA total of 29 RCT studies were included, with a total of 4389 patients with functional constipation who were randomly assigned to receive placebo or one of the nine different non-pharmacological treatment methods. The assessment of bias risk showed that the bias risk of most included studies was low. The results showed that the first-ranked treatment method for clinical efficacy was acupuncture; the first-ranked treatment method for changes in spontaneous bowel movement (SBM) and complete spontaneous bowel movement (CSBM) was fecal microbiota transplantation (FMT); the first-ranked treatment method for changes in the Bristol Stool Form Scale (BSFS) score was FMT; the first-ranked treatment method for changes in the Patient Assessment of Constipation Quality of Life (PAC-QOL) score after treatment was the Vibration capsule; the first-ranked treatment method for changes in the Patient Assessment of Constipation Symptoms (PAC-SYM) score after treatment was percutaneous electrical stimulation; and the treatment method with the lowest incidence of adverse reactions was probiotics.ConclusionBased on the SUCRA values and NMA results, we found that FMT showed better effects and higher safety on BSFS scores, SBM, and CSBM. In addition, acupuncture showed a good clinical efficacy. We hypothesize that the combination of FMT and acupuncture may be an effective and safe treatment option for functional constipation, but further high-quality clinical studies are needed to confirm this.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024625747.

BACKGROUND:Crocin (CRO) holds promise as a treatment for hypoxic pulmonary hypertension (HPH); however, its pharmacological mechanism remains poorly understood. OBJECTIVES:We investigated how CRO improves HPH by acting on multiple cell types and pathological pathways, using single-cell RNA sequencing (scRNA-seq). MATERIALS AND METHODS:We first established a hypoxia-induced HPH rat model to evaluate the therapeutic effects of CRO. We then performed scRNA-seq to analyze how CRO alters cell populations and gene expression. Then, the effects of CRO on neutrophil migration and activation were investigated. Furthermore, molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) were used to validate the direct target of CRO. Finally, a co-culture system of neutrophils and pulmonary arterial smooth muscle cells (PASMCs) was used to confirm the link between CRO-mediated inhibition of PASMCs proliferation and neutrophil migration and activation. RESULTS:In HPH rat model, CRO treatment significantly improved hemodynamic parameters and alleviated pathological changes in lung. scRNA-seq analysis revealed a marked reduction in the proportions of neutrophils and PASMCs. KEGG analysis of differentially expressed genes (DEGs) in neutrophils showed significant enrichment in cell migration and activation-related pathways. In vitro, CRO inhibited fMLP-induced neutrophils migration and PMA-induced neutrophil extracellular traps (NETs) formation. Molecular docking, CETSA, and DARTS analyses identified HCK as a primary binding target of CRO. Subsequent experiments using an HCK inhibitor confirmed that CRO inhibited neutrophils migration and activation through HCK. Furthermore, neutrophil-PASMCs co-culture experimental system confirmed that the inhibitory effects of CRO on PASMCs were associated with the inhibition of neutrophils activation. CONCLUSION:CRO targets HCK to inhibit neutrophils migration and activation, and subsequently preventing neutrophil-induced PASMCs proliferation. These results highlight a novel therapeutic target for HPH and provide a scientific basis for the potential clinical application of CRO.

[This corrects the article DOI: 10.3389/fcimb.2025.1565801.].

The intestine is a vital organ of the digestive system, with its function largely reliant on the continuous regeneration of mucosal epithelial cells by healthy intestinal stem cells (ISCs). However, as we age, the regenerative potential of ISCs declines, primarily due to deleterious aging processes, such as cellular senescence, which contribute to the development of various chronic gut diseases. A growing body of evidence indicates that both healthy ISCs, which maintain intestinal homeostasis, and aging-associated senescent ISCs are profoundly influenced by epigenetic mechanisms. At the molecular level, dynamic and often reversible epigenetic modifications including chromatin remodeling, histone modifications, DNA methylation, N6-methyladenosine (m6A) modifications, and non-coding RNAs (long non-coding RNAs, circular RNAs, and microRNAs) play a pivotal role in modulating ISCs gene expression and function. This review explores the role of epigenetics in regulating ISCs stemness, proliferation, differentiation, and plasticity to maintain epithelial homeostasis, as well as the impact of aging-associated epigenetic changes on these processes. A deeper understanding of these mechanisms may inform researchers on the development of translational approaches, therapeutic strategies, and effective interventions aimed at enhancing the regenerative capacity of gut ISCs and mitigating the onset of age-related gut disorders.

This study aims to focus on GM at species level, exploring the causal associations with different kinds of lymphoma to provide some information on potential intervention directions in lymphoma. Data of GM taxa were extracted from the genome-wide association study conducted by the MiBioGen and Dutch Microbiome Project (DMP), and those of lymphomas were obtained from the FinnGen consortium. Inverse variance weighted (IVW) method and Bonferroni multiple correction were utilized to assess the causal associations of GM species with different kinds of lymphoma. The effect size was expressed by odds ratios (ORs) with 95% confidence intervals (CIs). Reverse causal association analysis has also been performed. Additionally, scatter plots and leave-one-out test were conducted for sensitivity analysis. After correction, the IVW estimates suggested that elevated relative abundance of species Faecalibacterium_prausnitzii had a negatively causal association with increased odds of Hodgkin's lymphoma (HL) (OR = 0.584, 95% CI: 0.516-0.662). Relative abundance of species Gordonibacter_pamelaeae, Holdemania_filiformis, Sutterella_wadsworthensis and Coprococcus_sp_ART55_1 was negatively associated with follicular lymphoma (FL) odds, whereas that of species Bifidobacterium_catenulatum and Coprococcus_comes were positively associated with FL odds (all p < 0.05). Relative abundance of species Akkermansia_muciniphila and Coprococcus_sp_ART55_1 had a negatively causal association with non-follicular lymphoma (NFL) odds, respectively, while that of Bacteroides_uniformis had a positive one (all p < 0.05). Relative abundance of species Flavonifractor_plautii was negatively linked to diffuse large B-cell lymphoma (DLBCL) risk (OR = 0.471, 95% CI: 0.344-0.645). Relative abundance of species Eggerthella_unclassified was positively associated with T/NK cell lymphoma (TNK) risk while that of Ruminococcus_lactaris was negatively associated with TNK risk (all p < 0.05). Elevated relative abundance of Parabacteroides_unclassified was associated with higher risk of non-Hodgkin's lymphoma (NHL) (OR = 1.955, 95% CI: 1.654-2.312). The relative abundance of species Holdemania_filiformis was negatively associated with mantle cell lymphoma (MCL) risk (OR = 0.637, 95% CI: 0.544-0.746). The relative abundance of species Rothia_mucilaginosa and Lachnospiraceae_bacterium_3_1_46FAA had positively causal association with marginal zone lymphoma (MZL) risk, while that of species Alistipes_senegalensis had a negative one (all p < 0.05). This study identified 16 GM species that have potential causal associations with different kinds of lymphoma, which provided some new idea for further exploration on prevention and treatment targets in lymphoma.