The rising prevalence of chronic diseases, including cancer, metabolic disorders, neurodegenerative, and cardiovascular conditions, presents a growing challenge to modern medicine and public health.

Sarcopenia is highly prevalent in individuals with diabetes and is associated with impaired physical function and increased mortality. Diabetes-associated skeletal muscle atrophy is driven by chronic inflammation, dysregulated anabolic-catabolic signaling, and activation of ubiquitin-proteasome-mediated protein degradation. Emerging evidence suggests that histone deacetylases (HDACs) act as epigenetic regulators of metabolic and inflammatory pathways; however, their role in diabetic sarcopenia remains incompletely understood.

The WRKY transcription factor is a key regulatory protein involved in defence hormone signalling and plays a pivotal role in plant hormone-mediated disease resistance. However, the specific mechanism by which WRKY transcription factors regulate the jasmonic acid (JA) pathway to confer resistance against Verticillium wilt in cotton remains poorly understood. In this study, we demonstrated that GbWRKY11 expression in Gossypium barbadense was induced by both Verticillium dahliae and methyl jasmonate (MeJA), and its encoded protein functioned as a nuclear transcription activator. Functional analyses revealed that GbWRKY11 enhances Verticillium wilt resistance by modulating JA pathway-related gene expression in both cotton and Arabidopsis. Exogenous MeJA application restored resistance in GbWRKY11-silenced plants, further supporting its role in JA-mediated immunity. Mechanistically, GbWRKY11 directly binds to the W-box motif in the promoter of GbLOX5, a key JA biosynthesis gene, and activates its transcription. Silencing GbLOX5 compromised cotton resistance to Verticillium wilt, confirming the importance of JA synthesis in this defence response. Our findings elucidate the molecular mechanism by which GbWRKY11 mediates immune responses against Verticillium wilt, providing novel insights into the genetic resources associated with disease resistance in G. barbadense.

Staphylococcus aureus biofilm formation enhances survival on host tissues and medical devices. This study tested how oxidative stress (H₂O₂), pH (5-9), NaCl (0-10%), and human serum (5-50%) affect the Newman strain biofilm and key genes (icaA, icaD, sarA). Biofilm was quantified by crystal violet assays and Lowry protein assay methods, and gene expression was measured by quantitative real-time PCR. Biofilm biomass was quantified using crystal violet staining and Lowry protein assays under various environmental conditions. Statistical significance was determined using ANOVA with post hoc analysis (p < 0.001). Hydrogen peroxide induced a dose-dependent reduction in biomass, with significant repression of icaA, icaD, and sarA expression at 3% H₂O₂ (≤ 22.8%, p < 0.001). Similarly, deviations from neutral pH markedly impaired biofilm formation, with acidic (pH 5) and alkaline (pH 9) conditions reducing biomass by 34.6% and 41.7%, respectively, accompanied by strong downregulation of biofilm-associated genes (p < 0.001). In contrast, NaCl exerted a biphasic effect: mild osmotic stress (1.25% and 5%) enhanced biofilm biomass (up to 154.2%) in the case of crystal violet assays and at 5% biomass increased to 130.8 ± 10.8*%; at 10%, it was 103.5 ± 6.1% (no significant change) in the case of protein quantification, and gene expression (icaA 160.55%, icaD 168.18%, sarA 149.8%, p < 0.001), whereas higher concentrations (≥ 10%) restored expression to near-control levels. Serum exposure produced a threshold-dependent response, with low concentrations (5-10%) slightly enhancing gene expression (~ 110%), while higher concentrations (20-50%) significantly repressed both biomass and transcription, with profound inhibition found at 50% (icaA 12.94%, icaD 10.88%, sarA 12.79%, p < 0.001). In addition, confocal laser scanning microscopy technique is used as a confirmatory step for qualitative determination of the effects of both various saline and serum concentrations on the biofilm formation, which induces similar results. Environmental stressors modulate S. aureus biofilm formation in a dose-dependent manner via regulation of the ica operon and sarA, offering molecular insights that may guide strategies for biofilm control. KEY POINTS: • Oxidative stress (H₂O₂) dose-dependently inhibits S. aureus Newman biofilms. • Mild NaCl levels enhance biofilm formation via upregulation of ica and sarA. • High serum concentrations (≥ 20%) suppress biofilm biomass and gene expression.

Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the "synthetic lethality" principle to cancers with abnormal epigenetic changes provides more opportunities for developing novel therapeutic strategies. It is necessary to identify more molecules that are involved in the DNA damage repair response or cell fate determination to reach this end. Malignant brain tumor (MBT) domain proteins are important for development and cell fate. L3MBTL4 is a new member of this family, but its function remains to be clarified.

The distinct chemical behaviors of Cadmium (Cd) and arsenic (As) make the co-contaminated paddy soils pose severe risks to rice safety and public health. This study first demonstrates the manganese(II) sulfate (MnSO4) mitigates Cd and As co-accumulation and co-toxicity in rice, and elucidates the underlying mechanisms by employing integrated ionomic, transcriptomic and metabolomic analyses. Application of moderate to high doses of MnSO4 in pot experiments increased brown rice yield by 208.78-428.60% while reducing Cd and As content by 4.89-21.98% and 60.65-81.73%, respectively. MnSO4 mediates Cd distribution through direct competitive antagonism, whereas As sequestration is governed by more complex and indirect regulatory pathways. The MnSO4 amendment also orchestrates a remodeling of the mineral element network by regulating key genes and metal transporters. This mechanism ultimately limits the accumulation of Cd and As in the grain via distinct pathways: by hindering root to brown rice Cd translocation and inhibiting stem/leaf to brown rice As translocation. Transcriptomic and metabolomic analysis further revealed that Mn alleviates combined Cd-As stress by downregulating key pathways involved in lipid peroxidation and sphingolipid metabolism, thereby enhancing cellular membrane stability. Collectively, MnSO4 integrates transporter regulation, ionomic reconfiguration, and metabolic adaptation to alleviate Cd-As co-stress in rice. Our findings provide a effective approach to ensure rice safety in contaminated regions.

Gastric cancer (GC) is one of the most common and lethal cancers globally. methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) RNA methylation plays a crucial role in tumor initiation and progression by regulating RNA function. STM2457, a highly efficient METTL3 inhibitor, can inhibit METTL3 activity and may serve as a potential therapeutic strategy in cancers. However, the role of STM2457 for GC cells is still unknown. In this study, we analyzed the expression profile data of GC in TCGA and GEO databases, and further explored the expression involvement of METTL3 in GC cell line, investigated the therapeutic effect of STM2457 targeted inhibition of METTL3 in GC both in vitro and in vivo experiments. The results indicated that STM2457 could suppress GC cell proliferation and migration by inhibiting METTL3, and also promoted cell apoptosis and arrest the cell cycle in S phase. In addition, STM2457 could inhibit tumor growth in subcutaneous xenotransplantation mouse model. Our findings suggested that STM2457 had great potential for the treatment of GC and could serve as a foundation for future clinical applications.

Methine sulfoxide reductase (MSR) plays a crucial role in protecting plants from oxidative damages. However, their involvement in copper (Cu) detoxification remains largely uncharacterized. In this study, we identified 17 MSR genes in wheat (Triticum aestivum), 12 MSR genes in Triticum dicoccoides (Td), 6 in Triticum urartu (Tu), and 5 in Aegilops tauschii (Aet). Strong collinearity and conservation were found among orthologs. Three constitutively expressed homoeologs of TaMSRB5 were significantly upregulated in leaves and downregulated in roots of wheat seedlings when exposed to excessive Cu. Overexpression of TaMSRB5 in Arabidopsis significantly enhanced Cu tolerance as evidenced by increased fresh weight and root length in transgenic plants, compared to wild-type (WT, Col-0). Under Cu toxicity, Arabidopsis overexpression lines accumulated similar levels of Cu in their leaves and roots compared with WT. However, they exhibited elevated levels of oxidized glutathione (GSSG), total glutathione (T-GSH), along with Glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities. Simultaneously, they showed reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and a lower GSH/ GSSG ratio, indicating enhanced ROS scavenging ability. Consistent with the moderation of oxidative stress, comparative transcriptome analysis revealed that four GST genes were upregulated in transgenic Arabidopsis plants under Cu stress, suggesting the potential relationship between these genes with TaMSRB5 in Cu detoxification. The findings demonstrate the pivotal role of TaMSRB5 in enhancing Cu tolerance in Arabidopsis and provide novel insights into the molecular mechanisms underlying Cu detoxification.

Vitamin D (VD) deficiency is commonly observed in obesity, which may increase morbidity risk. This study explores the effect of fructooligosaccharide (FOS) on VD signaling and inflammatory status in diet-induced obese mice.

The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistance to these therapies often develops rapidly, and the underlying resistance mechanisms remain largely unclear. Here, we identified the aryl hydrocarbon receptor (AHR) as a crucial operator of ENZ-resistant CRPC. AHR is upregulated in three ENZ-resistant human CRPC cell lines (C4-2BENZR, CWR-R1ENZR, and VCaPENZR) as well as in high-grade prostate tumors from patients receiving ENZ treatment. Stable knockdown of AHR substantially reduced the growth of ENZ-resistant CRPC cells and xenografts. Mechanistically, AHR engages in distinct transcriptional programs in a cellular context-dependent manner. AHR directly regulates the transcription and expression of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes in CWR-R1ENZR cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2BENZR cells, indicating an AR-indifferent mechanism of ENZ resistance. The diverse mechanisms triggered by ENZ were also manifested in clinical samples. Collectively, these findings characterize AHR's contribution to ENZ resistance in CRPC and illuminate the potential of targeting AHR for treating ARSI-resistant advanced prostate cancer.

Epigenetic dysregulation is a fundamental cancer hallmark, and lysine demethylase 1 (LSD1) is a central target for cancer intervention. Developing novel LSD1 inhibitors with high selectivity, favorable bioavailability, and safety for acute myeloid leukemia (AML) remains challenging. We developed DC551040, a highly potent, selective irreversible LSD1 inhibitor with good tolerability in Phase I AML clinical trial (CTR20222026). DC551040-LSD1 complex crystal structure uncovered a new binding pocket, providing molecular insights for subsequent LSD1 inhibitor design. Given the significant role of LSD1 in epigenetic regulation, we performed comprehensive transcriptomic and proteomic analyses to investigate gene and protein expression dynamics following DC551040 treatment in an MV-4-11 xenograft model. These analyses revealed that multiple immune and inflammation related pathways are activated upon DC551040 treatment, including the key members STAT5, NF-κB, and AKT, suggesting the potential for adaptive resistance. Through a search of the Connectivity Map (CMAP) database, we identify homoharringtonine (HHT), an approved anti-leukemia drug, which mimics the anti-transcriptional activation of inflammatory pathways. Subsequent in vitro and in vivo experiments validated the efficacy of combining HHT with DC551040, demonstrating a synergistic antitumor effect and extended survival in MV-4-11 disseminated xenograft model mice. Together, this study not only introduces a novel LSD1 inhibitor but also delves into the molecular mechanisms underlying LSD1 inhibitors, while proposing a promising combination therapy for AML individuals in clinical trials.

Conventionally, KDM5C functions as a specific demethylase that targets histone H3 lysine 4 dimethyl and trimethyl modifications, crucial for gene expression. However, the role of KDM5C in multiple myeloma (MM) progression and bortezomib (BTZ) resistance has remained elusive. In this study, we found noncanonical functions of KDM5C in MM. Specifically, KDM5C binds to CBP and MYC, conferring BTZ resistance in MM through a demethylase-independent mechanism. Our investigations revealed that KDM5C is markedly upregulated in BTZ-resistant MM patients as well as those with relapsed MM. Significantly, the expression level of KDM5C exhibits an inverse correlation with the overall survival of MM patients. Moreover, KDM5C is indispensable for MM cell proliferation. Depletion of KDM5C augmented the sensitivity of MM cells to BTZ treatment both in vitro and in vivo. We found that KDM5C forms a novel complex with CBP and MYC via its PHD2 domain. This complex formation triggers lysine 27 acetylation in histone H3 (H3K27ac) and subsequent enrichment of H3K27ac on the PERK promoter. As a result, PERK transcription is activated, and Nrf2 phosphorylation is promoted, bolstering the unfolded protein response within the endoplasmic reticulum of MM cells. In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.

The rapid rise of antibiotic-resistant Gram-negative pathogens underscores the critical need for alternative therapeutic approaches. Biofilm formation contributes significantly to pathogen resistance and persistence. This study aimed to investigate the antibacterial and anti-biofilm activity of Fumaria officinalis (FO) extract prepared via a green ionic liquid-based extraction method, evaluating its effect on type 1 fimbriae (fimH) and outer membrane protein L (oprL) gene expression. A heat-assisted extraction method is designed and presented in the research with the objective of obtaining valuable biochemical from natural FO using the green solvent 1-butyl-3methylimidazolium chloride (BMIMCl). Quantitative spectrophotometric assays showed high concentrations of secondary metabolites including total phenols (38.84 ± 1.71 mg GAE/g), total flavonoids (36.80 ± 4.51 mg QE/g), and total terpenoids (36.52 ± 7.3 mg OAE/g). Non-volatile bioactive markers, including fumaric, caffeic, and ferulic acids, alongside flavonoids and twenty-five volatile bioactive compounds were identified via HPLC and Gas chromatography-mass spectrometry (GC-MS) analysis. Biofilm inhibition was quantified via the microtiter plate method and antibacterial activity was evaluated by agar well diffusion against biofilm-producing isolates; minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays were also performed. The effect of FO extract on the expression of the fimH and OprL genes was evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) technique. Out of 14 isolates, only three were found to be strong biofilm producers, while 4 isolates were shown to be moderate biofilm producers. The extract exhibited higher inhibitory activity against moderate biofilm-producing isolates, with MIC values 265 and 512 μg/mL. qRT-PCR demonstrated down-regulation of fimH and OprL expression in treated isolates. FO extract obtained via a sustainable green process showed antibacterial and anti-biofilm properties, partly via suppression of fimH and OprL genes expression; therefore, this study records the first green and sustainable method for FO plant biochemical compound extraction. Additionally, this work shows the inhibitory effect of FO on the two fundamental genes responsible for biofilm formation and bacterial colonization, aiming to balance the ecosystem and human well-being.

This study aims to systematically investigate the molecular mechanisms through which parabens may contribute to head and neck squamous cell carcinoma (HNSCC) carcinogenesis using integrated network toxicology and molecular docking.

Streptococcus mutans (S. mutans) is a primary cariogenic pathogen responsible for acid production, exopolysaccharides (EPS) production and biofilm formation. Two-component systems (TCS) regulate EPS metabolism, especially the VicRK TCS. Overexpression of antisense vicR (ASvicR) can reduce EPS production and thereby weaken the cariogenicity of S. mutans. Although the antimicrobial monomer dimethylaminohexadecyl methacrylate (DMAHDM) exhibits potent antibacterial properties, mature S. mutans biofilms can protect themselves by extracellular matrix. Emerging evidence suggests that genetic intervention enhances drug efficacy, yet the underlying regulatory mechanisms remain largely unexplored.

To explore the protective effects of cassia polysaccharides on myopia by examining their influence on ARPE-19 cells with reduced PAX6 expression.

The zebrafish vestibular otolith organs, like those of other vertebrate species, are organized into central (striolar) and peripheral (extrastriolar) zones that drive different vestibular circuits. How and when these spatial hair cell patterns develop in the zebrafish is unknown. We determined that early-developing hair cells (<36 h) expressed both striolar and extrastriolar transcriptomic markers. After 36 h, these hair cells become specified as extrastriolar hair cells. Later-developing hair cells (>36 h) mostly develop directly as striolar or extrastriolar. We observed complementary patterns of retinoic acid (RA) degrading and synthesizing enzymes that colocalize with striolar and extrastriolar hair cells, respectively, indicating evolutionarily conserved molecular signaling. RA treatment during development increased the proportion of extrastriolar and intermediate-type hair cells, indicating that increased RA reduces striolar development. However, in fish with mechanotransduction dysfunction from a cadherin 23 mutation, normal RA patterning is insufficient to finalize the fate of early-born hair cells, which remain transcriptomically unresolved. RA treatment further exacerbates this abnormal patterning. We conclude that hair cell fate, and thus normal zonal patterning, depends on both hair cell activity and the RA gradient.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although an immune checkpoint blockade can reduce metastasis, its effectiveness is hindered by the immunosuppressive microenvironment in TNBC. EZH2 is overexpressed in TNBC, and patients with high EZH2 expression are associated with poor prognoses. The study developed EIP103 as a first-in-class peptide degrader that targets EZH2 through multivalent, high-affinity interactions and induces conformational destabilization, representing a mechanism distinct from that of the small molecule inhibitor EPZ-6438. The results demonstrated that EIP103 induces immunogenic cell death through lipid peroxidation, resulting in enhanced immune cell infiltration. Additionally, molecular dynamics (MD) simulations and biochemical assays revealed that the peptide EIP103 binds to the SET domain of EZH2, altering its structure and triggering proteasomal degradation via Praja Ring Finger Ubiquitin Ligase 2 (PJA2)-mediated ubiquitination. Harboring both enzymatic inhibition and post-translational regulation properties, EIP103 exerts durable efficacy and activates antitumor immunity, making it a promising therapeutic candidate for TNBC.

Enzalutamide resistance (EnzR) is a major challenge in the current treatment of castration-resistant prostate cancer, as tumors frequently progress to drug resistance after an initially effective treatment. Therefore, there is an urgent need to characterize the genes alterations that accompany EnzR in prostate cancer and to identify new therapeutic targets. In this study, we analyzed a total of 1273 publicly available transcriptomics datasets from patients who underwent prostate cancer surgery. We investigated transcriptomic changes after enzalutamide (ENZ) treatment, identified key genes involved in the process of EnzR, and developed EnzR scores to predict tumor progression. We further investigated the role of IGFBP3 in the regulation of EnzR in prostate cancer. The effect of IGFBP3 expression level on the malignant degree of EnzR cells was explored in vitro. In addition, we explored the downstream mechanism of IGFBP3 involvement in EnzR. We found that epithelial-mesenchymal transition (EMT), cancer stem cell-like properties, and neuroendocrine transformation occurred in tumor cells after ENZ treatment. Subsequently, we developed and validated EnzR scores to predict prostate cancer tumor progression. Furthermore, we experimentally confirmed that IGFBP3 promotes the proliferation of drug-resistant cells and enhances ENZ resistance via EMT signaling. Overall, we established a new EnzR scoring model through multidimensional analysis of EnzR patterns. This model can accurately predict the clinical prognosis of prostate cancer patients after surgery. Moreover, IGFBP3 can be used as a potential therapeutic target for ENZ resistance in prostate cancer.

Metastatic gastric cancer (GC) has a poor prognosis. Recent research demonstrated the aberrant expression of nuclear receptor HNF4α and the regulatory roles of its isoforms during the processes of tumorigenesis and development. However, the expression patterns of HNF4α and its potential as a therapeutic target in metastatic GC remain elusive. In this study, we unveiled that P2 promoter-driven HNF4α (P2-HNF4α) was highly expressed in distant metastasis of GC, playing a pivotal role in fostering the migration and metastasis of GC cells both in vitro and in vivo. The transactivational activity was essential for HNF4α to promote GC cell migration. An integrative analysis of transcriptome and metabolome implied the involvement of the glycolytic pathway in the promotion of GC cell migration by P2-HNF4α. We further found that P2-HNF4α directly bound to the enhancer of the HKDC1 gene and upregulated its expression, thereby orchestrating a metabolic rewiring conducive to promoting GC migration and metastasis. Mycophenolic acid, an active metabolite of the FDA-approved drug mycophenolate mofetil, demonstrated the ability to suppress HKDC1 expression and GC migration and metastasis in vitro and in vivo through antagonizing HNF4α. Therefore, this study sheds light on the HNF4α-HKDC1 axis as a key player in GC metastasis, providing a promising targeted therapeutic strategy for metastatic GC.