Emerging data indicate that chromatin licencing and DNA replication factor 1 (CDT1) plays an important role in several cancers. However, it remains unclear whether CDT1 is functionally indispensable in lung cancer. Here, constructing tissue microarrays and performing in vitro and vivo experiments, we showed that CDT1 was significantly overexpressed in lung adenocarcinoma tissues, and its expression level significantly correlated with pathological stage, tumour invasiveness, and overall patient survival. Mechanistic investigations revealed that CDT1 possibly interacted with the transcription factor adenovirus early region 2 binding factor 1 (E2F1), thereby cooperatively enhancing the transcriptional activity of the targeting protein for Xenopus kinesin-like protein 2 (TPX2) gene. This phenomenon subsequently increased the expression of glycolysis-related molecules aldolase C and pyruvate kinase M2 via the PI3K/AKT signalling pathway, which promoted the proliferation and migration of non-small cell lung cancer (NSCLC) cells. Critically, knockdown of TPX2 or treatment with either the AKT pathway inhibitor MK-2206 2HCl or the glycolysis inhibitor AZ33 effectively reversed the promoting effects of CDT1 on AKT pathway activity, glycolytic metabolism, and tumour progression in CDT1-overexpressing NSCLC cells. Collectively, this study elucidates that CDT1 and E2F1 mutually promote the glycolysis and progression of NSCLC cells by activating the TPX2/AKT pathway. These findings provide novel therapeutic targets for refractory NSCLC treatment.

Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound CD-15, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, CD-15 displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of CD-15. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of CD-15 in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that CD-15 covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, CD-15 exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, CD-15 emerges as a promising candidate for the treatment of PCa and deserves further investigation.

Short chain fatty acids (SCFAs), the primary metabolites produced by gut microbiota, play an essential role in maintaining hepatic homeostasis. Recent studies have indicated that Cadmium (Cd) not only directly triggers oxidative stress and mitochondrial damage, but also indirectly exacerbates Cd-induced hepatotoxicity by depleting SCFAs, thereby compromising their protective effects on the liver. Cd alters gut microbiota composition by reducing the Firmicutes/Bacteroidetes ratio and depleting SCFAs-producing bacteria such as Lachnospiraceae and Ruminococcaceae, thereby decreasing SCFAs production. It induces intestinal epithelial necrosis and downregulates tight junction proteins (occludin, claudin-1, and ZO-1), which impairs SCFAs absorption, compromises intestinal barrier function, and promotes the translocation of endotoxins to the liver via the gut-liver axis. Cd further disrupts SCFAs metabolism and promotes lipid accumulation by suppressing β-oxidation related genes and proteins, thereby synergistically exacerbating hepatic damage. We also highlight the potential of exogenous SCFAs supplementation to alleviate Cd toxicity by restoring microbial balance, elevating SCFAs levels, and enhancing barrier integrity. These insights offer a novel perspective and strategic basis for dietary interventions in preventing and treating heavy metal related liver diseases.

Rationale:Castration-resistant prostate cancer (CRPC) poses significant therapeutic challenges due to its aggressive nature and limited effective treatments. Although PARP inhibitor olaparib has been approved for metastatic CRPC patients bearing BRCA1/2 mutations, its application is confined to this specific patient subpopulation. The induction of "BRCAness" feature in CRPC patients without BRCA1/2 mutations becomes a significant challenge. Methods:A transcriptomic analysis to identify potential "BRCAness" regulator was performed on 921 prostate cancer (PCa) patients from 6 public datasets and validated in our own cohort. D45, a selective small-molecule protein degrader for cyclin-dependent kinase 9 (CDK9), alone or combined with olaparib, was applied in CRPC cell lines (C4-2 and 22Rv1) lacking BRCA1/2 mutations for cell viability, colony formation and apoptosis-related assays. "BRCAness" phenotype was characterized by Western blotting and γH2AX foci accumulation assays. RNA-seq and CUT&Tag assays were used to reveal how D45 regulated homologous recombination repair (HRR)-related genes. Results:We found the transcriptional regulator CDK9 was overexpressed in CRPC and correlated with advanced Gleason scores, metastasis, and poor prognosis. D45 treatment decreased cell survival, and led to downregulation of HRR-related genes (BRCA1/2 and RAD51) with the reduced recruitment of phosphorylated-RNA polymerase II (pSer2) to the ends of these genes with increased DNA damage, indicating a "BRCAness" phenotype induction. The synthetic vulnerability synergized with D45 plus olaparib was thus tested in vitro, showing the enhanced apoptosis in CRPC cells. Moreover, sequential D45 and olaparib administration significantly suppressed 22Rv1 xenograft growth in vivo (P < 0.001), reduced RAD51 expression and increased DNA damage. Toxicity was tolerable and consistent with prior reports. Their synergistic effect was confirmed in ex vivo explants from human PCa specimens. Conclusions:Our findings demonstrated CDK9 as a master regulator of BRCAness and proposed targeting CDK9 as a potential strategy to sensitize CRPC patients without BRCA1/2 mutations to PARP inhibition.

BackgroundEvidence regarding the hepatotoxic effects of co-exposure to multiple heavy metals in the general middle-aged and older adults population remains limited. This study aimed to investigate the association between heavy metal mixtures and liver function in the population of Northwest China, with key findings supported using an animal model.MethodsWe conducted a cross-sectional study involving 451 participants from the Dongdagou Xinglong cohort. Concentrations of heavy metals and liver function indices were measured. Multiple linear regression, Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS), and quantile-based g-computation (Qgcomp) regression were employed to evaluate the combined effects of co-exposure to multiple heavy metals on liver function. A sub-chronic cadmium (Cd) exposure rat model was further established to validate population-based findings.ResultsMultiple linear regression analysis revealed that blood Cd was positively correlated with GGT (β = 0.236), TBA (β = 0.162), ALT (β = 0.142) and AST (β = 0.114), while negatively correlated with DBil (β = −0.207), TBil (β = −0.166) and IBil (β = −0.157) (all P < 0.05). Similarly, other heavy metals also exhibited significant associations with liver function indicators. BKMR analysis showed that heavy metal mixture exposure was positively associated with ALT, AST, ALP, GGT, CHE, and TBA, but negatively associated with TBil, DBil, and IBil; WQS regression indicated that positive associations between the metal mixture and GGT as well as CHE; and the Qgcomp model demonstrated that the metal mixture was positively associated with ALT, GGT, and TBA, and negatively associated with TBil, DBil, and IBil. Notably, all three statistical models consistently identified Cd as the factor associated with liver function biomarkers. Furthermore, animal experiments provided experimental evidence consistent with the human findings: Cd exposure led to elevated serum GGT and ALP levels and induced histopathological alterations in the liver. Transcriptomic sequencing suggested that hepatic lipid metabolism pathways may be involved in Cd-induced liver injury.ConclusionsOverall, our study shows that co-exposure to heavy metals is associated with liver function biomarkers in middle-aged and older adults, with Cd identified as the predominant factor associated with liver function biomarkers.

Tumor-associated macrophages (TAMs) are key determinants of the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) and critically influence the efficacy of immunotherapy. However, how metabolic regulators shape TAM immunophenotypes and subsequent CD8⁺ T cell dysfunction in HCC remains incompletely understood. Single-cell RNA sequencing data and primary tumor samples from patients with HCC were used to characterize xanthine oxidoreductase (XOR) expression on TAMs, and to clarify the underlying mechanisms mediating the effects of XOR⁺ monocytes/macrophages on CD8⁺ T cells. An in-house small-molecule library was screened to identify compounds capable of modulating XOR activity, followed by mechanistic and therapeutic validation in vivo. We identified a marked downregulation of XOR expression in TAMs within HCC tumors, which was significantly associated with poor clinical outcomes. Mechanistically, loss of XOR disrupted PPARγ signaling and cholesterol homeostasis in macrophages, driving their polarization toward an alternatively activated, immunosuppressive M2 phenotype. XOR-deficient TAMs exhibited an impaired capacity to support CD8⁺ T cell activation through enhancing PD-L1 expression, thereby facilitating tumor progression. Notably, a resveratrol derivative, Res616, directly bound to and stabilized the XOR protein, restoring cholesterol metabolic balance and reversing the immunosuppressive phenotype of TAMs. Therapeutically, targeting XOR with Res616 significantly enhanced intratumoral CD8⁺ T cell responses and synergized with anti-PD-L1 therapy to suppress tumor growth in murine HCC models. Our study identified XOR as a pivotal metabolic checkpoint governing TAM-mediated immunosuppression in HCC. Pharmacological stabilization of XOR to restore macrophage cholesterol homeostasis represented a previously unrecognized strategy to remodel the tumor immune microenvironment and improve the efficacy of immune checkpoint blockade.

Paraptosis plays a critical role in mediating anti-tumor effects by inducing cell death in cancer cells. However, its specific involvement in lung adenocarcinoma (LUAD) remains inadequately understood. This study aims to systematically investigate the prognostic significance and underlying mechanisms of paraptosis-related genes (PRGs) in LUAD. Differentially expressed genes were identified between LUAD and control samples from the training set and cross-referenced with PRGs to generate candidate genes (CGs). Prognostic genes were selected from CGs using regression analysis, leading to the development of a LUAD risk model, which was validated in an independent validation set. Clinical characteristics were analyzed to identify independent prognostic factors for constructing a nomogram. Functional and immune infiltration analyses were performed on high-/low-risk cohorts from the training set. Drug predictions related to prognostic genes were made and subsequently validated through molecular docking. Polymerase chain reaction was performed to validate the expression of prognostic genes. Four prognostic genes (CDKN3, PEBP1, TNFRSF19, and PHB) were identified from 27 CGs through regression analysis. The prognostic risk model demonstrated robust predictive capacity for LUAD prognosis and exhibited generalizability. Significant associations were observed between risk scores and clinical features, including age, TNM.stage, T-stage, and N-stage (P < .05). These risk scores served as independent prognostic factors for the nomogram model, offering strong predictive power for LUAD. Vorinostat and raloxifene exhibited notable binding affinity for PEBP1. Elevated CDKN3 expression was observed in LUAD, while PEBP1 and TNFRSF19 expressions were reduced. This study highlights the prognostic value of PRGs, specifically CDKN3, PEBP1, TNFRSF19, and PHB. CDKN3 and PHB emerged as risk factors for LUAD prognosis, whereas PEBP1 and TNFRSF19 did not. In-depth analysis of the tumor microenvironment revealed the distribution and correlations of immune cell types influenced by PRGs and risk score. Furthermore, an independent prognostic model for LUAD was developed, enhancing our understanding of high-/low-risk cohorts' functional pathways. Drug prediction results provided valuable insights into potential therapeutic strategies for LUAD, warranting further investigation.

Environmental heavy metal exposure poses significant endocrine-disrupting risks, yet evidence regarding the impact of metal mixtures on sex hormones in susceptible populations remains limited. We conducted a cross-sectional study involving 434 participants (167 males, 267 postmenopausal females) from the Dongdagou Xinglong cohort, a well-established cohort residing in a historically heavy metal-polluted region in Northwest China. Concentrations of eight metals (aluminum, chromium, copper, zinc, arsenic, selenium, cadmium, lead) in whole blood and a panel of six sex hormones (including androgens and estrogens) in serum were measured. Multiple linear regression analysis revealed significant positive associations between blood cadmium and dehydroepiandrosterone sulfate (β = 0.468), androstenedione (β = 0.571), testosterone (β = 0.680), and estradiol (β = 0.528) in males (all P < 0.05). Conversely, in females, blood cadmium was negatively associated with dehydroepiandrosterone sulfate (β = -0.221), androstenedione (β = -0.375), testosterone (β = -0.256), progesterone (β = -0.258), estradiol (β = -0.437), and estrone (β = -0.432) (all P < 0.05). Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS), and quantile-based g-computation (Qgcomp) regression models consistently demonstrated that heavy metal mixture exposure elevated androstenedione and testosterone levels in males while reducing estradiol levels in females. Cadmium was consistently identified as the primary risk factor in both males and postmenopausal females. Furthermore, animal experiments corroborated above findings: Cadmium-exposed rats exhibited dose-dependent cadmium accumulation, disruption of blood metals homeostasis, elevated serum estradiol, and reduced testosterone levels (all P < 0.05). Collectively, our analyses of a metal-exposed cohort highlight that heavy metal mixtures are associated with sex-specific dysregulation of sex hormones, wherein cadmium appears to be a primary driver. This study offers insights for assessing reproductive health risks in similar metal-polluted contexts.

ABSTRACT The detection of non‐nucleic acid targets encapsulated in extracellular vesicles (EVs) faces two major challenges: (1) difficulties in efficient isolation and the risk of content degradation, and (2) the low abundance of target molecules encapsulated in EVs always leads to failed signal transduction and inadequate output signal intensity. To overcome these limitations, we propose a high‐efficiency in‐vesicle analysis strategy that integrates targeting probe delivery and regulation by protein signal amplification. By applying aptamer‐mediated membrane fusion and “locked‐activated” CRISPR‐Cas12a‐AcrVA1 (LACA) for protein signal regulation, we fabricated a yly12‐aptamer‐functionalized self‐assembled nanovesicle which encapsulate LACA‐system (yly12‐lipo@Cas12a nanovesicle) as an in‐vesicle bioanalytical platform. Leveraging the high specificity of the aptamer and the regulatory function of AcrVA1 in selectively modulating Cas12a activity, the platform enables highly specifiec and sensitive detection, offering advantages of simple operation and versatility across platforms within only 2.5 h. Clinical analysis demonstrated effective differentiation between patients and healthy controls, yielding high diagnostic performance with an AUC of 0.965. The proposed platform shows great potential for EV‐carrying protein biomarker analysis and has broad prospects for the disease's diagnosis in clinical settings.

Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa, has emerged as a research hotspot in medicinal chemistry owing to its unique diarylheptadienone skeleton (C6-C7-C6), broad-spectrum bioactivities, and multi-target mode of action. However, its inherent drawbacks, including poor water solubility, low in vivo stability, and rapid metabolic rate, have severely hindered its clinical translation and application. In recent years, breakthrough progress has been made in the structural modification and scaffold reconstruction of the curcumin nucleus. Through diverse strategies including monocarbonyl modification, heterocyclic fusion, metal coordination, halogen substitution, and pharmacophore hybridization, a series of derivatives with improved druggability and enhanced bioactivity have been successfully developed. This review systematically collates relevant research literature from 2020 to April 2026, summarizes the latest research advances of curcuminoids in core fields including anticancer, antibacterial, antiviral, anti-inflammatory, antioxidant, and neuroprotective activities by bioactivity classification, and focuses on the structural characteristics, activity advantages, structure-activity relationships (SARs), and molecular mechanisms of representative derivatives. Furthermore, key SAR insights, including the modification of the β-diketone group, regulation of aromatic ring substituents, and the synergy of scaffold fusion with metal coordination, are further refined, and future research directions are prospected. This review aims to provide systematic SAR guidance and insights for the rational design of innovative drugs based on the curcumin scaffold.

Cadmium (Cd) is a globally persistent toxic metal with extraordinary biological retention and cumulative tissue toxicity. Ferroptosis has emerged as a proposed mechanism of Cd-induced cytotoxicity. However, current research is characterized by profound methodological heterogeneity, supraphysiological dosing, incomplete ferroptosis validation, overlapping cell death pathways, and inconsistent mechanistic interpretations. Here, we perform a systematic, mechanism-centered, and dose-aware critical review of Cd-induced ferroptosis, based on a newly established four-tier causality framework that distinguishes genuine ferroptosis from non-specific oxidative injury. We integrate existing data into three mechanistic axes: LIP expansion via ferritinophagy, dysregulation of the Nrf2/SLC7A11/GPX4 antioxidant defense system, and mtROS amplification. At the same time, we highlight two major mechanistic paradoxes: the HO-1 functional switch and the dose-duration discrepancy. Based on a critical review of all available data, current data do not support ferroptosis as a universal mechanism of Cd toxicity. Instead, it is a context- and dose-dependent phenomenon that appears to become most prominent under acute high-dose exposure conditions. Finally, we propose a comprehensive research roadmap including physiologically realistic exposure models, establishment of ferroptosis-specific validation standards, ferroptosis biomarker development, and mechanistic resolution of the HO-1 and dose-duration paradoxes. This work aims to refine conceptual oversimplifications, address methodological weaknesses, and establish a rigorous toxicological foundation for future research.

The heavy metal cadmium (Cd) is an important environmental factor that induces liver injury and contributes to liver disease. Ongoing research aims to refine our understanding of the pathogenesis of cadmium-induced liver injury and the interactions between the various mechanisms. Oxidative stress, described as a pathophysiological basis of liver injury, is a process in which reactive oxygen species are generated, causing the destruction of hepatocyte structure and cellular dysfunction. Additionally, the activation of oxidative stress downstream signals regulates several forms of cell death, such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis, which significantly contributes to liver damage. Furthermore, the interplay between different types of programmed cell death highlights the complexity of liver injury mechanisms. This review summarizes the role of programmed cell death in Cd-induced liver injury and explores the relationships between different programmed cell death pathways, which is expected to provide new insights into the mechanisms of Cd-induced liver injury.

Gastric cancer (GC) is a significant global health challenge due to its high incidence and mortality rate. However, the existing classification methods for GC still have limitations. Given the pivotal role of aberrant glycosylation in GC progression, there is a compelling need to develop a novel molecular classification for this disease. Using a comprehensive analysis of 186 glycogenes across seven public datasets encompassing 1547 GC patients, a 12-glycogene signature-based molecular classification was established, which was linked to tumor stage and prognosis. Among them, the overexpression of glucoside xylosyltransferase 2 (GXYLT2) was positively associated with tumor stage, diffuse subtype, and unfavorable survival outcomes in GC patients. Furthermore, GXYLT2 depletion significantly inhibited the proliferation, invasion, and sphere formation capacities in HGC-27, MKN1, and MKN45 GC cells with diffuse-subtype features, whereas its ectopic expression in AGS and MKN74 GC cells with intestinal subtype did not enhance their aggressive properties. Moreover, RNA sequencing analysis revealed that GXYLT2 knockdown resulted in the decrease of Wnt/β-catenin signaling, which was corroborated by TOPFlash reporter activity, β-catenin phosphorylation, immunofluorescence staining, and nuclear-cytoplasmic separation assays for its nuclear location, via the activation of PP2A complex dependent on GXYLT2-PP2A Aα interaction. Notably, GXYLT2 knockdown significantly suppressed tumorigenicity in vivo. Taken together, we identified GXYLT2 as a potential prognostic biomarker for GC patients, and targeting GXYLT2 suppressed the tumor aggressiveness and inhibited the Wnt/β-catenin pathway, which may provide a potential therapeutic target for GC patients.

Gastric cancer (GC) is a significant global health challenge due to its high incidence and mortality rate. However, the existing classification methods for GC still have limitations. Given the pivotal role of aberrant glycosylation in GC progression, there is a compelling need to develop a novel molecular classification for this disease. Using a comprehensive analysis of 186 glycogenes across seven public datasets encompassing 1547 GC patients, a 12-glycogene signature-based molecular classification was established, which was linked to tumor stage and prognosis. Among them, the overexpression of glucoside xylosyltransferase 2 (GXYLT2) was positively associated with tumor stage, diffuse subtype, and unfavorable survival outcomes in GC patients. Furthermore, GXYLT2 depletion significantly inhibited the proliferation, invasion, and sphere formation capacities in HGC-27, MKN1, and MKN45 GC cells with diffuse-subtype features, whereas its ectopic expression in AGS and MKN74 GC cells with intestinal subtype did not enhance their aggressive properties. Moreover, RNA sequencing analysis revealed that GXYLT2 knockdown resulted in the decrease of Wnt/u03B2-catenin signaling, which was corroborated by TOPFlash reporter activity, u03B2-catenin phosphorylation, immunofluorescence staining, and nuclear-cytoplasmic separation assays for its nuclear location, via the activation of PP2A complex dependent on GXYLT2-PP2A Au03B1 interaction. Notably, GXYLT2 knockdown significantly suppressed tumorigenicity in vivo. Taken together, we identified GXYLT2 as a potential prognostic biomarker for GC patients, and targeting GXYLT2 suppressed the tumor aggressiveness and inhibited the Wnt/u03B2-catenin pathway, which may provide a potential therapeutic target for GC patients.

Environmental heavy metal exposure and endogenous sex hormones are implicated in breast cancer (BC) etiology, but their combined effects remain incompletely characterized. This study aimed to investigate the associations between blood heavy metals and BC risk, while examining the potential mediating role of sex hormones and their interaction effects. We analyzed data from 2,939 female participants in the National Health and Nutrition Examination Survey (NHANES) 2013–2020. Multivariable logistic regression, weighted quantile sum (WQS) regression, quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR) models were employed to examine the independent and combined associations of 5 blood metals—lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn)—with BC risk. Nonlinear relationships were evaluated using restricted cubic splines (RCS). Mediation and moderation analyses were conducted to elucidate the mechanistic role of sex hormones in heavy metal-associated BC risk. In the single-exposure models, the fully adjusted analysis results revealed significant positive associations for blood Pb (OR = 2.71, 95

BACKGROUND:Accurate assessment of the risk of familial aggregated hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and regular surveillance for these patients at high risk may be valuable to reduce the occurrence and improve the prognosis of HCC. AIM:This study aimed to develop a simple and reliable prediction model for the risk of HCC in these patients. METHODS AND RESULTS:This study analyzed clinical laboratory results from a database of 1285 patients with familial aggregated HBV who attended the First Hospital of Lanzhou University from January 2010 to December 2019. Univariate and multivariate logistic regression (LR) analysis showed that hemoglobin (Hb), neutrophil percentage (NP), total protein (TP), glutamyl transpeptidase (GGT), alglucosidase alfa (AFU), aspartate aminotransferase (AST) to Alanine aminotransferase (ALT) ratio (AAR), and alpha-fetoprotein (AFP) were identified to be independent risk factors for HBV-associated HCC. Prediction models were developed using a multivariate LR model, classification and regression tree, Native Bayes, Bagged tree, AdaBoost, and random forest. We used a multivariate LR model as a benchmark for performance assessment (AUC = 0.737). The results showed that the Native Bayes model had an AUC of 0.749, which was better than that of the other models. CONCLUSION:Finally, the Native Bayes model demonstrated better predictive performance for HCC, which helped in the clinical decision-making and identification of HCC high-risk groups.

Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1–FPR2 in complex with heterotrimeric Gi to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED50 values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.

The new generation of strobilurin fungicides, due to their chemical stability and water solubility, may lead to persistent residue accumulation, posing significant risks to nontarget organisms. Zebrafish, with cardiac structural and functional similarities to humans, serve as an ideal model for assessing SF-induced cardiotoxicity. Studies show that widespread use of these fungicides is closely linked to cardiac damage in zebrafish, yet the mechanisms remain unclear. This review summarizes the impact of strobilurin fungicides on zebrafish cardiac toxicity, focusing on mitochondrial dysfunction, oxidative stress, apoptosis, and heart development pathways. Using a two-dimensional quantitative structure-activity relationship model, we explore the relationship between structural variations in SFs and their cardiotoxic potential. Understanding these mechanisms is essential for developing strategies to mitigate cardiotoxicity and protect aquatic health, providing a scientific basis for the design of safer, more effective pesticides.

Introduction: Prostate cancer (PCa) often progresses to castration-resistant prostate cancer (CRPC), which is linked to higher treatment resistance and recurrence rates. This highlights the urgent need for new therapeutic options. Natural products, especially flavonoids, have shown promise in reducing drug resistance and possess both antioxidant and anticancer effects. Developing drugs that specifically target CRPC could offer significant therapeutic advantages. Methods: Chrysosplenetin B (CspB) was extracted and purified from the herb Laggera pterodonta (DC.) Benth. using traditional flavonoid extraction techniques, followed by high-performance liquid chromatography (HPLC) for purity assessment and nuclear magnetic resonance (NMR) for structural identification. The effect of CspB on the viability of PCa cells was evaluated using the Cell Counting Kit-8 assay. Subsequently, transcriptome analysis was conducted, and cell cycle progression was assessed through flow cytometry in conjunction with propidium iodide (PI) staining. Additionally, western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to confirm the expression levels of relevant proteins and genes. Results: CspB was found to inhibit the proliferation of PC3, DU145, and LNCaP cells in a dose-dependent manner, with a stronger effect noted in PC3 and DU145 cells. Transcriptomic analysis revealed that CspB treatment led to cell cycle arrest, particularly in PC3 cells. Flow cytometry with PI staining confirmed that CspB caused G1 phase cell cycle arrest in PC3 cells. Moreover, CspB treatment significantly increased the expression of essential members of the Cip/Kip family, including CIP1/P21 and KIP1/P27, as well as CDKN2B (P15) and CDKN2D (P19) from the INK4 family. Additionally, CspB exposure notably raised the expression of the G1 phase-negative regulatory gene CDKN1C, while key cell cycle regulators like CDK6 and E2F1 were significantly downregulated at the protein level. Conclusion: Our findings indicate that CspB effectively inhibits the proliferation of CRPC cells by reducing the activity of cell cycle proteins and cyclin-dependent kinase (CDK) complexes while upregulating the expression of P21 and P27 and inducing G1 phase cell cycle arrest. These results highlight the potential of CspB as a promising candidate for developing therapeutic agents aimed at targeting CRPC.