Osteosarcoma (OS) is an aggressive bone cancer that mainly occurs in children and adolescents. OS patients are mainly treated with neoadjuvant chemotherapy and surgical resection. This treatment is effective for early osteosarcoma. However, the effect declines as the disease progresses. Currently, our research on osteosarcoma is not enough to meet the clinical needs. Exosomes play a critical role in osteosarcoma progression by mediating intercellular communication. They carry molecular signals, including miRNAs and proteins, which can influence tumor growth, metastasis, and drug resistance. Recent studies have shown that exosomes from osteosarcoma cells can promote cell proliferation and migration, making them potential biomarkers for early diagnosis and therapeutic targets in osteosarcoma. This opens up new possibilities for the research of osteosarcoma. The combined genes of exosomes and DEGs were identified by searching GeneCards and GEO databases. Subsequent analyses included GO and KEGG Enrichment, GSEA. The core gene set was derived from the intersection of LASSO and SVM-RFE outputs, ensuring minimal redundancy through dimensionality reduction. Osteosarcoma was diagnosed and predicted by differential expression levels, ROC curve analysis, and nomogram. Immune cell infiltration in osteosarcoma was evaluated by the ssGSEA algorithm. Drug enrichment analysis and molecular docking simulations were conducted to discover the most promising drug leads. In vitro experiments included Wound Healing Assay and qRT-PCR to detect the therapeutic effect of the drug. Through multiple analyses and dimensionality reduction of the data set, six genes were selected (WNT5A, GCA, ANXA6, BIRC5, IL1β, and ARPC3). We examined differential expression in the control and tumor groups and made a gene prediction nomogram. Analysis of immune cell infiltration revealed significant alterations in the composition of immune cell subsets. Drug enrichment analysis and molecular docking of these six core genes were conducted to screen out the most suitable candidate drug: Mifepristone. Finally, Mifepristone was proved to inhibit the growth of osteosarcoma cells in vitro. Bioinformatics analysis identified six exosome-associated osteosarcoma genes (WNT5A, GCA, ANXA6, BIRC5, IL1β, and ARPC3) that could serve as potential biomarkers. Through screening, Mifepristone, which can act on BIRC5 and IL1β at the same time, has a very effective osteosarcoma treatment effect.

Panax vietnamensis, a medicinally valuable perennial herb, is highly susceptible to leaf blight under cultivation; however, the molecular mechanisms underlying this disease remain poorly understood. In this study, we identified Neofusicoccum ribis as the causal agent of P. vietnamensis leaf blight through pathogen isolation and fulfilment of Koch's postulates. Transcriptomic analysis revealed activation of phytohormone signalling (salicylic acid, jasmonic acid, and melatonin [MT]) and phenylpropanoid metabolism during infection. Among these, MT exhibited superior efficacy in inducing lignin biosynthesis compared to other hormones, with exogenous application of MT significantly enhancing lignin accumulation and improving disease resistance by 8 days post-inoculation. Further, we identified PvWRKY40 as a negative regulator of lignin synthesis, which directly binds to the W-box motif in the PvCOMT2 promoter to suppress its expression. MT counteracted this repression by downregulating PvWRKY40. Heterologous overexpression of PvCOMT2 in Nicotiana benthamiana increased lignin content and conferred enhanced resistance to Fusarium oxysporum. This study reveals a novel MT-PvWRKY40-PvCOMT2 regulatory axis governing lignin-mediated defence in P. vietnamensis, providing critical insights for combating leaf blight in cultivated ginseng.

This study investigates the individual and combined effects of aqueous Stevia rebaudiana extract (SAE) and clomiphene citrate (Clom) on the expression of key ovarian regulatory genes -growth differentiation factor 9 (GDF9), phosphatase and tensin homolog (PTEN), and bone morphogenetic protein 15 (BMP15)- as well as on antioxidant enzyme activities in a letrozole-induced polycystic ovary syndrome (PCOS) model in adult female Wistar rats. The estrous cycles of 50 rats were monitored and randomly divided into five groups of 10 rats each. The control group received carboxymethyl cellulose, while the remaining groups were administered letrozole (1 mg/kg) for 21 days to induce PCOS. From day 22 onward, the treatment groups received SAE (400 mg/kg), Clom (100 mg/kg), or their combination for 28 days. Gene expression levels of GDF9, BMP15, and PTEN were analyzed using real-time PCR, and antioxidant levels were assessed using diagnostic kits. Data were analyzed using SPSS software (version 21) with one-way ANOVA followed by Tukey's post hoc test. Treatments with SAE and Clom restored normal estrous cycles. Significant differences in gene expression were observed: PTEN levels were higher in the control group compared to SAE and combined groups, while GDF9 and BMP15 were elevated in the PCOS group compared to controls. SAE and Clom treatments also significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in ovarian tissues. The combined SAE and Clom therapy demonstrate potential as an effective strategy to manage PCOS by regulating ovarian gene expression and oxidative stress.

Compound mylabris capsules (CMC) are widely used in the treatment of various malignant tumors; however, their mechanisms of action in diffuse large B-cell lymphoma (DLBCL) remain poorly understood. To address this, we analyzed DLBCL-related datasets from GEO and TCGA, identifying 943 key genes through differential expression gene analysis and weighted gene co-expression network analysis. By constructing a drug-active ingredient-target network, we determined the top five active CMC ingredients and their associated 1053 gene targets. Intersection analysis between CMC targets and key DLBCL genes revealed 50 overlapping targets. Enrichment analysis highlighted critical pathways, including the cell cycle and p53 signaling. Single-cell RNA sequencing further demonstrated that these targets are predominantly expressed in DLBCL tumor cell subsets. Protein-protein interaction network analysis identified pivotal genes such as CDK1 and CDK2, which showed robust diagnostic and prognostic value, as confirmed by receiver operating characteristic and survival analyses. Molecular docking and dynamics simulations validated the high binding affinity of sitosterol (a primary CMC component) to these targets. In vitro experiments demonstrated that sitosterol significantly inhibits DLBCL cell proliferation and induces apoptosis. In conclusion, our study elucidates the anti-tumor effects of CMC (mainly sitosterol) in DLBCL, mediated through the regulation of targets like CDK1 and CDK2. These findings provide critical evidence supporting the therapeutic potential of CMC in DLBCL treatment.

Strigolactones (SLs) are butenolide-type plant hormones that play several roles in plants, such as suppressing shoot branching and promoting arbuscular mycorrhizal symbiosis. Recently, SLs have been reported to positively regulate disease resistance in plants. In this study, we analyzed the effect of the synthetic SL analog rac-4-bromodebranon (rac-4BD) on systemic acquired resistance (SAR) in rice. First, we demonstrated in vitro that rac-4BD, similar to the common SL analog rac-GR24, promotes the interaction of SL and karrikin receptor, D14 and D14-like (D14L), respectively, with signaling factor D3. Gene expression analysis and inoculation tests indicated that pretreatment with rac-4BD promotes the effect of the SAR inducer BIT. Activation of SAR was also significantly observed in the SL and karrikin signal-deficient rice mutant d3. These results suggest that D3-mediated SL/karrikin signaling by rac-4BD treatment does not directly activate rice immunity but induces a priming state in the plant that enhances SAR induction.

The treatment of head and neck squamous cell carcinoma (HNSC) faces significant challenges, primarily due to the lack of reliable biomarkers and effective therapeutic drugs. This study reveals the crucial mechanistic role of STXBP1 in the HNSC tumor microenvironment: STXBP1 promotes tumor immune escape through dual pathways, not only enhancing the infiltration of M2-type macrophages but also activating the 'don't eat me' signaling pathway through upregulation of CD47. Clinical data analysis demonstrates that STXBP1 expression levels significantly correlate with HNSC patient prognosis, suggesting its potential as a diagnostic marker and prognostic indicator. Mechanistic studies show that targeted inhibition of STXBP1 effectively downregulates CD47 expression and restores the anti-tumor function of macrophages. Based on bioinformatics screening and experimental validation, we discovered that the natural compound Catechin can specifically inhibit STXBP1 expression and significantly suppress tumor growth. These findings not only elucidate the molecular mechanism of STXBP1 in HNSC but also provide a new candidate drug for clinical treatment, holding significant translational medical value.

Cholangiocarcinoma (CCA) is a highly aggressive cancer that arises from the bile duct and has an extremely poor prognosis. Pemigatinib is the only Food and Drug Administration (FDA)-approved CCA-targeted drug. The CCA treatment options are insufficient considering its poor prognosis and increasing morbidity. Recently, Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been reported to promote resistance to chemotherapy. In this study, we investigated the role that ROCK2 plays in the development of resistance of CCA cells to Pemigatinib. Here, we developed Pemigatinib-resistant CCA cells, performed mRNA sequencing, retrieved The Cancer Genome Atlas (TCGA) data, and analysed ROCK2 expression in a large CCA cohort. The expression level of ROCK2 in CCA cells was significantly higher than that in adjacent noncancerous tissues. Increased expression of ROCK2 in CCA was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of ROCK2 promotes the ferroptosis of CCA cells, and enhances sensitivity to Pemigatinib. Moreover, upregulation of ROCK2 increased the expression of Drp1 protein. The effect of downregulating ROCK2 was reversed by Drp1 overexpression, and Drp1 knockdown inhibited Ferroptosis driven by ROCK2 overexpression. Mechanistically, ROCK2 stabilized the expression of Drp1 by competing with UBA52 to bind Drp1 and inhibiting the ubiquitination-mediated degradation of Drp1. Blocking of the UBA52- Drp1 axis inhibited the antitumour effect of Pemigatinib in ROCK2-knockdown cells both in vitro and in vivo. In conclusion, the ROCK2/UBA52/Drp1 axis is a pivotal driver of Pemigatinib resistance in CCA cells. These results provide novel insights into Pemigatinib resistance in CCA cells, suggesting that ROCK2 is a promising therapeutic target for the treatment of CCA.

In ~70% of patients with pancreatic ductal adenocarcinoma, the TP53 gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multicenter patient data and multi-omics, we report that the misp53R273H/C mutant is associated with cell cycle progression and a basal-like state compared to the misp53R248W/Q mutant. Loss of misp53R273H/C decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53R273H/C specifically regulated the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor reduced misp53R273H/C mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53R273H/C-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.

This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM) and striatum. Key markers were analyzed at 4, 8, 24, and 48 h post-injections: the hydroxylated form of the purine guanine (8-hydroxy-2'-deoxyguanosine; 8-OHdG), a marker of oxidative stress; the methylated form of cytosine (5-methylcytosine; 5-mC), associated with gene silencing; the hydroxy methylated form of cytosine (5-hydroxymethylcytosine; 5-hmC), involved in demethylation and gene regulation. The results showed a pronounced decrease in 8-OHdG levels in the VM, suggesting a rapid oxidative stress response, whereas the striatum exhibited a less pronounced response, reflecting regional differences in oxidative stress vulnerability DNA methylation patterns revealed complex and biphasic changes in 5-mC levels in the VM, contrasted with a less pronounced response in the striatum, suggesting disrupted methylation homeostasis and regional epigenetic variability. MPTP treatment also significantly reduced in 5-hmC levels in the VM, pointing to impaired active DNA demethylation and compromised epigenetic flexibility. In contrast, the striatum maintained consistently high 5-hmC levels, reflecting compensatory hydroxymethylation mechanisms specific to this region. These findings highlight pronounced regional differences in oxidative stress vulnerability and epigenetic regulation, with the VM showing heightened sensitivity to oxidative damage and impaired epigenetic flexibility. This underscores the importance of understanding the role of oxidative and epigenetic mechanisms in Parkinson's disease pathophysiology, The changes pave the way for novel therapeutic strategies targeting oxidative DNA damage and epigenetic homeostasis.

Diethylnitrosamine (DEN) is a highly toxic compound with teratogenic, mutagenic, and carcinogenic properties. Embelin, a natural benzoquinone derived from Embelia ribes, has shown potential therapeutic effects. This study evaluated embelin's impact on biochemical, histopathological, and gene expression changes in DEN-induced liver injury. Twenty-eight male Wistar albino rats were assigned to four groups: Sham, Embelin (E), DEN, and DEN + E. DEN groups received a single intraperitoneal dose of 200 mg/kg DEN, while E and DEN + E groups were administered 1.2 mg/kg embelin for 14 days. Liver enzyme levels, lipid profiles, total antioxidant status (TAS), and total oxidant status (TOS) were measured. RT-PCR analysis was performed to assess sonic hedgehog (Shh, Ptch1, Smo, Gli1), inflammatory (TNF-α, IL-6, IL-1β) and apoptotic (Tp53, casp3, Bcl-2, Bax) gene expression in liver tissue. Histopathological examination showed that DEN induced fibrosis, congestion, apoptosis, and bile pigment accumulation, which were significantly mitigated by embelin. Embelin decreased liver enzyme and lipid levels, increased the activity of TAS, which is an antioxidant capacity, decreased the gene expression levels of pro-inflammatory cytokines TNF-α, IL-6, IL-1β, and the activation of the Shh signaling pathway. It also increased the expression of Bcl-2 and decreased the gene expression levels of Tp53, Casp3, Bax, and inhibited liver apoptosis. These results imply that embelin may have a therapeutic effect on DEN-induced liver damage by preventing degenerative liver problems, regulating liver functions, suppressing oxidative stress, the inflammatory and apoptotic response, and modulating the Shh signaling pathways.

Breast cancer is currently the most prevalent malignancy among females, representing a substantial threat to both physical and psychological health. Moreover, its incidence rate continues to rise annually. Therefore, screening potential therapeutic targets and developing candidate drugs for breast cancer treatment holds significant clinical implications.

Neuroblastoma (NB) is frequently associated with high-risk pediatric cases that demonstrate limited response to cisplatin, contributing to a poor prognosis. Recent studies have explored the role of tumor cell senescence in increasing sensitivity to this chemotherapy agent. This study aims to identify genes related to cell senescence in children diagnosed with NB, evaluate their influence on cisplatin sensitivity, and investigate potential strategies to enhance the efficacy of chemotherapy.

Methylglyoxal (MGO), a toxic byproduct of glycolysis, acts as a signaling molecule at low levels, but its overaccumulation during drought stress disrupts redox balance and accelerates cell death in plants. Contrarily, melatonin maintains redox balance, particularly during stress. The redox status and MGO levels might differ in drought-sensitive and drought-tolerant varieties, so shall the melatonin's effect. This present study evaluated the effect of melatonin priming on MGO detoxification and autophagy during seed germination under polyethylene glycol (PEG)-induced drought stress in drought-sensitive (L-799) and drought-tolerant (Suraj) varieties of upland cotton. Melatonin priming increased endogenous melatonin content, reduced MGO accumulation and advanced glycation end-products (AGEs), and downregulated the expression of MGO biosynthesis genes in L-799 under stress. The expression and activities of glyoxalases and nonglyoxalases were upregulated, showing melatonin's effectiveness in MGO detoxification. Additionally, melatonin priming upregulated TPI1, PGK5, and PK1 expressions and downregulated HK3 expression, allowing better conversion of glucose to pyruvate, leading to reduced MGO in L-799. The downregulated expression of necrosis-related genes with reduced cell death in L-799 shows the potential of melatonin priming in maintaining cell viability under stress. Furthermore, the upregulated expression of SnRK1.1 and SnRK2.6 genes and the KIN10 protein levels confirmed improved autophagy in melatonin-primed L-799 under stress, as evidenced by enhanced autophagy markers (ATGs, MDC-stained bodies, lipidated-ATG8). Despite lowered ABA, melatonin-mediated MGO homeostasis likely activated MAPK6, thus inducing autophagy independent of ABA in stressed plants. Conversely, Suraj seedlings showed a limited response to melatonin priming under stress possibly owing to its inherent stress tolerance and higher endogenous melatonin. Overall, this study illustrates melatonin's role in regulating MGO homeostasis and autophagy under drought stress in cotton.

Pancreatic cancer is a highly aggressive malignancy characterized by limited treatment options, poor prognosis, and high mortality rates. nuclear activating miRNA (NamiRNA) enhances gene expression by interacting with nuclear enhancers, offering a novel avenue for understanding gene regulation in cancer. This study explores the dual role of mir-200c in regulating tumor proliferation and migration in pancreatic cancer, with the aim of identifying potential therapeutic strategies.

Derepression of transposable elements (TE) by epigenetic therapy leads to the activation of immune response in cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenetic drugs to systematically inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal, esophageal, and prostate cancer cells. We show that distinct TE subfamilies are derepressed by inhibition of different CMEs in cell type-specific manner. Co-inhibition of DNMT and HDAC (DNMTi-HDACi) had the most consistent effect across cancer types. Loss of p53 results in stronger TE activation and TE-chimeric transcript expression and this effect is largely mediated by the non-genomic actions of p53. Robust immune response elicited by DNMTi-HDACi is due to induced inverted repeat Alu expression concomitant with reduced ADAR1-mediated Alu RNA editing. Collectively, our systematic analyses provide insights for rational use of epigenetic therapies in distinct cancers.

Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable hepatocellular carcinoma (HCC) in 2007. This investigation aims to elucidate the involvement of aquaglyceroporin-7 (AQP7) in regulating sorafenib resistance (SR) in HCC. AQP7 was downregulated in HCC-SR cells. AQP7 upregulation inhibited lipid accumulation, enhanced the sorafenib sensitivity of SR cells, and improved immune evasion. TBX19 protein was elevated in HCC-SR cells, and TBX19 repressed AQP7 transcription by binding to its promoter. E3-ubiquitin ligase MGRN1 was reduced in HCC, and its overexpression promoted TBX19 degradation. MGRN1 overexpression enhanced AQP7 and improved SR and immune evasion in HCC, which was reversed by TBX19 overexpression. Mouse HCC cells Hepa1-6 were used to construct an orthotopic tumor model and to analyze the effects of AQP7 and MGRN1 expression on the in vivo antitumor effects of Sorafenib, lipid accumulation in tumor tissues, and immune cell infiltration. MGRN1 silencing in Hepa1-6 cells induced sorafenib resistance and created an immunosuppressive tumor microenvironment, which was repressed by AQP7 upregulation. In conclusion, MGRN1 loss in HCC-SR cells blocked TBX19 degradation and strengthened TBX19-mediated AQP7 repression, leading to immune evasion. Targeting this signaling might offer a promising therapeutic strategy to overcome SR in HCC.

Antimicrobial resistance threatens the viability of modern medical interventions. There is a dire need to develop novel approaches to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to the low levels of genetic resistance observed in bacteria against these compounds. However, here we show that subpopulations of stationary phase Escherichia coli and Pseudomonas aeruginosa survive tachyplesin treatment without acquiring genetic mutations. These phenotypic variants display enhanced efflux activity to limit intracellular peptide accumulation. Differential regulation of genes involved in outer membrane vesicle secretion, membrane modification, and protease activity was also observed between phenotypically resistant and susceptible cells. We discovered that the formation of these phenotypic variants could be prevented by administering tachyplesin in combination with sertraline, a clinically used antidepressant, suggesting a novel approach for combatting antimicrobial-refractory stationary phase bacteria.

Metastasis remains a predominant contributor to cancer-related mortality worldwide. Elucidating the molecular mechanisms underlying cancer metastasis is crucial for developing strategies to inhibit tumor progression and improve clinical outcomes. Protein glycosylation, a hallmark of cancer pathogenesis mediated by specific glycosyltransferases, has emerged as a critical regulatory mechanism. This study investigates the functional role of glycosylation in cancer progression and explores its therapeutic potential.

Triple-negative breast cancer (TNBC) remains the deadliest subtype of breast cancer owing to high metastatic potential and poor prognosis. Herein, we examined the antitumor effects of ursolic acid (UA), a pentacyclic triterpene compound, against TNBC and the underlying mechanisms.

Epigenetic alterations are crucial in gastric cancer (GC) development and progression. As these modifications are reversible, targeting them may offer preventive and therapeutic benefits. Origanum onites L. essential oil (OOEO) has demonstrated anticancer properties in various cancers, but its epigenetic effects in GC remain unexplored.