Numerous studies have highlighted the anti-cancer effects of nonsteroidal anti-inflammatory drugs (NSAIDs), although the underlying mechanisms remain unclear. This study focuses on elucidating the impact of the NSAID ibuprofen (IBU) on cancer cells exposed to hypoxia, as the hypoxic microenvironment significantly influences tumor progression, metastatic potential, and therapy resistance. Given that carbonic anhydrase IX (CA IX) is a key hypoxia-associated protein and a promising therapeutic target due to its tumor-specific expression, we primarily examined the impact of IBU on CA IX and the transcription factors regulating CA IX expression. We found that IBU downregulates expression and protein level of CA IX in hypoxic colon carcinoma and head and neck cancer cells, resulting in a reduction of membranous CA IX. To elucidate the mechanism of this phenomenon, we analyzed the key CA IX-regulating transcription factor HIF-1 and found decreased levels of the HIF-1α subunit in IBU-treated cells, leading to its impaired binding to the CA9 promotor. Analysis of another transcription factor involved in CA IX expression, NFκB, showed suppressed NFκB pathway under IBU treatment. Moreover, we demonstrated IBU-mediated induction in apoptosis in cancer cells, as well as a decrease in their ability to migrate. Our study is the first to demonstrate that ibuprofen downregulates carbonic anhydrase IX expression in hypoxic colon and head and neck tumor cells by decreasing HIF-1α levels. Additionally, ibuprofen impairs key transcription factors NFκB and STAT3, leading to reduced adaptation to hypoxic stress, decreased tumor cell viability, and migration. This indicates its potential as a therapeutic agent in combination therapy for colon carcinoma or head and neck cancer.

The presence of UV-360, a commonly utilized benzotriazole ultraviolet stabilizer, has been frequently detected in diverse environments and organisms. However, existing knowledge regarding the potential impacts of UV-360 exposure on organisms remains limited. To evaluate the influence of UV-360 exposure on zebrafish during their initial developmental phases. The study began with an assessment of the developmental impact of UV-360 on larval stages. Subsequently, the investigation focused on examining its effects on locomotor behaviors. Additionally, analyses were conducted on neuronal development, the expression of genes associated with neurotoxicity, and electrophysiological recordings. Finally, the research extended to an exploration of transcriptome-level gene expression profiles. Exposure to UV-360 exhibited significant adverse effects on larvae, evidenced by a marked reduction in hatching rate, decreased heart rate, and impaired development of total body length. Furthermore, UV-360 exposure induced notable behavioral alterations, malformations in spinal motor neuron axons, and a substantial decrease in both the area and volume of these axons. Additionally, the expression of neurotoxicity-related genes and electrophysiological spike activity were significantly altered by UV-360 exposure. Lastly, exposure to UV-360 triggered significant modifications in the transcriptomic profile of zebrafish larvae, with a considerable proportion of differentially expressed genes associated with signal transduction processes and the neuroactive ligand-receptor interaction pathway. The results of this study revealed a dose-dependent developmental and neurobehavioral toxicity associated with UV-360 exposure in zebrafish larvae. The observed modifications in neuroactive ligand-receptors and disruptions in neurotransmitter systems suggested a potential mechanism for the neurotoxicity induced by UV-360 exposure in zebrafish larvae. These findings contribute significantly to the understanding of the toxicological effects of UV-360 on zebrafish larvae and provide strong evidence to help clarify the mechanisms of UV-360-induced toxicity.

Camellia oleifera, a vital woody oil crop in China, suffers substantial yield losses due to frequent physiological fruit abscission during cultivation. Ethylene signaling, mediated by Ethylene-Insensitive3/Ethylene-Insensitive 3-like (EIN3/EIL) transcription factors encoded by a multigene family, plays a pivotal role in plant organ abscission. However, the EIN3/EIL family remains understudied in C. oleifera. Here, genome-wide analysis identified four CoEIL genes encoding proteins with conserved EIN3 domains. Phylogenetic classification grouped these proteins into Group A and Group B, revealing evolutionary proximity between C. oleifera and tea (Camellia sinensis). Cis-acting regulatory element analysis implicated CoEIL genes in hormone responsiveness and stress adaptation. Quantitative real-time PCR analysis was performed to investigate the expression patterns of these CoEIL genes in the fruit abscission zone following ethephon and brassinolide treatments. This study elucidates the genetic architecture and functional divergence of CoEIL genes, laying the foundation for exploring molecular mechanisms of abscission in C. oleifera.

Ligustrazine (LSZ), an ingredient of Ligusticum chuanxiong, has long been used to treat neurovascular diseases in China. This study investigates its protective effects for the impairment of the blood-brain barrier (BBB) and the underlying mechanisms.

Epigenetic changes caused by methylphenidate hydrochloride on paternal inheritance have been suggested in fish, yet a subject to be determined in mammals. In rats, we showed increased sperm DNA fragmentation and reduced embryonic viability. In the present report, male Wistar rats (n = 21) were divided into two groups: control and methylphenidate. The control group received 1 mL/kg of distilled water, while the methylphenidate group received 5 mg/kg by gavage from 38 to 68 days of age on a single daily dose. After this period, there was an interval before exposed rats started a mating schedule with untreated/normally cycling females. Morphological quality and key epigenetic marks in the blastocysts were assessed. Immunocytochemistry was performed in fresh blastocysts to quantify the trimethylated histones H3K4, H3K9, and H4K20. Treatment with methylphenidate reduced the mean quality of blastocysts by 43.57% (p = 0.02), as well as increased those classified as "poor" by more than 150% (p < 0.001). Epigenetic marks were also altered, with an increase in the intensity of H3K9me3 (p = 0.01), a reduction of H4K20me3 (p = 0.05) and a nonsignificant increase of H3K4me3 (p = 0.34). The results suggest that the decline in blastocyst quality is highly associated with subchronic use of this psychostimulant by adolescent males. This is the first report showing the risks posed by methylphenidate to the epigenetic signature of a mammalian blastocyst following paternal exposure.

BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE 1 (BAK1)-INTERACTING RECEPTOR-LIKE KINASE (BIR) proteins are negative regulators of cell death and defense against microbes in Arabidopsis thaliana. Here, we demonstrate that the members of the BIR family function as negative regulators of antiviral resistance in Arabidopsis. We show that during tobacco rattle virus (TRV) infection, BIR1 and BIR3 gene expression is antagonistically regulated by salicylic acid and jasmonic acid signaling pathways. BIR1 and BIR3 negatively regulate TRV resistance via distinct mechanisms. Our data indicate that BIR1 modulates antiviral defense through mechanisms that include pattern-triggered immune (PTI) gene expression, plasmodesmata callose deposition alongside yet unidentified defense pathways independent of the receptor-like kinases BAK1 and SUPPRESSOR OF BIR1-1 1 (SOBIR1), or the lipase-like PHYTOALEXIN DEFICIENT 4 (PAD4). BIR3 negatively regulates a pathway that involves BAK1 and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1)/PAD4, suggesting that BIR3 disrupts an immune response similar to effector-triggered immunity (ETI) driven by nucleotide-binding leucine-rich intracellular receptors. This response helps control virus proliferation without causing a hypersensitive reaction. Our findings also reveal that BIR2 represses antiviral defense against TRV, highlighting the conserved function of BIR proteins as pivotal modulators in plant-virus interactions. We propose that the induction of BIR proteins during viral infection helps maintain a balance between defense activation and suppression to prevent viral overaccumulation and plant damage.

Alternative splicing (AS) is consistently linked to tumor progression. SRSF1, the first identified proto-oncogene in the serine/arginine-rich splicing factor (SRSF) protein family, plays a crucial role. However, the specific functions and potential mechanisms of SRSF1 in advancing bladder cancer (BCa) progression and influencing chemosensitivity remain largely unexplored.

Insects and mammals share a similar innate immune system. Galleria mellonella (L.), a beekeeping pest, is an alternative model organism for human health studies due to its immune response similarity and ability to be maintained at 37 °C. While oxidative stress and genotoxicity cause diseases, antioxidant enzymes and epigenetic mechanisms are effective in immunological response processes. Although parasitoid venoms are potential candidates for pharmacological applications such as anticoagulant, antibiotic, painkiller, antiviral and anticancer agents, the information pool is scarce to reflect their effects in humans. In an attempt to reveal the pharmaceutical significance of parasitoid venoms and their potential effects on human health, different venom doses of Pimpla turionellae (L.), the solitary endoparasitoid of G. mellonella, were injected into the host. Then, the levels of protein content, advanced oxidised protein products, lipid peroxidation, antioxidant power and glutathione in host haemolymph, and the amounts of methylation marker 5-methyldeoxycytidine monophosphate and strand breakage rates under neutral and alkaline conditions in host DNA were analysed. Principal component analysis was performed to determine the number of components that oxidative parameters depend on, and multivariate correlation analysis was applied to evaluate the effects of the parameters on each other. It was concluded that P. turionellae venom appeared to be one of the most effective pharmaceutical agents among parasitoid venoms. Also, the 0.01 venom reservoir equivalent dose qualified as immunotherapeutic dose.

Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neurodevelopmental disorders and birth defects. To explore the effects of PAE on gastrulation, we used an in vitro model with subchronic moderate (20 mM) and severe (70 mM) ethanol exposures during the differentiation of human embryonic stem cells into germ layer cells. We analyzed genome-wide gene expression (mRNA sequencing), DNA methylation (EPIC Illumina microarrays) and metabolome (non-targeted LC-MS) of the endodermal, mesodermal and ectodermal cells. The largest number of ethanol-induced alterations were observed in endodermal cells, whereas the most prominent changes were in ectodermal cells. Methionine metabolism and genes of the main signaling pathways involved in gastrulation and body patterning were affected by ethanol in all germ layers. Many of the altered genes, including BMP4, FGF8, SIX3 and LHX2, have previously been associated with PAE and phenotypes of FASD, like defects in heart and corpus callosum development as well as holoprosencephaly. Our findings support the early origin of alcohol-induced developmental disorders and strengthen the role of methionine cycle in the etiology of FASD.

Radiation therapy has revolutionized the treatment of primary or liver metastases in colorectal cancer (CRC). In colorectal cancer, conventional fractionation (1.8 ~ 2.0 Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potential implications of radiation therapy-induced alterations in the expression levels of regulatory genes on resistance to chemotherapy agents. Herein, we explored the mechanism by which conventional fractionation drives 5-fluorouracil (5-FU) resistance and metformin (Met) rescued 5-FU resistance in CRC.

Colorectal cancer (CRC) is emerged as a global problem with high mortality rate; hence, finding of alternative treatment approaches is essential. The purposes of this research are to assess the impact of chitosan nanoparticles conjugated with the cell free supernatant of Bifidobacterium bifidum (CTNP/B.b-sup) on genes associated with CRC signaling pathways.

Chromatin remodeling factors are involved in the inflammatory responses, contributing to tissue damage and multi-organ dysfunction in COVID-19 patients. However, the underlying mechanisms remain unclear. In this study, high-dimensional analyses of single-cell RNA sequencing and single-cell ATAC sequencing data revealed increased chromatin accessibility at the promoters or enhancers of the pro-inflammatory cytokine tissue inhibitor of metalloproteinase-1 (TIMP1), as well as altered gene transcription profiles in monocytes from COVID-19 patients. Motif enrichment and positive regulators analyses identified SMARCC1, the core subunit of the chromatin remodeling complex, and the transcription factor JUND as positive regulators to co-modulate TIMP1 expression. In-vitro experiments, co-immunoprecipitation and chromatin immunoprecipitation (ChIP)-qPCR, and others, demonstrated the collaboration of SMARCC1 and JUND. Increased 7α,25-dihydroxycholesterol (7α,25-OHC) enhanced SMARCC1-JUND interactions to co-regulate TIMP1 expression. Further investigation indicated that 7α,25-OHC promoted the expression of SMARCC1 and its co-localization with H3K27ac, which involved in the expression of TIMP1 and inflammatory responses. Our study highlights the critical roles of SMARCC1 and JUND in COVID-19 inflammation, and offers the potential targets for the prevention and treatment of COVID-19.

Endocrine disrupting compounds such as bisphenol A (BPA) negatively affect oocyte maturation and embryo development, while promoting epigenetic changes in miRNAs (miRs), including that of miR-21. miR-21 is an integral miR involved in various developmental processes, such as oocyte maturation, granulosa cells function and embryo development. Connexin (Cx) gap junction proteins play an important role in the communication among granulosa cells and cumulus cells and are impacted by bisphenols and linked to specific miRs. We hypothesize that miR-21 downregulation and BPA exposure affect Cxs mRNA and downstream miRNAs expression. Oocyte maturation was unaffected by miR-21 downregulation, but was significantly decreased (p = 0.0059) following BPA exposure. Also, BPA significantly increased Cx 43 mRNA levels when miR-21 is knocked-down in cumulus cells (p = 0.0476). miR-378a, a target of Cx 43 and 37, increased due to BPA and combination treatment in denuded oocytes (p = 0.0349) and cumulus cells (p = 0.0177). miR-96, a Cx 26 target, displayed a significant decrease in all samples following BPA exposure, in a miR-21 independent manner (p < 0.05). These data strengthen previous evidence of a strict relationship among BPA, miR-21 and especially Cx 43 and miR-378a. Further investigations are worthy in elucidating these interactions and their response to BPA exposure during early development.

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in China. Despite the use of some targeted therapies in lung cancer treatment, the prognosis remains suboptimal, highlighting the urgent need for new, effective drugs to enhance outcomes. Ticagrelor, a marketed anti-platelet drug, has been reported to have anti-tumor effects. This study primarily investigates the inhibitory effect of Ticagrelor on lung adenocarcinoma in both in vivo and in vitro models, as well as its molecular mechanisms. Firstly, the effects of ticagrelor on the proliferation (CCK-8 and Edu staining), migration (scratch test), and invasion (Transwell chamber) of lung adenocarcinoma cells were evaluated using a variety of lung adenocarcinoma cell models. Secondly, the efficacy of ticagrelor on lung adenocarcinoma in vivo was evaluated by A549, H1975 tumor-bearing mouse models. Finally, transcriptomic sequencing (RNA-Seq) and immunohistochemistry were used to explore the molecular mechanism of the intervention effect of ticagrelor on lung cancer. Ticagrelor significantly inhibits the proliferation, migration and invasion of various lung cancer cells in vitro, and markedly suppressed tumor growth in A549 and NCI-H1975 CDX model in vivo. The pathological results showed that the number of tumor cells in the intervention group was significantly reduced, with large area necrosis, and the expression of Ki-67 in the intervention group was significantly decreased by immunohistochemistry. RNA-seq sequencing results from NCI-H1975 xenograft showed that several integrin-related pathways were down-regulated in the Ticagrelor treatment group, along with a significant reduction in spleen tyrosine kinase (SYK), a pivotal protein related to integrin signaling. Furthermore, we demonstrated that ticagrelor inhibits lung adenocarcinoma by down-regulating SYK and regulating PI3K/AKT pathway using WB. Ticagrelor has obvious inhibitory effect on a variety of lung adenocarcinoma cell lines and cell line transplanted tumors, and its antitumor effect may be related to the inhibition of SYK signaling pathway and PI3K/AKT pathway.

Finding the molecular targets involved in the severity and drug resistance of Colorectal cancer (CRC) and applying targeted treatments against them is a promising approach. In this study, some candidate oncogenes related to disease severity and mortality were identified by extracting bioinformatics data, and the effect of Fe3O4@Glu-Cinnamon NPs on the survival of CRC cells (SW480) and the expression of these oncogenes was investigated. The NPs were characterized by FT-IR, XRD, DLS and zeta potential measurement, TEM and SEM imaging, EDS-mapping and VSM analysis. Cytotoxicity of the NPs was evaluated by the MTT assay and a flow cytometry analysis was done to investigate cell apoptosis/necrosis levels and cell cycle analysis of cancer cells. The Fe3O4@Glu-Cinnamon NPs with spherical morphology were correctly synthesized, containing no elemental impurities, with a size range of 26.8-60.2 nm, DLS of 213 nm, zeta potential of -15.4mV and maximum magnetization level of 20.33emu/g. Treatment of cancer cells with the NPs elevated primary and late apoptosis and cell necrosis levels to 20.85, 16.83 and 9.56% and treated cells were mainly arrested at the S and G2/M phases. The expression level of the oncogenes associated with mortality, SNAI1, THBS2 and INHBA reduced to 0.74, 0.66 and 0.7 folds, respectively. The magnetic properties of Fe3O4 NPs enable their potential use in targeted drug delivery, allowing for site-specific accumulation within tumors. This could minimize systemic toxicity while enhancing treatment efficacy.

The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2 synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.

Seed aging or deterioration can affect germination rate, vigor, and viability. Allium mongolicum seeds stored for different years were used to obtain germination indicators, physiological indicators, and proteomic and transcriptomic sequencing in seeds treated with spermidine (Spd). The germination ability of A. mongolicum seeds increased and then decreased with the extension of storage life. The germination rate was only about 40% after 6 years. Relative conductivity, malondialdehyde (MDA), and hydrogen peroxide (H2O2) content first decreased and then increased, while catalase activity (CAT), peroxidase activity (POD), superoxide dismutase activity (SOD), Ascorbate peroxidase activity (APX), and respiratory rate first increased and then decreased. Spd increased the seed germination rate, CAT, POD, SOD, and APX activity. However, it significantly reduced MDA, H2O2 content, and relative conductivity. Differentially expressed proteins were concentrated in energy metabolism pathways. Ten proteins related to the aging of A. mongolicum seeds were identified. The gene expression trend was basically consistent with the proteomic assay results. Energy metabolism is a key pathway in the aging of A. mongolicum seeds. Regulating the expression of genes involved in energy metabolism pathway can effectively alleviate A. mongolicum seed aging. The results enriched the molecular mechanism of the seed storability of A. mongolicum, providing theoretical bases for molecular marker-assisted breeding of its storability traits.

Adenosine kinase (ADK, EC: 2.7.1.20) is an evolutionarily ancient ribokinase, which acts as a metabolic regulator by transferring a phosphoryl group to adenosine to form AMP. The enzyme is of interest as a therapeutic target because its inhibition is one of the most effective means to raise the levels of adenosine and hence adenosine receptor activation. For these reasons, ADK has received significant attention in drug discovery efforts in the early 2000s for indications such as epilepsy, chronic pain, and inflammation; however, the report of adverse events regarding cardiovascular and hepatic function as well as instances of microhemorrhage in the brain of preclinical models prevented further development efforts. Recent findings emphasize the importance of compartmentalization of the adenosine system reflected by two distinct isoforms of the enzyme, ADK-S and ADK-L, expressed in the cytoplasm and the cell nucleus, respectively. Newly identified adenosine receptor independent functions of adenosine as a regulator of biochemical transmethylation reactions, which include DNA and histone methylation, identify ADK-L as a distinct therapeutic target for the regulation of the nuclear methylome. This newly recognized role of ADK-L as an epigenetic regulator points toward the potential disease-modifying properties of the next generation of ADK inhibitors. Continued efforts to develop therapeutic strategies to separate nuclear from extracellular functions of adenosine would enable the development of targeted therapeutics with reduced adverse event potential. This review will summarize recent advances in the discovery of novel ADK inhibitors and discuss their potential therapeutic use in conditions ranging from epilepsy to cancer.

Endostar is a human recombinant endostatin which is an attractive anti-angiogenesis protein. Because inefficient antigen presenting MHC class I expression (which can be downregulated by HIF-1) is an important strategy for cancer immune evasion, besides its anti-angiogenesis effect, it remains unclear whether Endostar has an inhibitory effect on HIF-1 expression by upregulating MHC class I expression in cancer cells to facilitate immunotherapies, including PD-1/PD-L1 inhibitors. In this study, A549 and NCI-H1299 lung cancer cells were treated with Endostar (6.25 μg/ml, 12.5 μg/ml, and 25 μg/ml, respectively). HIF-1 expression was detected by Immunocytochemistry and Western blot. Proteins of the MHC class I α-heavy chain and β2 m light chain, STAT3 and pSTAT3 were detected by Western blot. The mRNAs of MHC class I α-heavy chain and β2 m light chain were detected by RT-qPCR. It was shown that decreased expression of HIF-1 and promotion of β2-microglobulin were observed after Endostar treatment. In addition, elevated levels of MHC class I α-heavy chain mRNA and protein, as well as downregulation of STAT3 and pSTAT3, were also observed following Endostar treatment. Endostar inhibited HIF-1 expression in A549 and NCI-H1299 lung cancer cells, upregulated expression of MHC class I α-heavy chain and β2 m light chain, with the upregulation of STAT3 and pSTAT3, suggesting involvement of STAT3 pathway. It is important because only in combination with MHC class I on target cells can tumor antigenic peptides be recognized by CD8+ CTLs which destroy target cells. However, MHC class I is frequently deficient in cancer cells.

Benign prostatic hyperplasia (BPH) poses a significant public health challenge, affecting a substantial portion of aging men worldwide. Current therapeutic options offer limited efficacy. The pathogenesis of BPH is multifactorial, involving ferroptosis, oxidative stress, and chronic inflammation. Hydroxycitric acid (HCA) is a natural compound with diverse pharmacological activities, including the inhibition of ferroptosis, anti-inflammatory, anti-oxidative stress, and anti-tumor effects. However, its role in BPH remains unexplored. This study aimed to investigate the effects of HCA on BPH and elucidate the underlying mechanisms, with the goal of providing novel therapeutic insights for BPH treatment.