KRIBB11, a heat shock factor1 (HSF1) inhibitor, sensitizes cancer cells to several anticancer drugs. We have previously demonstrated that KRIBB11 alone induced the apoptosis of A172 glioblastoma cells. However, the molecular basis of its anticancer activity remains unclear. Hence, we aimed to examine the alterations in cell cycle regulators and the relevance of HSF1 activity following KRIBB11 treatment in A172 cells.

Erianin is a biphenyl compound with low toxicity and a single structure that is extracted from Dendrobium officinale. The wide spectrum of pharmacological properties and excellent toxicity of erianin have been comprehensively proven in multiple tumors. However, less is known about the toxicity of erianin in acute myeloid leukemia (acute myeloid leukemia AML). Here, we explored the anti-AML capacity and potential mechanisms of erianin. Cells proliferation and cytotoxicity of AML cells of erianin was detected by CCK-8 assay and flow cytometer was conducted to assess AML cells apoptosis rate. Erianin blocked the AML cells cycle at the G2/M phase by regulating cell cycle-related protein and P21, P27, and P53 mRNA expression. Additionally, we first filtered PPARɑ and PIK3R1 through network pharmacology, protein-protein interaction (PPI) network, and GO and KEGG pathway enrichment analysis and confirmed their binding with erianin by molecular docking analysis.The cellular thermal shift assay (CETSA) and the drug affinity responsive target stability assay (DARTS) further verified that PPARɑ was an effective target of erianin. Specifically, erianin was found to inhibit the transcriptional level of PIK3R1 by promoting the protein expression of PPARɑ, thereby inhibiting the PI3K/AKT pathway. The inhibitory effect of erianin was partially neutralized by GW6471, a PPARɑ inhibitor. Notably, erianin revealed vigoroso coordinate repression with LY294002 on AML cells. Our findings indicate that erianin showed a potent cytotoxic effect on AML cells and affected AML cells via PPARɑ to regulate PI3K/AKT signaling pathways. We demonstrated the potent anti-AML effects of erianin and reported its potential mechanisms of action, indicating its potential for further development as a novel anti-AML drug.

We explored JMJD2C's role in platinum resistance in ovarian cancer and its modulation by metformin to propose strategies for overcoming treatment limitations.

Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.

The present study aimed to investigate how sevoflurane (SEV) regulated the apoptosis of glioma cells through the mitochondrial apoptosis pathway. First, an evaluation was performed on the viability, apoptosis, mitochondrial reactive oxygen species levels, mitochondrial membrane potential and apoptosis and autophagy‑related protein expression of glioma cells according to experimental groups. Next, the expression of microRNA‑211‑5p (miR‑211‑5p), silent information regulator 1 (SIRT1) and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway was detected by reverse transcription‑quantitative PCR or western blotting. Dual luciferase reporter gene assay confirmed the targeting relationship between miR‑211‑5p and SIRT1. In addition, SEV suppressed the proliferation and induced the apoptosis in human glioma cell line cells via the mitochondrial apoptosis pathway. In mechanistic analysis, the miR‑211‑5p level in glioma cells was low, while following SEV treatment, it was increased. Furthermore, SEV regulated SIRT1 by upregulating miR‑211‑5p expression, thereby blocking the PI3K/AKT signaling pathway activation. Moreover, functional rescue experiments showed that downregulation of SIRT1 or miR‑211‑5p could reverse the effects of SEV on glioma cells. Collectively, SEV promoted apoptosis in glioma cells by inducing miR‑211‑5p, which regulated SIRT1/PI3K/AKT pathway, mediating mitochondria‑dependent apoptosis pathway. This finding may open new possibilities for SEV as a potential treatment for glioma in the future.

Chondrosarcoma is the second most common form of primary bone cancer originating from cartilage. Chondrosarcoma cells have a high propensity to spread to other organs during the advanced stage, with the lung being a preferred site. Although surgery is the most effective treatment for chondrosarcoma, it has low efficacy in the metastasis stage. Antrodia cinnamomea is the source of the triterpenoid antcin K, which exhibits immunomodulatory and anti‑inflammatory properties. However, the therapeutic function of antcin K on chondrosarcoma has not yet been elucidated. The inhibitory effect of antcin K was evaluated using migration and invasion assays while cell toxicity was determined using the MTT assay. Molecular function regulation by antcin K was investigated by RNA sequencing and Ingenuity Pathway Analysis. The present study revealed that antcin K decreases migration and invasion in two chondrosarcoma cell lines. RNA sequencing revealed that MMP‑7 serves a key role in antcin K‑mediated motility of chondrosarcoma cells. Antcin K diminished MMP‑7 expression, and overexpression of MMP‑7 antagonized antcin K‑induced inhibition of cell migration and invasion. Antcin K abolished the activation of PI3K, Akt, mTOR and NF‑κB pathways. The present study demonstrated that antcin K is a novel candidate for chondrosarcoma motility inhibition by decreasing the PI3K, Akt, mTOR and NF‑κB signaling cascades, which inhibits MMP‑7 production.

With the acceleration of the pace of modern life and the increase of environmental pressure, women are facing increasingly prominent health problems, ovarian dysfunction will not only lead to fertility decline, but also may lead to a series of endocrine disorders, seriously affecting women's quality of life. The purpose of this study was to explore the potential role of American panax panax in improving ovarian dysfunction by activating the BDNF/AKT/Bcl-2/Bax signaling pathway via miR-151-5p based on infrared thermal imaging technology. The study constructed an animal model of ovarian dysfunction, and used infrared thermal imaging technology to monitor the ovarian region in real time and record its temperature changes to evaluate the treatment effect. Through these data, we analyzed the activation effect of American ginseng extract on the signaling pathway and its relationship with the improvement of ovarian function. The results of the study showed that the infrared thermography of the ovarian region treated with American ginseng extract showed a significant increase in temperature, indicating increased ovarian blood flow and enhanced metabolic activity. These changes suggest that American ginseng extract can effectively activate the BDNF/AKT/Bcl-2/Bax signaling pathway, thereby improving ovarian dysfunction. The results showed that American ginseng extract can effectively promote the repair and functional recovery of ovarian tissue, and infrared thermal imaging technology has a good application prospect in monitoring the therapeutic effect.

Lead (Pb) is highly toxic and widely distributed in the soil, causing adverse effects on plant growth and yield formation. Herein, the combination of transmission electron microscope (TEM), energy dispersive X-ray Spectroscopy (EDS), and comparative transcriptome analyses was conducted to reveal the cytological mechanism and regulatory network of in the ZmbZIP54-mediated Pb tolerance in maize. As results, ZmbZIP54 helped in Pb2+ retention in the cell wall and intercellular space, inhibiting Pb2+ entering the cells and reducing its toxic effects on cell ultrastructure. Meanwhile, ZmbZIP54 was involved in the transition between the HCl-extracted and CH3COOH-extracted Pb speciations. At the molecular level, ZmbZIP54 affected the macromolecule metabolism, thus decreasing Pb accumulation in the roots. Moreover, ZmZIFL1 and NRT1/PTR were the direct targets of ZmbZIP54, which participated in heavy metal binding, nitrogen uptaking, and IAA transport and thus mediated Pb transport, Pb speciation transition, and antioxidant enzyme activation. Collectively, we proposed a model to explain the complex regulatory network mediated by ZmbZIP54 and its target genes in maize tolerance to Pb stress.

Exogenous salicylic acid (SA) enhances plant tolerance to cadmium (Cd) stress by preserving chlorophyll, stabilizing osmoprotectants, and upregulating antioxidant activity alongside the ASA-GSH system. However, the role of endogenous SA in plant tolerance to Cd stress remains poorly understood. Therefore, we cultivated Monochoria korsakowii hydroponically and sprayed the SA biosynthesis inhibitors (2-aminoindane-2-phosphonic acid and 1-aminobenzotriazole) in an attempt to explore the correlation between endogenous SA and other Cd tolerance mechanisms. Compared with control, 0.3 mM Cd treatment induced reductions of net photosynthetic rate (Pn), total chlorophyll (T Chl), catalase (CAT), and soluble protein (SP), while malondialdehyde increased. To mitigate Cd toxicity, M. korsakowii upregulated peroxidase (POD), superoxide dismutase (SOD), glutathione reductase (GR), ascorbic acid (ASA), nonprotein thiols (NPT), phytochelatin (PC), and proline. High concentrations of SA inhibitors exacerbated Cd-induced oxidative damage and suppressed these tolerance mechanisms. Compared with T4, T6 plants exhibited marked reductions in Pn, T Chl, CAT, POD, SOD, GSH, GR, ASA, ascorbate peroxidase, NPT, PCs, SP, and translocation factors. Concurrently, T6 plants sprayed with SA inhibitors exhibited suppressed SA, methyl salicylate, and zeatin accumulation, contrasting with heightened jasmonic acid and abscisic acid concentrations. We propose that endogenous SA is crucial for preserving the photosynthetic apparatus, activating the antioxidant system, and promoting the accumulation of chelators and SP in M. korsakowii under Cd stress. Furthermore, endogenous SA may function synergistically with methyl salicylate and zeatin to regulate plant physiological responses to Cd. This study provides valuable insights into the Cd tolerance mechanisms in M. korsakowii.

Glaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict potential interactions among upregulated and downregulated genes. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP gene was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, and an increase in ECM proteins like Collagen 1 and FN accumulation and fibril formation suggest increased fibrosis of TM in diabetic conditions, potentially elevating IOP. Metabolic changes in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations.

Hydroxyurea promotes HbF elevation in b-thalassemia and sickle cell anemia patients however, its mechanism is not completely elucidated. Previous studies have associated microRNAs with the regulation of HBG2, prompting this study to investigate specific microRNAs linked to HbF regulation in patients treated with hydroxyurea. 150 patients were recruited in the study. miRNA microarray panel of 754 miRNAs was used, and a further customised microarray card was designed. In silico tools predicted target genes of miRNAs and in vitro transfection functionally validated miRNAs in erythroblast cells from patients and K562 cells. Global microarray revealed 59 differentially expressed miRNAs, with 42 upregulated and 17 downregulated significantly following 3/6 months of hydroxyurea treatment (p < 0.001). Further, the customised miRNA panel of these 59 miRNAs confirmed the results. Among 59 miRNAs, 12 upregulated and 3 downregulated miRNAs correlated with HBG2 expression and HbF levels. In silico predictions and in vitro cells study identified miR-150, miR-155, miR-374, miR-486-3p (BCL11A, MYB); miR-190, miR-26a, miR-30b, miR-362, miR-411 (BCL11A); miR-192, miR-454 (MYB); miR-326 (KLF1); miR-150 (GATA1) and miR-15a, miR-484, miR-105 commonly share BCL11A, MYB, KLF1 and GATA1. Our study uncovers how microRNAs influence fetal hemoglobin induction in patients with hydroxyurea treatment, thus offering insights for developing treatment strategies and alleviating clinical severity.

Isaridin E, a cyclodepsipeptide derived from the marine fungus Beauveria felina (SYSU-MS7908), has been demonstrated to possess multiple biological properties. In this study, we employed both lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) and a LPS-induced murine endotoxemia model to investigate its anti-inflammatory effects. Our results revealed that isaridin E suppressed the expression of pro-inflammatory cytokines and adhesion molecules in a concentration dependent manner, while also reducing monocyte adhesion to endothelial cells. Furthermore, this compound attenuated vascular hyperpermeability and inflammatory cell infiltration in the lungs, as well as preserving the integrity of the aortic and pulmonary tissues. At the molecular level, isaridin E was found to downregulate TLR4 expression, increase IκBα levels, and inhibit the LPS-induced phosphorylation and nuclear translocation of NF-κB p65. In conclusion, our findings indicate that isaridin E exerts robust anti-inflammatory effects in LPS-induced endotoxemia through the suppression of the TLR4/NF-κB signaling axis, positioning it as a promising therapeutic candidate for vascular inflammatory disorders.

Attenuated strains of the intracellular pathogen Listeria monocytogenes can deliver genetically encoded payloads inside tumor cells. L. monocytogenes preferentially accumulates and propagates in immune-suppressed tumor microenvironments. To maximize the payload impact in tumors and minimize damage to healthy tissues, it is desirable to induce payload synthesis when bacteria are eliminated from the healthy tissues but are grown to high numbers intratumorally. Here, we have engineered a tightly controlled gene expression system for intracellular L. monocytogenes inducible with a cumin derivative, cumate. Upon cumate addition, expression of a reporter gene is increased in L. monocytogenes growing in vitro by 80-fold and in intracellular L. monocytogenes in murine tumors by 75-fold. This study demonstrates the feasibility of activating gene expression in intracellular bacteria in live animals using an edible inducer. The system is expected to enhance the efficacy and safety of the attenuated L. monocytogenes strains as antitumor payload delivery bacterial drones.

Chronic refractory wounds are a common, costly and recurrent complication of diabetes. Platelet-rich plasma (PRP), a new therapy for chronic wounds, is limited by a long treatment period and unstable effects. FG-4592(Roxadustat) is a new prolyl-4-hydroxylation domain(PHD) inhibitor, which can stabilize hypoxia-inducible factor-1α(HIF-1α) effectively. It is a promising drug for wound repair and needs to be demonstrated via various appropriate application scenarios. This study investigated the effects of combining FG-4592 and PRP to promote diabetic wound healing. Diabetic rats were randomly assigned to five groups: nondiabetic control, diabetic untreated, diabetic + PRP, diabetic + FG-4592, and diabetic + PRP + FG-4592. Diabetes was induced with streptozotocin (STZ). A full-thickness skin defect was created, and FG-4592 (peritoneal injection) and PRP (periwound injection) were administered alone or together. Wound healing was assessed by histological analysis (Hematoxylin-Eosin (HE) and Masson staining) and protein expression of HIF-1α, VEGF(vascular endothelial growth factor), α-SMA(α-smooth muscle actin), CoL1α1(collagen type 1 alpha 1), and SDF-1(Stromal Cell-derived Factor 1) via Western blotting and qRT-PCR(Quantitative real time polymerase chain reaction). Immunohistochemistry(IHC) and immunofluorescence(IF) were also used to evaluate CD34 (Cluster of Differentiation 34), CD31(Cluster of Differentiation 31), VEGF(vascular endothelial growth factor), SDF-1(Stromal Cell-derived Factor 1), PCNA(Proliferating Cell Nuclear Antigen), and Integrin-β1 expression. The untreated diabetic group exhibited impaired wound healing, histological damage, and reduced expression of key proteins compared to the nondiabetic control group. Both PRP and FG-4592 alone improved wound healing, reduced damage, and upregulated protein expression. However, the combination of FG-4592 and PRP showed the most significant improvement. This study suggests that FG-4592 combined with PRP accelerates diabetic wound healing by enhancing endothelial progenitor cell recruitment, neovascularization, and cell proliferation and migration via upregulation of HIF-1α and its target genes. This combination therapy may provide a novel approach for treating chronic diabetic wounds.

High c-Myc protein accumulation contributes to the proliferation, invasion, and drug resistance in multiple cancer cells, but the underlying mechanism about c-Myc accumulation remains not to be elucidated. Here, we demonstrate that TTC36 promotes c-Myc protein accumulation in hepatocellular carcinoma cells, thereby driving the proliferation and sorafenib resistance in hepatocellular carcinoma cells. Ttc36 depletion disrupts the interaction between SET and PPP2R1A, consequently activating PP2A. Activated PP2A directly dephosphorylates p-c-MycS62 and activates GSK3β, relying on AKT, leading increased phosphorylation of p-c-MycT58, finally promotes FBXW7-mediated polyubiquitination and degradation of c-Myc. Inhibitors targeting GSK3β and PP2A effectively reverse the sorafenib resistance promoted by TTC36. These findings highlight the crucial role of TTC36 in c-Myc accumulation-caused proliferation and sorafenib resistance in HCC, providing a promising combination strategy for treating patients with c-Myc protein accumulation in advanced HCC.

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective in cells with homologous recombination (HR) deficiency, including BRCA1/2 mutation. However, PARP inhibitors remain a therapeutic challenge in breast and ovarian cancer due to inevitably acquired resistance in most cases. Therefore, strategies to overcome PARP inhibitor resistance are unmet clinical need. SRY-box transcription factor 5 (SOX5) plays a crucial role in development of various cancers but the role of SOX5 in PARP inhibitor resistance is poorly understood. This study identified SOX5 as a potential biomarker associated with PARP inhibitor resistance and addressed potential treatment strategies to overcome PARP inhibitor resistance using the olaparib-resistant preclinical model. We observed that SOX5 was significantly upregulated in olaparib-resistant cells and contributed to PARP inhibitor resistance by upregulating DNA repair pathway genes. Ectopic SOX5 overexpression contributed to PARP inhibitor resistance by suppressing DNA double-strand breaks (DSBs) in BRCA-mutated breast and ovarian cancer. SOX5 small interfering RNA combined with olaparib sensitized olaparib-resistant cells and suppressed the growth of olaparib-resistant xenografts in mice via increased DSBs represented by ɣH2AX formation. Mechanistically, SOX5 directly interacted with yes-associated protein 1 (YAP1) and promoted its nuclear translocation by suppressing the Hippo pathway. YAP1, in association with TEA domain family members (TEAD), upregulated HR-related gene expression and conferred PARP inhibitor resistance. Furthermore, the clinical relevance of SOX5 as a therapeutic target was supported by a significant association between SOX5 overexpression and poor prognosis in ovarian cancer on public mRNA microarray data sets. Therefore, we propose SOX5 as a promising therapeutic target for overcoming PARP inhibitor resistance in BRCA1/2-mutated breast and ovarian cancer.

Matrix metalloproteinases (MMPs), including MMP9, play a significant role in colorectal cancer (CRC) progression, mainly by extracellular matrix remodeling. However, little is known about MMP9 role in aberrant crypt foci (ACF) cluster formation, the earliest colon preneoplastic lesions.

Southern blight caused by Sclerotium rolfsii (S. rolfsii) represents a significant threat to the medicinal plant Atractylodes macrocephala Koidz. (A. macrocephala), with effective control measures remaining limited. Chrysanthemum indicum polysaccharides (CIP) have been identified as an elicitor capable of inducing defense responses in A. macrocephala against S. rolfsii infection. However, the molecular mechanisms underlying CIP recognition remain poorly understood. In this study, comparative transcriptome analysis revealed two potential LysM-receptor kinases, AmCERK1 and AmLYK3, as candidate receptors for CIP recognition. These genes, which are orthologous to Arabidopsis CERK1 and Medicago truncatula LYK3, exhibited significant up-regulation upon CIP treatment. Bimolecular fluorescence complementation (BiFC) assays demonstrated that AmCERK1 and AmLYK3 interact in a CIP-dependent manner. Transient overexpression experiments further confirmed that CIP treatment markedly enhanced the expression of these receptor genes. Virus-induced gene silencing (VIGS) assays indicated that CIP treatment could partially compensate for the suppression of AmCERK1 and AmLYK3, highlighting their critical role in CIP-induced defense responses. Collectively, these findings suggest that AmCERK1 and AmLYK3 form a pattern recognition receptor (PRR) complex essential for CIP perception, potentially facilitating pattern-triggered immunity (PTI) in A. macrocephala. These findings reveal a novel receptor recognition complex comprising AmCERK1 and AmLYK3, offering crucial insights into the mechanisms of innate immune recognition in plants.

Intramuscular fat is a critical determinant of meat taste and flavor. Therefore, regulating intramuscular fat content to enhance meat quality is considered a viable strategy. Lycopene, a natural antioxidant, has been shown to improve the oxidative stability and color of meat, both of which are crucial for maintaining meat product quality. Previous studies have suggested that lycopene may contribute to improved meat quality by influencing intramuscular fat deposition. However, the specific mechanisms underlying lycopene's effects on intramuscular fat deposition remain unclear and require further investigation. This study aimed to elucidate the molecular mechanisms through which lycopene regulates intramuscular fat deposition in muscle cells and to identify differentially expressed genes involved in this process. Using integrated transcriptomic and translatomic dual-omics analyses of C2C12 myoblasts treated with or without lycopene, we identified 55 functional genes implicated in transcriptional and translational regulation. Our findings suggest that lycopene may modulate lipid metabolism in C2C12 myoblasts by regulating the expression of Ankrd1. This study not only provides valuable insights into the coordinated regulation of gene expression at both the transcriptional and translational levels but also establishes a theoretical foundation for the beneficial role of lycopene in improving meat quality.

Traffic-related ultrafine particles (UFPs) are an emerging health concern affecting the brain and increasing the risk of Alzheimer's disease (AD). PI3K/AKT signaling is known to contribute to neuronal survival and to be altered in AD. The nasal olfactory mucosa (OM) is a sensory tissue exposed directly to ambient air, and a starting point for olfactory neural circuits towards the brain. Evidence of air pollution-induced transcriptional regulation via microRNAs (miRNA) and DNA methylation (DNAmet) is accumulating and air pollutant-mediated disturbances in PI3K/AKT signaling have been reported. By utilizing a highly translational human-based in vitro model of OM, we aimed to investigate possible gene regulatory mechanisms in PI3K/AKT signaling induced by UFPs, and to compare the responses between cognitively healthy and individuals with AD. miRNA expression was analyzed using next-generation sequencing (NGS) and chip-based methylation analysis was performed to detect differentially methylated loci (DML). These data were combined with previously published transcriptomics analysis (mRNA) to construct an mRNA-miRNA-DNAmet-integrative network. Protein level changes were studied by immunoassays. We observed UFP-induced reductions in viability and increases in oxidative stress and DNA damage without eminent cell death. Integrative network analysis revealed multiple connections of miRNAs to differentially expressed genes in the PI3K/AKT pathway, and effects were most prominent in AD cells. Similarly, in AD cells DML were identified in transcription factor and apoptosis genes, downstream of PI3K/AKT signaling. Conclusively, traffic-related UFPs influence gene regulation of PI3K/AKT signaling to modulate OM cell survival, with existing AD pathology resulting in heightened vulnerability to UFP effects.