Xiaoyao Powder (XYP) is a traditional Chinese medicine formula first recorded in the Tai Ping Hui Min He Ji Ju Fang. It has been used for over 900 years to treat "liver depression and spleen deficiency" syndrome. Acute drug-induced liver injury (DILI) often presents clinical features analogous to "liver depression and spleen deficiency" syndrome.

With increasing life expectancy, prostate cancer (PCa) has exhibited rising incidence and mortality rates. Although therapies such as androgen deprivation therapy (ADT) effectively extend patient survival, the development of drug resistance remains a major obstacle. Previous studies identified a key enzyme in the androgen metabolic pathway as essential to PCa progression, regulated by the epigenetic reader BRD4. Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion. Mechanistic investigations demonstrated that SRD5A1 promotes androgen receptor (AR) activity by elevating intracellular dihydrotestosterone (DHT) levels, thereby enhancing AR expression and facilitating tumorigenesis. Notably, both BRD4 and SRD5A1 were shown to modulate AR expression in PCa cells. Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development.

The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting zinc finger protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.

Oridonin is a diterpene compound extracted from Rabdosia rubescens. Although it has been shown to have anticancer effects on several cancers, including hepatocellular carcinoma (HCC), the mechanism remains unclear. HepG2 cells were treated with different concentrations of oridonin for 48 h. Cell viability was detected by CCK-8 assay. The Fe2+ level was detected by iron assay kit. Flow cytometry was used to quantify the lipid reactive oxygen species. The protein and mRNA levels were detected by Western blot and quantitative real-time polymerase chain reaction. The anti-HCC mechanism of oridonin in vivo was investigated using a xenograft tumor model. To explore the underlying mechanisms, bioinformatics methods, immunoprecipitation, and molecular docking were applied. Oridonin inhibited cell viability and induced oxidative stress and ferroptosis. Oridonin also suppressed tumor growth via the ferroptosis-related mechanism. HMOX1 was found to be an interacting protein of oridonin, and oridonin induced ferroptosis by targeting HMOX1. In addition, oridonin promoted the stability of the HMOX1 protein by suppressing its ubiquitination at the K86 site. This study demonstrated that oridonin may inhibit tumor growth via ferroptosis through the inhibition of the HMOX1 ubiquitination process. The study findings will provide new therapeutic targets for HCC.

cGAS/STING signaling activation driven by mitochondrial DNA (mtDNA) release contributes to chronic heart failure (CHF) pathogenesis. Although the traditional Chinese medicine Xin-Ji-Er-Kang (XJEK) shows cardioprotective potential, its regulation of mtDNA dynamics remains unclear.

Cellular junctions are vital for endothelial cell (EC) function, with ZO-1 being a key tight junction protein influenced by miR-126. This study examines how 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNMT inhibitor, affects ZO-1 and miR-126 levels in HMEC-1 cells in vitro. HMEC-1 cells were treated with 5-Aza-CdR. ZO-1 expression was measured by real-time PCR and western blot. The expression level of miR-126 and its promoter DNA methylation level were determined by real-time PCR and MS-PCR. The mRNA and protein expression levels of DNMTs were detected by real-time PCR and western blot. The global methylation level was detected by 5-mC-positive signal using laser confocal microscopy and by combined bisulfite restriction analysis (COBRA) for Alu and Long interspersed element-1 (LINE-1) methylation patterns. Cell apoptotic and cell cycle were analyzed using cytometry. The expression of ZO-1 was enhanced with the upregulation of miR-126 via its promoter DNA hypomethylation. The DNMT1 and DNMT3A as well as global methylation levels were decreased with the S-phase cell cycle arrested in HMEC-1 cells which were treated with 5-Aza-CdR. This study indicated that 5-Aza-CdR can induce the ZO-1 expression related to the up-regulation of miR-126 through the DNA methylation mechanism in ECs.

Chronic exposure to arsenic is associated with an increased risk of developing diabetes mellitus. Quinic acid (QA), a cyclic polyol compound with known antioxidant and anti-inflammatory properties, was evaluated for its protective effects against sodium arsenite (SA)-induced hyperglycemia and hepatotoxicity in mice. In this study, mice were divided into 6 groups: control, SA (10 mg/kg), QA (200 mg/kg), and three groups receiving SA + QA at doses of 50, 100, or 200 mg/kg. After 28 days of treatment, fasting blood glucose was measured, followed by a glucose tolerance test. On day 30, blood samples were collected for analysis of serum liver enzymes, triglycerides, and cholesterol. Hepatic oxidative stress markers, inflammatory markers, glucagon-like peptide-1 levels, and serum levels of gastric inhibitory polypeptide and insulin were also measured. Hepatic glucose transporter protein 2 (GLUT2) expression was assessed by Western blot. Histological analysis of liver and pancreatic tissues was also performed. Arsenic exposure resulted in impaired glucose tolerance, oxidative stress, inflammation, and liver injury. Treatment with QA significantly reduced these effects, restored antioxidant defenses, reduced inflammatory responses, and improved glycemic control. Western blot analysis showed that GLUT2 protein expression was decreased in the SA group, whereas QA increased hepatic GLUT2 expression in a dose-dependent manner.

Severe viral infections can cause cell death as a protective mechanism to eliminate defective cells and limit further viral propagation. However, the precise mechanism underlying the decision between cell survival and death remains unclear. Here, we demonstrate that Engulfment and Cell Motility 1 (ELMO1), an intracellular protein that facilitates cytoskeleton rearrangement through activation of Rac family small GTPase 1 (RAC1), is involved in the Toll-like receptor 3 (TLR3)-induced apoptosis in human umbilical vein endothelial cells. RNA sequencing of cells treated with ELMO1-targeting siRNA (siELMO1) revealed that knockdown of ELMO1 increased the transcripts of extracellular matrix genes including COL5A1 and decreased the expression of cell cycle and DNA replication-related genes such as CCND1 and CDK1. These siELMO1 treated cells also showed G1/S cell cycle arrest. When stimulated with polyinosinic-polycytidylic acid (poly(I:C)), a TLR3 agonist, inflammatory cytokines and chemokines such as CXCL8 and IL6 robustly increased in Mock-treated cells, while siNT (non-targeting) cells underwent massive cell death and showed reduced inflammatory responses, reflecting apoptosis-inducing effects of sequential TLR3 activation by siRNA and poly(I:C). Strikingly, siELMO1 cells were resistant to the cell death, and restored inflammatory cytokine responses to the same level as Mock-treated cells. Mechanistically, apoptosis in siNT increased through the activation of caspase-8, whereas downregulation of ELMO1 inhibited the cleavage of caspase-8. These results indicate that ELMO1 is involved in the regulation between survival or death in endothelial cells through the regulation of caspase-8 activity downstream of TLR3, suggesting the importance of the ELMO1 in cell proliferation as well as susceptibility to poly(I:C)-induced apoptosis.

Cadmium (Cd) adversely affects plant growth and human health. However, the precise mechanisms through which plants adapt to and tolerate Cd toxicity remain unclear. Here, we identified a NAM, ATAF1/2, and CUC2 (NAC) transcription factor, BEARSKIN2 (BRN2), that is crucial in regulating Cd tolerance in Arabidopsis thaliana. Four-week-old wild-type (WT), brn2 mutants, sam1 mutants, brn2-1:SAM1-OX lines were exposed to hydroponic cultures in solutions with or without 50 μM Cd for 7 days. Yeast one-hybrid (Y1H) analysis indicated a putative interaction between BRN2 and S-adenosylmethionine synthase 1 (SAM1). Dual-luciferase (LUC), and Chromatin Immunoprecipitation (ChIP) assay analysis confirmed that BRN2 directly increased SAM1 transcript levels. Loss of BRN2 function caused increased Cd sensitivity and accumulation, while overexpression of BRN2 caused a Cd-resistant phenotype and lower Cd accumulation. The sam1 mutant exhibited higher Cd accumulation compared to the WT and displayed increased susceptibility to Cd stress, and brn2-1 ×sam1 double mutant showed Cd sensitivity similar to that of the sam1 mutant, while the overexpression of brn2 mutant rescued Cd tolerance and exhibited lower Cd accumulation, indicating that BRN2 contributes to Cd tolerance by facilitating SAM1 expression. Here, by examining the NAC family mutants that exhibit Cd resistance, we showed that BRN2 directly interacts with the NACRS regions of the SAM1 promoters and functions as a transcriptional activator to enhance Cd sensitivity.

Liver diseases, a cluster of diseases such as acute liver injury, chronic hepatitis, liver fibrosis, and hepatoma, pose a serious threat to public health. There is pressing clinical need to develop multiple effective approaches for the treatment of liver diseases. Sirtuin 5 (SIRT5), a member of the sirtuin family of NAD+-dependent deacylases, primarily regulates desuccinylation, demalonylation, and deglutarylation modifications. Through these activities, SIRT5 participates in key biological processes such as cellular growth, proliferation, and apoptosis, and affects the pathogenesis of various diseases. However, the mechanisms of SIRT5 contributing to liver diseases, particularly liver fibrosis, remain incompletely understood. Dysregulation of SIRT5 has been implicated in promoting the liver diseases progression by metabolism imbalance, excess mitochondrial oxidative stress, pro-inflammatory cytokines release, and abnormal autophagy. Given its unique post-translational modification activity and biological and physiological functions, SIRT5 has recently emerged as a promising therapeutic target against liver diseases. In this review, we summarize the current knowledge regarding SIRT5 in liver diseases to provide a comprehensive understanding of the research progress of SIRT5 in liver diseases.

As a principal species in freshwater aquaculture, the redclaw crayfish (Cherax quadricarinatus) depends on a competent immune system to mitigate environmental and pathogenic challenges. Quercetin, a ubiquitous plant-derived flavonoid, has garnered scientific attention due to its pleiotropic bioactivities, including antioxidant, anti-inflammatory, and immunomodulatory properties. This study investigated the effects of waterborne quercetin exposure on transcriptional regulation and antioxidant capacity in C. quadricarinatus. Over a 28-day period, crayfish were subjected to five quercetin concentrations (0, 1.0, 2.5, 5.0, and 10.0 mg/L), with outcomes evaluated against an untreated control. At the concentration of 5.0 mg/L, which showed the most pronounced effects among the tested concentrations, quercetin exposure was associated with significant downregulation of key transcripts in the NLRP3 inflammasome pathway (NLRP3, GSDMD, Caspase-1), as evidenced by the downregulation of NLRP3, GSDMD, and Caspase-1. Simultaneously, the transcriptional changes were consistent with the modulation/activation of the Nrf2 signaling axis, upregulating the expression of Nrf2, NQO1, and Keap1. These transcriptional changes indicate that quercetin attenuates pyroptosis and augments cellular antioxidant defenses via the Nrf2-Keap1 cascade. Correspondingly, the hepatopancreas displayed markedly elevated activities of SOD, CAT, and GSH-Px, accompanied by a significant reduction in MDA levels, indicating enhanced antioxidative capacity and diminished lipid peroxidation. This study provides valuable toxicological insights and elucidates part of the molecular basis for quercetin's immunomodulatory and antioxidant roles in freshwater crustaceans.

Transcriptional dysregulation by aberrant transcription factors (TFs) is a key driver of drug resistance. Resistance to adriamycin (ADR) frequently develops following first-line treatment for multiple myeloma (MM). This study aims to identify novel TFs associated with ADR resistance in MM and to elucidate their underlying mechanisms.

Gleditsia sinensis is an important economic and ecological tree species in China. However, severe flower and fruit abscission occurs during cultivation, which limits its yield. To investigate the regulatory mechanisms of its flower and fruit abscission, we applied various types and concentrations of plant growth regulators (PGRs) to 10-year-old female plants and analyzed early fruit development and abscission zone (AZ) cell morphology, carbohydrate content and sugar metabolism enzyme activity, endogenous hormone levels, and related gene expression. Our study demonstrated that application of 20 mg/L 2,4-Dichlorophenoxyacetic acid (2,4-D) at the flowering stage significantly enhanced the fruit setting rate and promoted earlier fruit development. The treatment with 2,4-D can make the cells in the AZ of the fruitlet arrange uniformly, reduce the gaps formed by the fracture of abscission tissues due to excessive tightness between the cells in the AZ, and enhance the activity of sugar metabolism enzymes and hormone content in the fruits, reducing fruit abscission. After 2,4-D treatment, the contents of auxin (IAA) and cytokinin (CTK) in the fruit pedicel, AZ, and fruitlet exhibited tissue specificity. Specifically, 2,4-D treatment promoted an increase in CTK content in the AZ and fruit pedicel, significantly elevated the IAA content in the AZ, and simultaneously reduced the GA7 content, thereby reducing fruitlet abscission. 2,4-D increased GsIAA levels in the AZ by up-regulating GsAUX1 (Auxin resistant 1 gene), GsARF, and GsIAA, while significantly down-regulating GsGH3. These expression changes are associated with increased IAA accumulation in the AZ, which likely enhances fruit set. Concurrently, after 2,4-D treatment, the down-regulating GsAUX1 and GsGH3 expression maintains a lower IAA concentration in the fruit pedicel. By simultaneously increasing IAA in the AZ and decreasing it in the fruit pedicel, 2,4-D establishes and maintains an IAA concentration gradient between the AZ and its proximal tissues. This gradient effectively inhibits the activation of AZ cells, thereby reducing fruitlet abscission. This study elucidates the physiological mechanism by which foliar application of 20 mg/L 2,4-D during flowering enhances fruit set in G. sinensis: by maintaining an IAA gradient in the AZ and optimizing carbohydrate supply. These findings provide a crucial theoretical foundation for improving cultivation practices for G. sinensis and other economically important tree species.

Quiescent leukemic stem cells (LSCs) that persist in the bone marrow microenvironment are responsible for chronic myeloid leukemia (CML) relapses and tyrosine kinase inhibitors (TKIs) resistance. This highlights a critical need to uncover alternative gene targets and pathways involved in LSC maintenance. Network biology in drug development has become essential for predicting drug targets in CML disease. This present computational study aims to identify key regulatory genes that are differentially expressed and involved in molecular pathway alternative to BCR-ABL, which may facilitate the eradication of leukemic stem and progenitor cells. Comparative analysis between CML stem and progenitor cells and their normal counterparts revealed 182 differentially expressed genes (DEGs). Applying Weighted Gene Co-expression Network Algorithm (WGCNA) identified a significant gene module comprising 73 hub genes. Protein-protein interaction and enrichment analyses indicated these genes are involved in mitochondrial translation elongation, steroid metabolism, cholesterol, and fatty acyl-CoA biosynthesis. Furthermore, a three-node regulatory network composed of hub genes, CML-associated transcription factors (TFs), and differentially expressed microRNAs (DEMs) was constructed, highlighting three key regulators: ELOVL6, SP1 (TF), and miR-1207-5p. To explore the therapeutic potential of the overexpressed target gene ELOVL6, we performed high-throughput virtual screening of phytochemical compounds against the ELOVL6 protein structure. Subsequent molecular docking, pharmacokinetics, toxicity, and molecular dynamics (MD) simulations revealed two phytochemicals - withaphysalin A and chelidimerine -as potential inhibitors of the ELOVL6 therapeutic biomarker in CML.

Our prior research has demonstrated that dysfunction of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is a common causal factor in the development of pulmonary vascular remodeling, as it accelerates cell proliferation and migration in pulmonary artery smooth muscle cells (PASMCs). Inflammation is known to play a critical role in pulmonary vascular remodeling. However, the contribution of SERCA2 dysfunction to inflammation within the pulmonary vasculature has not been previously reported. In this study, we observed significant inflammatory cell infiltration in the lungs of mice with SERCA2 dysfunction, particularly around the blood vessels. In PASMCs, SERCA2 dysfunction triggers inflammation and oxidative stress by downregulating peroxisome proliferator-activated receptor γ (PPARγ) and its downstream targets peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) and nuclear factor erythroid 2-related factor 2 (Nrf2). Targeting to improve PPARγ with pioglitazone, PGC1α with nicotinamide riboside, or to suppress reactive oxygen species (ROS) with 4-Hydroxy-TEMPO could efficiently ameliorate SERCA2 dysfunction-induced pulmonary vascular remodeling. Our study elucidates the direct regulation of SERCA2 dysfunction in initiating inflammation, which promotes cell proliferation, migration, and recruitment of inflammatory cells in PASMCs, ultimately contributing to the development of pulmonary vascular remodeling. Furthermore, SERCA2, PPARγ, PGC1α, and ROS may serve as potential therapeutic targets in the prevention and treatment of pulmonary hypertension.

Four nr1j1 gene sequences were recently reported in the marine mussel Mytilus galloprovincialis. These genes are orthologs of the nuclear receptor family NR1I found in vertebrates, whose members like the pregnane x receptor (PXR) are known to play a major role in the regulation of xenobiotic metabolism. Building on recent evidence that these four genes encode functional proteins, this study aims to deepen our understanding of nr1j1 genes by analyzing their expression in adult mussels exposed to different diets consisting of microalgae and cyanobacteria, and to the biotoxin okadaic acid. In parallel, we analyzed the expression of several nr1j1 putative target genes, such as cyp3-like and abcb1. Our results showed that gene expression regulation may be organ-specific and time-dependent, and that diet and food intake can affect the expression of the genes studied. The highest nr1j1 and cyp3-like transcriptional activation was observed in mussels fed with Tetraselmis sp., while abcb1 genes showed higher expression in mussels fed with toxic cyanobacteria. In contrast, exposure to okadaic acid did not induce changes in the expression of the analyzed genes. This work demonstrates that xenobiotic metabolism responses in mussels can be modulated by diet and exposure to biotoxins, underscoring the importance of diet in the elimination of toxic substances in mussels. The exact mechanisms underlying the observed transcriptional activation of the nr1j1 genes remain unknown.

The oligopeptide transporter (OPT) family belongs to a type of proton-coupled symporter and functions in the transport of metal ions, glutathione, phytochelatins (PCs), and metal-PC complexes, as well as in the regulation of metal homeostasis. Polplar, a fast-growing woody model species which has been resequenced multiple times, shows great potential in phytoremediation. However, the identification of OPT family genes and their responses to cadmium (Cd) and iron (Fe) remain poorly understood.

Cisplatin resistance remains a major challenge in the clinical treatment of bladder cancer (BC), and the epigenetic regulation of this resistance, particularly involving 5-hydroxymethylcytosine (5hmC), has not been fully elucidated. Here, we investigated the role of 5hmC and vitamin C (VC) in modulating cisplatin sensitivity in BC. Clinical analyses of 36 BC patients receiving cisplatin-based neoadjuvant chemotherapy showed that reduced 5hmC levels in pre-chemotherapy tumor tissues were significantly associated with cisplatin resistance (CR-BC) and poor prognosis, with low 5hmC correlating with shorter progression-free survival (PFS). In vitro, we established two cisplatin-resistant cell lines (T24-CR, UMUC-3-CR) that exhibited reduced 5hmC compared to parental cells. Treatment with 100 μM VC significantly restored 5hmC levels in CR-BC cells by activating TET enzymes, inhibited cell proliferation, and enhanced cisplatin sensitivity; these effects were abrogated by the TET inhibitor Bobcat339, confirming VC acts in a TET-dependent manner. Mechanistically, genome-wide 850 K methylation array and RNA-seq analyses revealed that VC upregulated methylation specifically at the promoter of ATF4, a downstream effector of the MAPK pathway, thereby downregulating ATF4 expression. ATF4 knockdown in CR-BC cells increasing cisplatin sensitivity, while Bobcat339 reversed VC-induced ATF4 downregulation. In vivo, VC combined with cisplatin significantly inhibited tumor growth in T24-CR xenografts, and co-treatment with ATF4 knockdown further enhanced this effect, accompanied by elevated 5hmC and reduced Ki67 in tumors. Collectively, our findings identify reduced 5hmC as a hallmark of cisplatin-resistant BC and reveal a novel mechanism by which VC enhances cisplatin sensitivity. VC activates TET enzymes to increase 5mC at the ATF4 promoter, downregulating ATF4 and modulating the MAPK pathway. This highlights VC as a potential epigenetic adjuvant to overcome cisplatin resistance in BC.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an emerging method that delivers chemotherapeutic agents as aerosols directly into the peritoneal cavity to overcome poor tissue penetration. Although early clinical outcomes are promising, challenges remain, such as variable patient responses and the lack of appropriate preclinical models. In this study, we investigated the efficacy of PIPAC combined with three cytotoxic agents (Cisplatin, Oxaliplatin, and Paclitaxel) using patient-derived colorectal cancer organoid models. Our results demonstrates that PIPAC, especially when combined with Cisplatin, significantly enhances the cytotoxicity against colorectal cancer organoids and modulates key cancer-related pathways. Transcriptomic analysis revealed significant alterations in gene expression patterns under PIPAC conditions, with notable impacts on cancer-related pathways such as epithelial-mesenchymal-transition and KRAS signaling. Pathway analysis further elucidated the modulation of cell-cycle related and oncogenic pathways by PIPAC, providing insights into its mechanism of action. These key findings suggest that PIPAC, particularly with Cisplatin, can enhance chemotherapeutic efficacy via transcriptomic modulation, supporting its potential clinical application in treating peritoneal carcinomatosis.

Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.