Despite advances in lymphoma therapy, significant challenges persist including R-CHOP resistance and CAR-T toxicity. Hydroxamate-based histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) offer epigenetic therapeutic potential but are limited by poor bioavailability and rapid clearance.

Mycotoxins, toxic secondary metabolites produced by pathogenic fungi contaminating agricultural commodities, represent a significant threat to food safety and human health. Notably, Aspergillus flavus and its associated aflatoxins are primary food contaminants requiring rigorous prevention and control strategies. This study elucidates the mechanism by which neocryptolepine, a natural antifungal compound, inhibits A. flavus growth and aflatoxin B1 accumulation in corn. Neocryptolepine effectively impedes the vegetative growth of A. flavus filaments and spores, disrupting cellular integrity by interfering with cell wall component synthesis. Furthermore, neocryptolepine treatment induces mitochondrial dysfunction in A. flavus cells, leading to disruptions in energy metabolism and reactive oxygen species homeostasis. Transcriptomic sequencing revealed that neocryptolepine downregulates the expression of aflatoxin biosynthetic gene clusters, such as aflJ, and related global regulatory factors, thereby suppressing aflatoxin biosynthesis. Importantly, the drug protected corn kernels from A. flavus infection without affecting their germination capacity. These findings suggest that neocryptolepine holds promise as a potential eco-friendly mycotoxin inhibitor for application in agricultural and food production.

Triptolide (TP) exhibits various pharmacological activities. Our previous studies have confirmed the efficacy of TP against lung adenocarcinoma (LUAD). However, the potent pharmacological activity of TP is underpinned by its complex mechanisms. Exploring its potential mechanisms is of great value for promoting the clinical application of TP and extending its clinical use.

Considered one of the most prevalent monounsaturated fatty acids (MUFA) from marine and plant sources, omega-9 fatty acids (n-9) have gained worldwide recognition since due to its strong anti-obesogenic properties. These findings highlight the anti-obesity efficacy and mechanism of n-9, gondoic acid (GA) for anti-obesity interventions, offering a novel research perspective at recent research field. The animals (BALB/c male mice) were segregated into six study groups: the control group (C) received normal chow diet; the vehicle control group (VC) received normal chow diet + olive oil; high fat diet (HFD) received by the obese control group (OC); and the treatment-I (T-I), treatment-II (T-II), treatment-III (T-III) group co-administered with GA as follows: 1 mg/kg GA + HFD; 2 mg/kg GA + HFD; 4 mg/kg GA + HFD. In this study, GA was delivered orally once daily for six weeks to diet-induced obese mice. According to the findings, administering GA decreased weight gain, blood lipid profile levels, improved inflammation and adipogenesis. The mRNA expression studies and western blot assay found that GA administration may boost glucose metabolism, enhance the process of thermogenesis and β-oxidation in mitochondria via the AMPK mechanism, reducing HFD-induced adiposity. In brief, our findings can point in a broader direction for the use of GA in obesity based on genetic indicators.

Immune checkpoint inhibitors (ICI) have transformed cancer therapy, but their efficacy in sarcomas remains limited. A seven-gene predictive signature (CD86, CHI3L1, CXCL10, CXCL9, LAG3, NR4A1, and VCAM1) was previously identified as a biomarker for response to combined antiangiogenic and PD-1 inhibitor therapy in soft-tissue sarcomas. This study aimed to externally validate the predictive utility of this signature [SIGNature for immuno-oncology PD-1 inhibitors in sarcoma (SIGNIOS)] in an independent cohort of patients with sarcoma treated with ICIs.

Vismodegib, a Smoothened (Smo) receptor antagonist, effectively suppresses Hedgehog (Hh) signaling activity during embryonic development and is known to influence craniofacial morphogenesis. However, its specific role in temporomandibular joint (TMJ) development remains unclear. In this study, a single dose of vismodegib (150 mg/kg) was administered to pregnant mice at embryonic day 14.5 (E14.5) to investigate its impact on fetal TMJ morphogenesis. At postnatal day 21, offspring from the treatment group exhibited significantly reduced condylar length and bone surface area density compared to vehicle-treated controls. Despite no observable differences in cellular proliferation or apoptosis-as assessed by phospho-Histone H3 (PHH3) and TUNEL assays-angiogenic markers, including VEGF, CD31, and CD34, were markedly upregulated in the condylar region of vismodegib-treated mice. Furthermore, at E15.5, expression of key components of the Ihh-PTHrP signaling axis (Gli1, Ptch1, and PTHrP) was significantly downregulated in the experimental group relative to controls. These findings suggest that vismodegib disrupts TMJ development by inhibiting the Ihh-PTHrP signaling pathway, thereby altering angiogenesis in the condyle and ultimately impairing cartilage growth and structural integrity.

Anoikis resistance, or evasion of cell death triggered by matrix detachment, is a hallmark of cancer cell survival and metastasis. We showed that repeated exposure to suspension stress followed by recovery under attached conditions leads to development of anoikis resistance. The acquisition of anoikis resistance was associated with enhanced invasion, chemoresistance, and immune evasion in vitro and distant metastasis in vivo. This acquired anoikis resistance was not genetic, persisting for a finite duration without detachment stress, but was sensitive to CDK8/19 mediator kinase inhibition that could also reverse anoikis resistance. Transcriptomic analysis revealed that CDK8/19 kinase inhibition induces bidirectional transcriptional changes in both sensitive and resistant cells, disrupting the balanced reprogramming required for anoikis adaptation and resistance by reversing some resistance-associated pathways and enhancing others. Both anoikis resistance and in vivo metastatic growth of ovarian cancers are sensitive to CDK8/19 inhibition, thereby providing a therapeutic opportunity to both prevent and suppress ovarian cancer metastasis.

The continuous increase in antibiotic resistance necessitates a global need to search for new sustainable antimicrobial agents, such as plant-delivered antimicrobial components. This study investigates the antimicrobial and antibiofilm properties of two tannins isolated from the flowers of Jatropha integerrima against multidrug-resistant Klebsiella pneumoniae. The two active tannins were isolated from the methanol-soluble portion of 70% aqueous methanol flower extract, by consecutive column chromatography. Their antimicrobial activity against the resistant K. pneumoniae isolate (BKP-122) was assessed through agar well diffusion and minimum inhibitory concentration (MIC) assays. Their antibiofilm activity was evaluated by using the microtiter plate method and real-time PCR to reveal their effect on the biofilm-associated genes.Their structures were identified as 2 hydrolysable ellagitannins, namely 1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-B1,4-glucopyranose (Jatrophenin-1) and 1-O-galloyl-3,6-(R)-valoneoyl-D-B1,4-glucopyranose (Jatrophenin-2), together with vicenin-2, acacetin 7-O-β-D-glucopyranoside, (E)-p-coumaric acid, and sucrose, based on the chromatographic characters, 1H-, and 13C NMR analyses. They were found to have potent antimicrobial activity and antibiofilm activity against the resistant K. pneumoniae isolate (BKP-122). Real-time PCR analysis indicated that treatment with tannins resulted in the downregulation of critical biofilm-related genes, including luxS, mrkA, pgaA, wzm, and wbbM. Additionally, the two compounds showed high docking binding scores against Topoisomerase IV, KPLpxH, and β-lactamase enzymes, and stable complexes, as evidenced by binding energy values ranging from -8.2 to -10 kcal/mol. These findings underscore the effectiveness of J. integerrima tannins as a viable therapeutic strategy to combat antibiotic resistance and biofilm-related infections, highlighting their role in modulating bacterial gene expression and biofilm development.

Emodin, a natural anthraquinone, exerts antitumor effects by increasing reactive oxygen species (ROS) and inducing apoptosis, autophagy, and cell-cycle arrest. However, its potential to induce ferroptosis, a distinct iron-dependent cell death, in hepatocellular carcinoma (HCC) remains unexplored.

Chronic inflammation promotes esophageal cancer (EC) progression through NFκB activation, yet the downstream effector genes driving EC progression remain incompletely characterized. Here, we identify syndecan-4 (SDC4) as a new NFκB target gene that is upregulated in EC and associated with poor prognosis. The pro-inflammatory cytokine IL1β stimulates EC cell proliferation and concurrently induces SDC4 expression in an NFκB-dependent manner. Mechanistically, NFκB directly binds to the SDC4 promoter region, which is enriched with the active chromatin marker H3K27Ac. Functional studies demonstrate that SDC4 is necessary for IL1β-driven proliferation, as its knockdown suppresses, whereas overexpression enhances EC cell proliferation. Notably, the natural compound epigallocatechin gallate (EGCG) effectively blocks this IL1β-NFκB-SDC4 axis by inhibiting NFκB nuclear translocation, thereby attenuating SDC4 upregulation and subsequent EC cell proliferation. Our findings establish SDC4 as a critical molecular link between inflammation and EC progression, and highlight EGCG as a potential therapeutic candidate targeting this pathway.

Air pollution has been implicated in various adverse health effects, including neurodevelopmental and neurodegenerative impairments. However, the long-term impact of early-life ultrafine particle (UFP) exposure on the brain remains poorly understood. Using a sequential exposure mouse model, we investigated how early-life ultrafine carbonaceous particles (UFPC) exposure programs neurobehavioural and molecular vulnerability upon adult re-exposure. Wild-type C57BL/6J mice were exposed to either HEPA-filtered air or UFPC during the prenatal (gestational days 8-9 and 16-17) and/or postnatal periods (postnatal days 4-7 and 10-13), followed by a 4-day re-exposure in adulthood (postnatal days 142-145). Behavioural assessments revealed hippocampus-dependent spatial memory deficits and anxiolytic-like behaviour following cumulative exposure. Brain proteomic analysis identified reduced protein levels of key modulators of synaptic signalling and neurovascular homeostasis (Erbb4 and Ddah1), accompanied by gene-specific promoter methylation changes and shortened telomere length, indicating persistent epigenetic reprogramming and accelerated cellular aging. We validated the epigenetic sensitivity of ERBB4 to prenatal air pollution in human cord blood from the ENVIRONAGE birth cohort. The integrative design, encompassing behavioural phenotyping and molecular profiling, offers a comprehensive systems-level perspective on the neurobiological effects of UFPC. Our findings suggest that developmental UFPC exposure induces increased susceptibility to re-exposure on behavioural, epigenetic, and proteomic outcomes. This work provides evidence for UFP as a potentially critical environmental determinant of brain health throughout life.

Phillyrin (KD-1), the principal bioactive component of Forsythia suspensa (Thunb.) Vahl, exhibits well-documented multifaceted anti-inflammatory and broad-spectrum antiviral activities. Notably, its specific antiviral efficacy against respiratory syncytial virus (RSV) and the underlying epigenetic regulatory mechanisms remain unexplored.

Proteolysis-targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI-/SNF-targeting agents in AR-negative CRPC. SWI-/SNF-targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT signaling-dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide that die yearly. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the proproliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Aberrant epigenetic regulation is a hallmark of diffuse midline glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the facilitates chromatin transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT co-occurred with the bromodomain and extraterminal domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition, revealed potent and synergistic cytotoxicity across a range of DMG cultures. These results were recapitulated in vivo, extending survival in three independent orthotopic patient-derived xenograft models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility and combined with BET inhibition to cause broad transcriptional collapse; silencing of several key oncogenes including MYC, PDGFRA, MDM4, and SOX2; and alterations to the splicing landscape. This combination also elicited immune-related effects, including activation of the interferon response and antigen presentation mechanisms in DMG cells and induction of an activated state in macrophages and T cells, as demonstrated in an immunocompetent setting with spatial transcriptomics. Together, our data highlight the therapeutic promise of simultaneously targeting FACT and BET proteins in DMG, offering a dual tumor-intrinsic and immune-mediated strategy for combating this devastating pediatric brain tumor.

Most antibiotics are natural compounds or their derivatives, and bacteria have evolved defensive mechanisms to resist them. Many of these mechanisms are still poorly understood or unknown. This study reveals that in Bacillus subtilis, the transcription factor HelD increases resistance to rifampicin by protecting its target, RNA polymerase (RNAP). This protection is mediated by the HelD N-terminal domain that penetrates into RNAP to the close vicinity of the rifampicin binding pocket. Importantly, the bacterium detects low rifampicin levels using a unique regulatory system involving two convergent promoters with finely tuned kinetic properties. In the absence of rifampicin, the stronger antisense promoter inhibits transcription from the sense promoter. In the presence of subinhibitory rifampicin concentration, the antisense promoter is more likely to encounter rifampicin-bound RNAP. This relieves the repression from the sense promoter, increasing its transcription by almost two orders of magnitude, boosting helD expression. A similar two-promoter arrangement also controls the pps gene, which encodes a rifampicin-modifying enzyme. These findings define a widespread bacterial response system sensitive to rifampicin, as this dual-promoter architecture is conserved across many bacterial species and found upstream of genes potentially involved in rifampicin resistance, such as those for hydrolases, transporters, and transferases.

Conventional treatments for bladder cancer exhibit various limitations. Therefore, natural products, such as jujuboside A (JuA), have been explored for their multi-target effects and low toxicity. However, the specific effects of JuA in bladder cancer remain unclear.

Myocardial infarction (MI) remains a major cause of morbidity and mortality. The ischemic myocardium undergoes necrosis and apoptosis, triggering inflammation and oxidative stress that drive fibrosis and heart failure. High-mobility group box 1 (HMGB1) protein acts as a key damage-associated molecular pattern, activating TLR4 and NFkappaB signaling to promote cytokine release and exacerbate injury. The present study investigated the role of HMGB1 in MI and its impact on inflammatory and redox-related pathways, focusing on the effects of HMGB1 blockade. Male WKY rats were divided into the following groups: sham, MI, and MI with anti-HMGB1 treatment (MI+aHMGB1). MI was induced in rats by coronary ligation followed by reperfusion, and the animals were evaluated seven days later. Plasma cytokines, total NOS activity and gene expression in the left ventricle were analyzed. MI significantly increased plasma TNF? and IL-6, while anti-HMGB1 treatment reduced both cytokines. Hmgb1 mRNA was markedly upregulated after MI and normalized by aHMGB1. MI suppressed Nos3 gene expression and total NOS activity, both of which were restored by aHMGB1. Tlr4 and NFkappaB mRNA levels were elevated after MI and remained high after HMGB1 inhibition, whereas Nos2 and IL-1beta gene expression declined. Antioxidant responses showed differential regulation: Sod1 and Sod2 were further upregulated by aHMGB1, Gpx4 expression normalized, and lipid peroxidation was found to be partially attenuated. These findings indicate that HMGB1 is a key driver of post-infarction inflammation and oxidative injury. Its inhibition modulates cytokine production, restores redox balance, and enhances endothelial protection, suggesting a promising therapeutic target for limiting myocardial damage.

Essential meiotic structure-specific endonuclease 1 (EME1) is integral to the maintenance of genomic stability in various cancers. However, its biological role and expression profile of this molecule in nasopharyngeal carcinoma (NPC) remain to be explored. In this study, we found that EME1 was overexpressed in NPC specimens compared to adjacent noncancerous tissues and was correlated with poorer overall survival outcomes. Furthermore, EME1 knockdown significantly inhibited the proliferation and migration of NPC cells in vitro and in vivo, with a corresponding sensitization to either camptothecin (CPT) or olaparib, evidenced by a further suppression of proliferation upon drug treatment. Notably, silencing EME1 significantly increased the sensitivity of NPC cell lines to CPT by enhancing ATM-CHEK2 phosphorylation and inducing nuclear abnormalities. Collectively, our findings suggest that combining EME1 modulation with agents such as CPT or olaparib could be an effective treatment strategy for NPC patients.

Chemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study aimed to investigate the role of DNA methylation in this complex process and evaluate the potential of the DNA methyltransferase inhibitor decitabine (DAC) in restoring chemosensitivity.

Testosterone synthesis in Leydig cells requires precise coordination between LH signaling and cholesterol metabolism, but the mechanisms underlying this regulation remain incompletely understood. In this study, we reveal a previously unrecognized YAP1-ACSL4 axis essential for LH-induced testosterone production by integrating transcriptomic profiling and functional studies in Leydig cells. Transcriptomic sequencing identified ACSL4 and YAP1 as key regulators of testosterone synthesis induced by LH. The inhibition of YAP1 led to the downregulation of ACSL4 expression, which significantly reduced testosterone production. Similarly, si-ACSL4 directly reduced testosterone production in Leydig cells. Notably, transcriptomic sequencing after interfering with ACSL4 showed that SOAT1 is a key molecule downstream of ACSL4. SOAT1 promoted testosterone synthesis by inhibiting esterification of free cholesterol and subsequently increasing cholesterol availability providing materials for testosterone synthesis. Mechanistically, ACSL4 modulates cholesterol availability through SOAT1 suppression, shifting metabolic flux from cholesterol ester storage toward cholesterol. These results indicate that LH promotes testosterone synthesis by upregulating YAP1 expression, which in turn increases ACSL4 expression, inhibits SOAT1 expression, and raises the concentration of free cholesterol. This finding provides the first evidence linking ACSL4-mediated lipid metabolism to gonadotropin-regulated steroidogenesis.