The aim of this study was to determine if remote ischemic per-conditioning (RIPerC) can provide protection to the kidneys from ischemia-reperfusion injury (IRI) by increasing the expression of the Gclc and Gclm genes involved in innate defenses. Rats undergoing sham surgery were used as controls. Induction of renal IRI involved blocking the renal pedicles for 60 min, then allowing 24 h of reperfusion. RIPerC involved 4 cycles (5 min) of limb I/R. Animals were divided into seven groups in a random manner: sham, I/R, I/R + RIPerC, I/R + NaHS (NaHS, 100 μmol /kg, i.p), I/R + RIPerC+NaHS, I/R + PAG (propargyl glycine, 50 mg/kg, i.p.) and I/R + RIPerC+PAG. Following reperfusion, samples of urine, blood, and renal tissue were gathered for functional, molecular, and histological analysis. Renal IRI impaired kidney function (reduced CCr, increased FENa, decreased water reabsorption, and reduced urine osmolality), increased oxidative stress (an increase in total oxidative status and a decrease in total antioxidant capacity), and reduced expression of CBS, CSE, Gclc and Gclm genes, causing tissue damage. RIPerC attenuated the IRI-induced kidney dysfunction, oxidative stress, and gene expression changes. Inhibiting hydrogen sulfide signaling with propargylglycine reduced the benefits of RIPerC, while the hydrogen sulfide donor NaHS enhanced them. These findings suggest RIPerC's renal protective effects involve upregulation of antioxidant defense pathways.

Chemotherapy is a primary therapeutic option in cancer treatment, but often associated with unwanted side effects and drug resistance. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are essential components of tight junctions, frequently overexpressed in ovarian cancer, serve as potential therapeutic targets. In this study, we utilized flow cytometry, qPCR, Western blot, and animal experiments to investigate the regulation of CLDN3 and CLDN4 by chemotherapy drug, gemcitabine, in the ovarian cancer cell line A2780. We reported that gemcitabine can induce expression of CLDN3 and CLDN4 in ovarian cancer cells. Mechanistically, we showed that gemcitabine induces expression of CLDN3 and CLDN4 through p38 MAP kinase mediated transcriptional regulation. Overexpression of CLDN3 or CLDN4 functionally protected A2780 ovarian cancer from gemcitabine induced cell killing. It appears that gemcitabine induced expression of CLDN3/4 is a chemoresistance mechanism for cancer cells. Gemcitabine-induced upregulation of CLDN3/4 suggests that ovarian cancer cells may be more effectively targeted using claudin-3/4-specific antibodies or antibody-drug conjugates (ADCs) in combination with chemotherapy, which could have clinical implications for ovarian cancer treatment in the future.

Alkali and drought stresses are two common abiotic factors affecting plants growth and development. Auxin signal also regulates plant responses to abiotic stresses. Especially, auxin early response genes can quickly respond after sensing auxin signal. However, auxin early response genes related to alkali and drought stresses are rarely reported in Leymus chinensis. In this study, LcSAUR1 (small auxin-up RNA) was isolated from the difference expression analysis of the transcriptome data in Leymus chinensis under alkali and drought stresses. And LcSAUR1 exhibited inhibitory expression under alkali and drought stresses. Further research showed that LcSAUR1 was localized in the nucleus, cell membrane, and chloroplast, suggesting that it might has special biofunction. Overexpression of LcSAUR1 led to shorter root lengths in LcSAUR1-transgenic Arabidopsis and rice. Under alkali and drought stresses, the OE-LcSAUR1-Col lines showed delayed germination and larger stomatal aperture, and the OE-LcSAUR1-NIP lines had lower survival rates. The determination of physiological indicators including hydrogen peroxide (H2O2), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), the contents of proline (PRO), and the staining of nitro-blue tetrazolium (NBT) and Diaminobenzidine (DAB) indicated that the overexpressed LcSAUR1-transgenic Arabidopsis and rice produced more reactive oxygen species (ROS). In addition, for the genes related to abiotic stresses, the expression of AtSnRK2.6, AtNCEB3, AtCAT2, and AtAPX1 in the OE-LcSAUR1-Col lines, and OsLEA3-2, OsABF1, OsCAT2, and OsAPX2 in the OE-LcSAUR1-NIP lines were all lower than their WT under alkali and drought stresses, suggesting that LcSAUR1 regulates alkali and drought tolerances might through those abiotic-related genes. The study suggests that the LcSAUR1 negatively regulates alkali and drought stresses, providing a novel insight into auxin signal and abiotic stresses.

Microplastics (MPs) and copper (Cu) are common co-pollutants in agricultural environments, yet their combined effects on plants remain poorly understood. This study investigated the individual and interactive impacts of Cu and polyvinyl chloride (PVC)-MPs on Perilla frutescens, a heavy metal hyperaccumulator and economically important crop, using hydroponic experiments. Low Cu concentrations (<2 mg L-1) promoted growth, whereas higher levels (>2 mg L-1) induced leaf chlorosis, curling, and root decay. PVC-MPs alone exhibited phytotoxicity only at high concentrations (>1000 mg L-1). In combined treatments, 10-100 mg L-1 PVC-MPs alleviated Cu-induced chlorosis and increased leaf area, though higher MP concentrations suppressed root growth. Physiologically, Cu stress impaired photosynthesis, enhanced antioxidant enzyme activity, and increased osmoregulatory substance content. PVC-MPs counteracted these effects by improving photosynthetic efficiency, enhancing peroxidase activity, and reducing osmotic stress markers. Transcriptomic analysis revealed that PVC-MPs upregulated endocytosis-related genes while downregulating jasmonic acid (JA) biosynthesis and lipid metabolism pathways. ABC transporter genes were differentially expressed, functionally linked to these processes. We demonstrate for the first time that PVC-MPs mitigate Cu stress via three synergistic mechanisms: enhanced membrane trafficking (endocytosis activation), suppression of stress-signaling phytohormones (JA), and lipid metabolism reprogramming. These findings redefine MPs' dual role as both pollutants and unexpected alleviators of metal toxicity. While these findings reveal MPs' unexpected capacity to alleviate metal stress, their persistent environmental accumulation necessitates comprehensive risk-benefit analysis and long-term ecological monitoring-highlighting the imperative for science-based evaluation rather than promoting field applications of MPs as stress mitigants.

Acute lung injury (ALI) is a devastating inflammatory lung disease with high morbidity and mortality. Characterized by diffuse alveolar damage, macrophages infiltration, and pulmonary edema, ALI currently lacks effective therapeutic strategies. Rebastinib is a small molecule inhibitor of the Tie2 receptor and an antineoplastic drug. This study investigated the effects of Rebastinib on lipopolysaccharide (LPS)-induced ALI and GSDMD-mediated pyroptosis and NLRP3 inflammasome activation in vitro and in vivo. Our results revealed that Rebastinib significantly attenuated GSDMD-dependent pyroptosis in macrophages, leading to reduced production of caspase-1, LDH and IL-1β. Mechanistically, Rebastinib promoted NLRP3 ubiquitination, thereby disrupting the connection between ASC and NLRP3 and effectively suppressing NLRP3 inflammasome assembly. Additionally, Rebastinib exhibited effective protection function on alveolar epithelial cells in a co-culture system. Furthermore, Rebastinib administration alleviated lung inflammatory damage in LPS-induced ALI mouse model. These findings suggest that Rebastinib holds promise as a therapeutic candidate for ALI by inhibiting the activation of pyroptosis and NLRP3 inflammasome on macrophages.

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.

In the present study, we aim to identify novel molecular targets for sensitizing Breast cancer stem cells (BCSCs) to common antitumor treatments. MicroRNAs (miRNAs) play key roles in pivotal cellular processes. Therefore, modulating the expression of these miRNAs may lead to increased sensitivity of BCSCs to current treatments or overcome their therapeutic resistance. Due to their pivotal roles in the regulation of apoptosis (via BCL2) and chemoresistance (via ABCG2) and their differential expression in BCSCs (compared to non-BCSCs), miR-34a and miR-328 were selected for analysis.

To investigate the response of the suppressor of the cytokine signaling (socs) gene family in rainbow trout following exposure to microplastics, this study conducted a bioinformatics analysis of the socs gene family using rainbow trout genome data, complemented by experiments involving microplastic exposure and gene expression detection.

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.

Overexpressed AlaAT3 in Populus enhances ammonium tolerance by modulating carbohydrate metabolism, nitrogen metabolism, and antioxidant system-related metabolic processes. Alanine aminotransferase (AlaAT) is a critical enzyme involved in the nitrogen assimilation process in plant cells, catalyzing the reversible transfer of an amino group from alanine to α-ketoglutarate. This reaction is essential for maintaining metabolic homeostasis. Previous studies have suggested that AlaAT plays a role in alleviating ammonium toxicity in plants. To investigate this hypothesis, transgenic Populus × xiaohei plants overexpressing AlaAT3 were generated, and their phenotypic, physiological, and transcriptional traits were compared with those of wild-type (WT) plants. Under treatment with 3 mM NH4+ ammonium nitrogen, the transgenic plants exhibited significantly enhanced root biomass. Compared with WT plants, the transgenic lines demonstrated higher activities of GS, SOD, and CAT enzymes, while POD activity was notably reduced. Levels of soluble protein, free amino acids, sucrose, starch, soluble sugars, and proline were significantly elevated, whereas concentrations of O2-, and NH4+ were markedly reduced. Transcriptomic analysis revealed significant enrichment in glutathione metabolism, peroxisome, nitrogen metabolism, and starch and sucrose metabolism pathway in the transgenic plants, with corresponding genes displaying notable transcriptional changes. Regulatory network analysis identified key transcription factors, including WRKY53, DOF3.4, and DOF1.5, as potential regulators of ammonium toxicity resistance in these transgenic lines. These findings demonstrate that AlaAT3 overexpression enhances Populus × xiaohei tolerance to NH4+ by modulating glutathione metabolism, peroxisome, nitrogen metabolism, and starch and sucrose metabolism pathway. This study provides candidate genes and lays a strong foundation for future research into the mechanisms underlying NH4+ tolerance in Populus plants overexpressing AlaAT3.

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.

The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors. It is imperative to conduct a comprehensive investigation into the distinctive biological functions and mechanisms by which SMARCA4 contributes to cancer development and to devise targeted therapeutic strategies. Despite numerous studies associating SMARCA4 with the regulation of essential genes, ferroptosis, autophagy, lipid metabolism, and oxidative stress, the precise mechanisms of SMARCA4 in tumors remain unclear. Patients with SMARCA4 mutations exhibit a poor prognosis and demonstrate limited responsiveness to surgery, targeted therapies, immunotherapy, and chemotherapies. Thus, SMARCA4 emerges as a promising biomarker and therapeutic target. However, the development of more effective precision therapy tools remains an urgent unmet need. The unique molecular characteristics of SMARCA4 pose significant challenges for targeted drug development. Notably, the discovery of inhibitors targeting SMARCA4 synthetic lethal partners and associated pathways has marked a breakthrough in this field. Monotherapies directed against SMARCA4 face several limitations, including drug resistance, suboptimal objective response rates, and dose-limiting toxicities. Consequently, the exploration of combinatorial therapeutic strategies for SMARCA4 deficiency populations represents a critical direction for future clinical translation.

Glioblastoma (GBM), Isocitrate Dehydrogenase-wildtype (IDH-WT) represents the most prevalent and clinically aggressive subtype of adult diffuse gliomas, typically associated with poor prognosis. Temozolomide (TMZ) remains the first-line chemotherapeutic agent for GBM; however, the emergence of TMZ resistance represents a major therapeutic obstacle in clinical practice. This study identifies placenta-specific 8 (PLAC8) as a novel mediator of TMZ resistance in IDH-WT GBM. Elevated PLAC8 expression was strongly correlated with poorer survival rates, higher tumor grades in glioma, establishing it as an independent prognostic factor. Notably, consistent upregulation of PLAC8 was observed in both TMZ-resistant GBM cells and TMZ-treated patients, suggesting its potential as a biomarker for TMZ resistance. Mechanistic studies revealed that PLAC8 regulates TMZ sensitivity in GBM cells through the AKT-mTOR signaling pathway. Additionally, integrated bioinformatics and clinical analyses demonstrated that PLAC8 expression positively correlates with immune cell infiltration while promoting an immunosuppressive tumor microenvironment and modulating immunotherapy-related biomarkers, suggesting its potential as a predictive biomarker for immunotherapy response. In conclusion, PLAC8 represents a promising biomarker and therapeutic target for overcoming TMZ resistance and guiding immunotherapy in GBM. This study provides valuable insights for the development of personalized treatment strategies aimed at improving patient outcomes.

Bacillus amyloliquefaciens exhibits significant efficacy in the production of alkaline protease. Identifying the factors that trigger alkaline protease overproduction during the fermentation process provides valuable insights for enhancing the performance of alkaline protease-producing strains. Transcriptomic analysis revealed that quorum sensing (QS) plays a crucial role in regulating alkaline protease production. Fermentation experiments demonstrated that the addition of exogenous surfactin, a key QS signaling molecule, enhanced alkaline protease production. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis indicated that the positive effects of surfactin are associated with carbon catabolite repression (CCR), QS, and the regulation of global nitrogen metabolism. Based on these findings, rational genetic modifications, including the deletion of the rapF and kinC genes, were performed, led to a 91.1 % increase in alkaline protease production and a 15 h reduction in fermentation time. This study not only provides insights into the molecular mechanisms of surfactin-mediated alkaline protease overproduction but also offers valuable strategies for improving the industrial performance of alkaline protease-producing strains.

The use of bisphenol A has been restricted due to its toxicity. However, the impact of its substitute, bisphenol Z (BPZ), on Leydig cell function remains uncertain. We aimed to examine the associations between BPZ exposure and the disruption of Leydig cell function via upregulating Mettl3 and inducing oxidative stress. To address this, in vivo, male adult Sprague-Dawley rats received BPZ (0, 1, 10, or 100 mg/kg/d orally) for 7 days, and in vitro, purified Leydig cells were treated with BPZ (0-20 μM, 24 h). Leydig cell morphology and function were assessed. The results showed that BPZ did not alter Leydig cell quantity but notably decreased serum testosterone levels. Furthermore, it significantly downregulated the expression levels of genes and proteins (SCARB1, STAR, CYP17A1, HSD17B3, and INSL3) in Leydig cells. Concurrently, BPZ treatment led to diminished expression of antioxidant genes (Gpx1 and Cat), an upregulation in m6A related gene (Mettl3) subsequent to the enrichment of RNA methylation fragments in the testis. In vitro analysis of primary Leydig cells demonstrated that BPZ heightened oxidative stress and diminished testosterone production. In conclusion, BPZ reduces rat testosterone by downregulating steroidogenic genes (Star, Scarb1, Cyp17a1, and Hsd17b3) via METTL3-m6A-Camkk2 pathway, impairing Leydig cell function.

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.

Liver fibrosis is a global health issue with limited treatments. While apigenin has demonstrated potential in alleviating liver fibrosis, its mechanisms remain unclear. This study employed an integrated proteotranscriptomic approach to elucidate the molecular mechanisms underlying apigenin's protective effects against CCl4-induced liver fibrosis. Liver tissues from mice with CCl4-induced fibrosis treated with different doses of apigenin (10, 20, and 40 mg/kg) were analyzed using transcriptomics and proteomics. Results demonstrated dose-dependent antifibrotic effects of apigenin. Notably, numerous genes and proteins were inversely regulated by CCl4 and apigenin, with generally low and variable mRNA-protein abundance correlations. We identified 82 biological processes or molecular functions that were inversely regulated by CCl4 and high-dose apigenin at both mRNA and protein levels. Among the 48 key proteins (KPs) involved, 11 and 14 KPs correlated with liver fibrosis in mouse and human data sets, respectively. Six KPs maintained consistent correlations with fibrosis severity across both species, highlighting their potential as both biomarkers for fibrosis progression and translational targets. These findings underscore apigenin's therapeutic potential and emphasize the importance of multiomics approaches in understanding complex diseases like liver fibrosis. This study also provides valuable insights for developing improved therapeutic strategies and diagnostic tools for liver fibrosis.

Akkermansia muciniphila is a beneficial gut bacterium because of its improving metabolic effect. However, it is not fully understood how A. muciniphila interacts with host substances to inhabit the human gut. To examine the effect of deoxycholate (DCA) produced by the combination of host and gut bacteria, which enhances the growth of A. muciniphila, on the metabolic changes of A. muciniphila using transcriptome and proteome analyses. Transcriptome analysis showed that carbohydrate metabolism, including glycosyl hydrolase activity and glycosyl bond activity, was significantly upregulated. Notably, transcriptome and proteome analyses demonstrated that the γ-aminobutyric acid (GABA) production pathway, which is related to acid or osmotic stress responses, was upregulated in the presence of DCA. Our results demonstrated that carbohydrate metabolism and GABA production were altered in response to DCA. Therefore, DCA may be a key intestinal substance for the physiological regulation and persistence of A. muciniphila in the gut. This study provides valuable insights into understanding the interaction between host and gut bacterium to persist in the gut.