Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for its potential protective effect on dox-induced cardiotoxicity with its effect on Apelin expression as a mediator of cardiac function. Methods: Wistar albino rats were equally divided into four groups as Control, DOX, CUR, and CUR+DOX. Dox was administered a single dose of 20 mg/kg bw intraperitoneally while 100 mg/kg bw curcumin was given orally for 14 days before the Dox use. Results: DOX group showed a prolonged QT interval on an electrocardiogram and elevated cardiac troponin levels. In biochemical analyses, decreased Superoxide Dismutase activity and increased Malondialdehyde level and Catalase activity were detected in DOX group. Gene expression of Apelin decreased significantly while NF-κB increased in DOX group. Degenerative changes in histopathology, and increased iNOS and nitrotyrosine immunoreactivity were detected in DOX group. However, no significant changes were observed at reduced Glutathione, TNF-, and IL-1β levels. Curcumin use in Dox-given rats altered most of the disturbed parameters investigated in this study, indicating an alleviating effect on Dox-induced cardiotoxicity. Serum and heart Apelin levels and mRNA expression in heart tissue were detected to significantly increase in CUR+DOX group as compared to DOX group. Furthermore, NF-κB mRNA expression was significantly decreased in heart tissue of CUR+DOX group compared with the DOX group. Conclusions: The results suggest that Apelin acts as an important mediator in Dox cardiotoxicity and may be used as a target for treatment of certain cardiomyopathies. By regulating Apelin expression, curcumin may serve as a potential adjunct in cardioprotective approaches.

Background and objectives: Exercise-induced muscle injury, a consequence of intense physical activity, is characterized by subsequent inflammation. Sports massage frequently employs massage oils, such as jojoba (Simmondsia chinensis (Link.) C.K.Schneid., Simmondsiaceae) oil, which is recognized for its anti-inflammatory properties. Therefore, this study investigated the potential of jojoba oil to alleviate exercise-induced muscle injury. Materials and Methods: Male hairless mice, aged eight weeks, were randomly allocated into one of four groups: a naïve control group, a sedentary group treated with jojoba oil (JO), an exercise group without oil application, and an exercise group treated with jojoba oil (JO + Ex). In the JO and JO + Ex groups, 4 μL of jojoba oil per gram of body weight was applied topically to the dorsal skin of the mice 30 min prior to treadmill exercise. Subsequently, plasma biochemical parameters, gene expression in various tissues, and plasma cytokine levels were evaluated. Results: Topical application of jojoba oil did not significantly impact plasma cytokine concentrations. However, it significantly decreased the expression levels of pro-inflammatory cytokines (Il-1b and Il-6 in the soleus muscle; Il-1b in the gastrocnemius muscle). Conclusions: Our findings suggest that sports massage with jojoba oil may aid in reducing exercise-induced muscle injury and inflammation.

The red seaweed Jania rubens (J. rubens) is prevalent along the Lebanese coast and has drawn attention for its notable antineoplastic properties. Our previous data showed that its dichloromethane-methanol (DM) extract possesses antioxidant, cytotoxic, and anti-migratory effects on colon cancer cells. In the present study, a GC-MS analysis of DM extract identified a diverse profile of bioactive compounds, including flavonoids and pyrazole derivatives with antioxidant and anticancer activities. In vitro assays demonstrated that the DM extract exerts significant cytotoxic activity against various cancer cell lines, including colon, breast, and cervical types. Further investigation into the underlying molecular mechanisms revealed that the extract induces G2/M cell cycle arrest and reduces the expression of EMT (epithelial-mesenchymal transition) markers, N-cadherin and Twist. In addition, the extract showed anti-metastatic properties through its ability to decrease MMP-2 and MMP-9 activity. Mechanistically, DM caused a substantial reduction in Ten-Eleven Translocation (TET) enzymes TET-1, TET-2, and TET-3, which are essential DNA demethylation regulators, thus decreasing their enzymatic product 5-hydroxymethylcytosine (5-hmC). Interestingly, despite a significant increase in intracellular ROS (reactive oxygen species), suggesting a contribution to cytotoxicity, no substantial change in the biogenesis of promyelocytic leukemia nuclear bodies (PML-NBs) was detected. These findings demonstrate that J. rubens DM extract contains bioactive compounds with multiple anticancer effects, thus making it a promising candidate for developing new therapeutic agents.

Mitochondria possess their own genome, which encodes subunits of the electron transport chain, rendering mitochondrial protein translation essential for cellular energy metabolism. Mitochondrial dysfunction affects nuclear transcription through the retrograde response. We applied RNA-seq to investigate whether and how the inhibition of mitochondrial translation by chloramphenicol (CAP) affects transcriptome regulation in proliferating or stationary-phase cells of Schizosaccharomyces pombe growing in fermentative or respiratory media. Stationary-phase cells in glucose medium exhibited the strongest transcriptome response to CAP, characterized by expression signatures similar to those observed under other stresses, including the retrograde response. The induced genes were also significantly enriched in cytoplasmic carbon metabolism pathways, reflecting a transcriptional reprogramming from respiration to fermentation. The transcription factors Scr1 and Rst2, regulators of carbon catabolite repression (CCR), controlled a common set of carbon metabolism genes in CAP-treated stationary-phase cells, and they showed opposing effects on the lifespan of these cells. Rst2 was required for the induction of carbon metabolism genes and maintained nuclear localization in CAP-treated stationary-phase cells. A systematic genetic interaction screen revealed functional relationships of Rst2 with processes related to stress and starvation responses. These findings uncover a complex transcriptional program in stationary-phase cells that adapt to inhibited mitochondrial translation, including stress- and retrograde-like responses, contributions of the CCR factors Scr1 and Rst2, and adjustment of carbon metabolism to deal with mitochondrial dysfunction.

Background: Ligusticum chuanxiong Hort. is a well-known traditional Chinese medicinal herb whose clinical application and international trade had been constrained by cadmium (Cd) contamination. However, the molecular mechanisms underlying its response to cadmium stress remained poorly understood. The ATP-binding cassette (ABC) transporter family plays crucial roles in various plant processes, including growth and development, hormone transduction, and stress responses. This study aimed to analyze the ABC transporter genes in L. chuanxiong to better understand their roles during cadmium stress responses. Methods: Genome-wide identification of ABC genes in L. chuanxiong was performed, and transcriptome sequencing of rhizomes under cadmium stress was conducted. Differentially expressed LcABC genes were screened using bioinformatic analysis. Results: A total of 368 LcABC genes were identified. Transcriptome analysis revealed 37 upregulated LcABC genes, which were classified into six subfamilies. Cis-element analysis indicated that their promoters contain hormone-, growth-, and stress-responsive elements. Notably, LcABCG8, LcABCG48, and LcABCG108 contain stress-responsive elements and show close evolutionary relationships with heavy metal-responsive genes such as AtABCC1/2/3 and AtABCG36/40, suggesting that they could be key candidates. qRT-PCR validation of nine LcABC genes confirmed their differential sensitivity to cadmium stress. Conclusions: This study conducted a comprehensive identification of the ABC gene family in L. chuanxiong. By integrating transcriptomic data with systematic bioinformatic analyses, we identified several LcABC transporters that may play important roles in cadmium stress responses. The results provide insights into the molecular mechanisms of ABC transporters in cadmium stress responses in L. chuanxiong and offer strategies for reducing cadmium accumulation.

Background: Currently, there are limited therapeutic or preventative strategies for neurodegenerative disorders due to the challenges in alleviating the progressive neuronal loss and neuroinflammation which are the primary characteristics of these diseases, ultimately leading to cell death and functional impairment. Cocoa-derived flavanols (Theobroma cacao) have been studied as potential bioactive compounds to modify and reverse various inflammation-associated diseases because of their remarkable antioxidant properties and capacity to modulate metabolic imbalance and reactive inflammatory responses. The faba bean (Vicia faba) extract obtained through nondenaturing biotechnological processes is a potent dopamine (DA) enhancer that has shown promising results as a neuroprotective agent against degeneration. Objective: This study will examine the synergistic effects of Neurofabine-C, a hybrid compound derived from cocoa and faba bean extracts, on various brain biomarkers in mice related to inflammatory, metabolic, and neurodegenerative processes. Methods: A triple-transgenic mouse model of neurodegeneration was treated with Neurofabine-C, and biomolecular data were obtained by performing biochemical and immunohistochemical analysis. Results: Neurofabine-C prevented neuronal degeneration (NeuN), mitigated the neuro-inflammatory processes triggered (decreased expression of reactive astrocytes (GFAP)), and induced an increase in neurogenesis in the treated cortical mice brain (PAX6). Epigenetic analysis revealed significant chromatin remodeling in the hippocampus. Neuroprotective genes, including FOXO3, ATM, and TRP73, were upregulated, whereas the expression of HIF1α and APOE decreased. In parallel, DNMT3A expression increased 20-fold, HDAC3 decreased by 60%, and global 5-methylcytosine levels increased four-fold. These coordinated changes suggest that Neurofabine-C promotes neuroprotective programs through enhanced DNA methylation and reduced histone deacetylation. Conclusions: The findings indicate that Neurofabine-C exhibits multiple neuroprotective mechanisms, making it a potent bioproduct for mitigating neuroinflammatory processes associated with neurodegenerative disorders.

Epigenetics refers to heritable modifications in gene expression that do not involve changes to the DNA sequence. Among these, DNA methylation, histone modifications, and non-coding RNAs play a key role in regulating gene activity and are influenced by environmental factors, including exposure to psychoactive substances. In recent years, it has been hypothesized that such alterations may serve as molecular markers with forensic relevance. This systematic review aims to evaluate whether current evidence supports the use of drug-induced epigenetic changes as potential toxicological fingerprints in human subjects.

Despite an initial favorable response of EGFR-mutant non-small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear.

ABC1K2 links stress response and seed development. The Activity of BC1 complex Kinases (ABC1K) family comprises atypical protein kinases with a conserved ABC1 domain and widespread distribution across life domains. In plants, ABC1Ks are predominantly localised in chloroplasts and mitochondria and have been implicated in energy metabolism, abiotic stress response, and developmental processes. Despite growing evidence of their biochemical activity, the functions of many ABC1Ks remain unclear. This study focuses on Arabidopsis thaliana ABC1K2, a plastidial clade member. ABC1K2 is principally localised in seeds; although it shows low expression in vegetative tissues, its transcription is induced by abscisic acid and stress. Functional analysis of abc1k2 mutants and overexpression lines reveals no major effects on plant development or fertility; however, mutant seeds exhibit increased size, mass, and altered pigmentation, along with reduced ABA levels and modified glucosinolate profiles. Transcriptomic data suggest that ABC1K2 integrates developmental signals with stress responses and secondary metabolism, particularly during seed development and germination. This work highlights a novel role for ABC1K2 in linking hormonal regulation and secondary metabolite biosynthesis, offering new insight into the functional diversification of the ABC1K protein family in plants.

Although berberine exhibits anticancer activity, its mechanistic role in esophageal cancer (ESCA) remains unclear. Long non-coding RNAs (lncRNAs) expression profiling was conducted on berberine-treated and control ESCA TE-1 cells, identifying differentially expressed lncRNAs. Prognostic lncRNAs were selected through integration with the TCGA database, followed by the construction of a prognostic nomogram. In vitro assays and bioinformatics analyses were performed to validate berberine's impact on cell proliferation, metastasis, and key lncRNAs. Berberine treatment significantly altered lncRNA expression in TE-1 cells, with 344 upregulated and 235 downregulated lncRNAs. The expression of CCDC18-AS1, TBILA, and LINC02084 was associated with poorer overall survival (OS) and served as independent prognostic factors in ESCA. The nomogram accurately predicted 1-, 3-, and 5-year OS rates. Berberine inhibited TE-1 cell proliferation, migration, and invasion, primarily through the upregulation of CCDC18-AS1 expression. Genes co-expressed with CCDC18-AS1 were enriched in mRNA processing, RNA splicing, spliceosome, and mRNA surveillance pathways. Among these, overexpression of PCMTD2 and AL391840.2 represented risk factors, while RBM43 and LRIG2 were identified as protective factors in ESCA. Berberine may inhibit ESCA progression by modulating CCDC18-AS1 expression, thereby improving patient prognosis.

Patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations often benefit from third-generation tyrosine kinase inhibitors (TKIs), such as aumolertinib (AUM). However, the development of drug resistance significantly limits the clinical efficacy of AUM. To address this, we established an in vitro model of AUM-resistant cell lines and performed RNA sequencing to identify resistance-associated differentially expressed genes. Using machine learning, we constructed an AUM resistance-related prognostic signature (ARRPS). Our results demonstrated that ARRPS effectively predicts the prognostic risk of patients. Notably, for patients with high ARRPS scores, the addition of CD-437 or TPCA-1 to conventional AUM treatment may help overcome drug resistance. These findings suggest that ARRPS serves as both a prognostic tool and a guide for personalized treatment strategies, potentially optimizing the clinical management of NSCLC patients.

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer, in which TP53 mutation is uncommon in contrast to high-grade serous carcinoma, the predominant subtype. Therefore, the functional reactivation of p53 is an attractive therapeutic opportunity for this subtype of ovarian cancer. Nevertheless, the therapeutic potential of targeting MDM4, a representative negative regulator of p53, has not yet been reported. In the present study, we investigated the impact of CEP-1347, an MDM4 inhibitor with a known safety profile in humans, on p53 pathway activity and the growth of OCCC cells.

OIP5-AS1, a long noncoding RNA, promotes the proliferation, invasion, and migration of diverse cancer cell types such as cervical, breast, lung, and head and neck cancer. In this study, we showed that OIP5-AS1 is involved in the promotion of colorectal cancer (CRC) cell proliferation via repressing apoptosis.

High-grade meningiomas are tumors with high recurrence rates and poor prognoses, and the development of effective pharmacological therapies remains a major challenge. Forkhead box protein M1 (FOXM1), a transcription factor known to play a key role in the malignancy of high-grade meningiomas, has gained attention as a potential therapeutic target. Class I histone deacetylase (HDAC) inhibitors have been shown to suppress FOXM1 expression and cell proliferation in various cancers; however, their efficacy in high-grade meningiomas remains unclear. The present study investigated the role of class I HDACs in regulating FOXM1 expression and cell proliferation in high-grade meningioma cell lines and examined the effects of the class I HDAC inhibitor domatinostat on FOXM1 expression and cell proliferation in these cell lines.

Bone morphogenetic protein 1 (BMP1) plays a role in the activation of both transforming growth factor-β (TGFβ) and BMP signaling pathways. We investigated whether BMP1 is involved in G-protein coupled estrogen receptor 1 (GPER1)-regulated progression of luminal A-type breast cancer cells.

Objectives: Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. Materials and Methods: The sensitivity of 22 PM cell lines-including 18 models established in our laboratory-to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as MYC copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. Results: Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to MYC copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. Conclusions: The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.

Dermatan sulfate (DS) is an animal glycosaminoglycan with significant structural heterogeneity and a high, but variable density of negative electric charge. Owing to these characteristics DS displays a high degree of biological reactivity that is subject to regulation. We previously demonstrated that structural variants of DS rapidly induce moderate necroptosis in luminal breast cancer cells. In the present study, we investigated the intracellular molecular mechanism(s) that may underlie this effect, focusing on the expression of key regulators of intrinsic (BCL-2A1) and extrinsic (cFLIP) apoptosis, autophagy (Beclin-1), and oxidative stress protection (heme oxygenase-1 (HO-1)). Using RT-qPCR, Western blotting, immunofluorescence, and pharmacological inhibition, we have shown for the first time that DS, depending on its structure and the cancer cell line, can rapidly, albeit transiently, upregulate either the long or short cFLIP splicing variant and also reduce the level of HO-1. These effects are mediated via DS-triggered PI3K and/or NFκB signaling. Moreover, DS can also influence the intracellular distribution of these proteins. In contrast, this glycan did not affect the expression of BCL-2A1 and BECN1. These findings indicate that DS induces coordinated molecular remodeling in luminal breast cancer cells that creates an intracellular environment favorable for necroptosis induction.

Statins that target HMG-CoA reductase (HMGR) in the mevalonate pathway have been used to inhibit cholesterol biosynthesis. Therefore, they have the potential as inhibitors targeting the sterol biosynthesis pathway of plant pathogenic fungi. Currently, their activity against Botrytis cinerea is unknown. In this study, we determined the effects of four statins on both development and pathogenicity of B. cinerea. The interaction modes between statins and HMGR in B. cinerea were characterized through qRT-PCR and molecular docking analysis. Fluvastatin, atorvastatin, simvastatin and lovastatin strongly suppressed hyphal growth of B. cinerea, with EC50 values of 0.66, 3.0, 10.0 and 22.21 µg/mL respectively. Furthermore, statin treatment significantly decreased conidiation, inhibited conidia germination and germ tube elongation, reduced formation of infection structures and attenuated pathogenicity of B. cinerea. Expression levels of HMGR gene were upregulated under treatment with higher concentrations of statins. Molecular docking analysis further predicted that four statins bind to the active site of HMGR in B. cinerea through hydrophobic interactions, hydrogen bonds and salt-bridges. We demonstrated that statins exert inhibitory effects on mycelial growth, development and pathogenicity of B. cinerea, with HMGR predicted as the molecular target. These findings collectively indicated that HMGR was a potential novel control target and statins could be used as lead compounds for developing novel agents.

The aim of this study was to elucidate the molecular mechanism by which MLN4924 affects the progression of acute myeloid leukemia (AML) by regulating TRIM58 DNA methylation.

The metabolic syndrome encompasses a state of inflammation and metabolic dysfunction, possibly mediated via a disturbed intestinal barrier. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide, have shown promising anti-inflammatory effects beyond glucose lowering and weight loss, but the underlying mechanism remains to be elucidated. We hypothesised that GLP-1RAs improve the intestinal barrier function and overall inflammatory status by direct gene activation in mucus-secreting Brunner's glands in the mouse duodenum, known for their high density of glucagon-like peptide-1 receptors (GLP-1Rs).