APETALA2/ethylene response factor (AP2/ERF) transcription factors constitute a significant family of transcription factors that play crucial roles in plant growth and development. Meanwhile, organ abscission is common in the growth and development of fruit trees. In particular, the economically important sweet cherry (Prunus avium L.) is highly affected by excessive fruit abscission, limiting its yield and economic benefits. Previous research identified the potential involvement of PavRAP2.3 (RELATED TO AP2.3) of the AP2/ERF family in fruit abscission based on the significantly higher PavRAP2.3 expression levels in abscised tissues. This study found the highest PavRAP2.3 expression level in mature fruits and significantly increased PavRAP2.3 expression in leaves treated with abscisic acid (ABA) and ethephon (ETH). PavRAP2.3 was localized in the nucleus and exhibited transcriptional activity in Y2H gold yeast. Yeast one-hybrid assays and dual-luciferase assays revealed that PavRAP2.3 induced abscission by regulating the PavCEL9-like, a gene associated with cell wall reconstruction. Furthermore, PavRAP2.3-overexpressing Arabidopsis thaliana exhibited promoted petal abscission, which was attributed to the upregulation of Cellulase 3 (CEL3), Mannase 7 (MAN7), ABA Insensitive 5 (ABI5), and ACC SYNTHASE6 (ACS6) genes. Therefore, PavRAP2.3 functions as a positive regulator involved in sweet cherry fruit abscission, chiefly via regulating PavCEL9-like. These findings could facilitate breeding efforts aimed at reducing fruit abscission in sweet cherry, as well as better the understanding of the function of the AP2/ERF family.

Plant biostimulants represent a promising option to improve agricultural production and stress resistance while reducing the use of fertilizers and pesticides. Despite various evidence demonstrating the beneficial role of biostimulants in preventing the negative effects of abiotic stress on plants, the ability of biostimulants to bolster defense mechanisms has been brought to light only recently. In this work, the impact of a biostimulant based on Ecklonia maxima and yeast extracts (S/Y) on the response of tomato infected with Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) was assessed. S/Y was selected after a screening to identify biostimulants capable of conferring resistance to Pst DC3000. S/Y boosts the early events of the plant's innate immunity. Indeed, biostimulation increased the Pst DC3000-induced oxidative burst by upregulating the NADPH oxidase/respiratory burst oxidase homolog and apoplastic class III peroxidases expression. Moreover, the deposition of callose was also promoted. Due to improved activation of early defense responses by S/Y, disease symptoms and bacterial spread 72 h after the infection were significantly reduced. Finally, levels of salicylic acid, a key hormone in plant innate immunity, were increased by S/Y, whilst those of jasmonic acid and auxin, which are negative regulators in defense responses to Pst DC3000, were hampered. Overall, these findings show that S/Y mitigates infection symptoms by acting on different defense mechanisms, thus providing evidence of the potential of the biostimulant to improve plants' response to biotic stresses.

Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models. Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses both in human and mouse solid tumor cell lines. This unique BCL-XL dependency was in clear contrast to hematological malignancies, which are largely dependent on BCL2 or MCL1 inhibition under epigenetic drug treatment. Mechanistically, co-targeting of epigenetic regulators and BCL-XL induced expression of endogenous retroelements that led to immunogenic cell death. We thus hypothesized that this response may sensitize tumor cells to immune checkpoint blockade (ICB). Accordingly, treatment with a triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody in vivo reduced tumor growth and prolonged overall survival in a panel of murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, as well as in an immunocompetent human colon cancer model. Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors.

Xenon and cobalt are representatives of hypoxia-inducible factor (HIF) activators stimulating erythropoiesis and are prohibited by the World Anti-Doping Agency (WADA). The expression profiles of 84 microRNAs circulating in blood plasma and involved in the regulation of the HIF-1α transcription factor and its downstream signaling pathways were analyzed in volunteers before and after intake of cobalt (II) and xenon preparations using quantitative real-time PCR and certified miRCURY LNA miRNA Focus Panel (Qiagen) for analysis of microRNA expression profiles. Intake of cobalt aspartate increased the expression of hsa-miR-15b-5p, while inhalation of the Xe/O2 mixture significantly increased the plasma levels of hsa-miR-378a-3p and hsa-miR-491-5p. Thus, we for the first time revealed differential expression of microRNAs circulating in plasma in response to various HIF activators. Potential microRNA markers for identification of cobalt and xenon abuse for anti-doping control are proposed.

Isorhapontigenin is an effective active ingredient in Rheum officinale, which has been reported to have anti-tumor effects. However, its effect and molecular mechanism on non-small cell lung cancer are still unclear. Firstly, potential therapeutic targets of Isorhapontigenin against non-small cell lung cancer were obtained through network pharmacology analysis. Secondly, bioinformatics analysis was conducted to identify key targets and potential signaling pathway mechanisms based on the obtained potential targets. Then, evaluated the binding ability between Isorhapontigenin and key targets by using molecular docking strategies. Finally, in vitro cell experiments were conducted to verify the effects and related targets of Isorhapontigenin on non-small cell lung cancer cells. 104 drug targets and 6688 disease targets were acquired from SwissTarget prediction, BATMAN-TCM, STITCH and Genecards databases.79 potential therapeutic targets were identified through analysis based on online Venn website and PPI interaction analysis was performed on these targets to ultimately obtain 55 key targets. GO and KEGG analysis revealed that Isorhapontigenin targets non-small cell lung cancer mainly through regulation of cell proliferation, cell cycle dynamics, and the PI3K/RELA/cell cycle axis. Molecular docking confirmed that Isorhapontigenin can bind to cell proliferation, cycle related proteins (CCND1, CDK2, PIK3CA, RELA). CCK-8 detection revealed that Isorhapontigenin significantly inhibited the proliferation of PC9 lung cancer cells, Moreover, RT-qPCR detection showed that Isorhapontigenin downregulated the expression of CCND1, CDK2, PIK3CA and RELA genes. CCND1, CDK2, PIK3CA and RELA are highly expressed in NSCLC tissues. Overall survival analysis of patients indicated that key genes in the PIK3CA and NF-κBp65 signaling pathway significantly affected overall survival. Our research has found that Isorhapontigenin can effectively against non-small cell lung cancer, and this effect may be achieved by inhibiting cell proliferation and cycle progression mediated by the PIK3CA/NF-KB signaling pathway. Isorhapontigenin is a new potential therapeutic agent for lung cancer.

Zinc sulfate is an important micronutrient for cell metabolism and stress protection. Acetic acid is a common inhibitor present in lignocellulosic hydrolysate, and the addition of zinc sulfate allows yeast cells to better cope with acetic acid stress. In-depth understanding of how zinc sulfate leads to changes in global gene transcription benefits efficient cellulosic ethanol production using robust yeast strains. Here, comparative transcriptomic analyses were performed using budding yeast Saccharomyces cerevisiae grown with and without zinc sulfate supplementation under acetic acid stress. Analysis showed enrichment of functions related to cell wall organization in the differentially expressed genes. Furthermore, we proved that deletion of two zinc-responsive genes, including TPS2 related to trehalose biosynthesis and CHS5 involved in protein export and chitin biosynthesis, respectively, impaired yeast growth under acetic acid stress. Meanwhile, weakened cell wall integrity of S. cerevisiae was observed by TPS2 deletion. Furthermore, overexpression of TPS2 and CHS5 exerted a positive effect on yeast growth under acetic acid stress. These results reveal a novel connection between zinc sulfate-mediated metabolic regulation and cell wall integrity, as well as provide a novel strategy for the development of robust yeast strains for sustainable production of fuel ethanol and bio-based chemicals using lignocellulosic biomass.

Developing a biomimetic platform that can effectively support myocardial repair and regeneration after a heart attack remains a major challenge for researchers. Polyurethanes (PU), known for their versatile properties, are increasingly being recognized as promising materials for creating cardiac patches. This research study developed the synthesis of a novel unsaturated chain extender via the Baylis-Hillman reaction for incorporation into the backbone of PU to create the unsaturated bridge for post-modification response. Thiol-ene chemistry performed post-modification of unsaturated hard domains of PU with thiolated gelatin as another reactant. Modification of the hard segment domains of PU with gelatin can have a synergistic effect on fabricating a new platform for repairing cardiac tissue. The films were characterized by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR), Nuclear Magnetic Resonance (NMR), mechanical tests, in vitro degradation rate, water contact angle measurement, and swelling measurement. Metabolic activity and cytocompatibility of the cells onto the films were assessed by MTT assay. An investigation of cardiac-specific marker expression was conducted using immunofluorescence staining and quantitative real-time PCR. The findings showed that none of the substances were cytotoxic to cardiomyocytes, and that the expression of cadiac-specific genes, such as Troponin T, GATA4, Connexin43, and Alpha-SMA, was higher than that of the control group.

Spent mushroom substrate (SMS) is a major agricultural waste generated as a by-product of industrial mushroom cultivation. To valorize SMS, we developed a method to convert it to a form of nanofiber dispersion, chitin/cellulose nanofiber complex (CCNFC), via nanofibrillation. CCNFC application induces plant disease resistance, local immune response, and systemic disease resistance. Because chitin nanofibers (NF) also induce these defense responses, their function has been proposed to contribute to CCNFC-induced disease resistance. Here, we aimed to determine the precise mode of action of CCNFC in inducing plant disease resistance. The local immune response and systemic disease resistance induced by CCNFC were not compromised in Arabidopsis and rice mutants for lysin motif-type pattern recognition receptors involved in chitin perception. Transcriptome analysis revealed similar systemic transcriptional responses in CCNFC- and cellulose NF-treated Arabidopsis plants. Cellulose NF-induced systemic disease resistance but not local immune response. Thus, the local immune response triggered by CCNFC also requires another component(s) in CCNFC other than cellulose, accompanied by chitin. In contrast, the systemic disease resistance induced by CCNFC could be caused mainly by cellulose NF.

This study examined the ability of insulin-like growth factor-1 (IGF-1) to improve the expression and function of cardiac sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) and reduce heart hypertrophy in obese rats. Adult male Wistar rats received a standard diet or a high-fat (HF) diet for 12 weeks. A bolus injection of IGF-1 (50 μg/kg, i.p.) was administered to half of the HF rats 24 hours before euthanasia. IGF-1 treatment increased: the activity of Na+/K+-ATPase and expression of phosphorylated and total Na+/K+-ATPase α1 subunit, the phosphorylation of IGF-1 receptor β /insulin receptor β at Tyr1131/Tyr1146, insulin receptor substrate-1 (IRS-1) at Tyr1222, mammalian target of rapamycin (mTOR) at Ser2481, protein kinase B (Akt) at Ser473 and the expression of type-2 angiotensin II (AngII) receptor (AT2R). Conversely, IGF-1 reduced the levels of IRS-1 phosphorylated at Ser307, mTOR at Ser2448, ribosomal protein p70 S6 kinase (S6K) at Thr421/Ser424, and the expression of type-1 Ang II receptor (AT1R) in the heart, as well as the serum levels of Ang II in obese rats. IGF-1 treatment reduced cardiac mass and elevated mRNA expression of the α-myosin heavy chain (MHC), and the α/β MHC ratio in the hearts of obese rats. The results of this study suggest that the administration of IGF-1 to obese rats reduces the adverse effects of HF diet, potentially by lowering Ang II-mediated activation of mTOR/S6K and enhancing the IRS-1/Akt pathway, which promotes Na+/K+-ATPase activity in the heart and diminishes cardiac hypertrophy.

Marsdenia tenacissima extract (MTE) from the stem of the Traditional Chinese herbal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as an anticancer remedy for decades.

The role of 2-keto-L-gulonic acid (2KGA), a downstream product of the ascorbic acid (ASA) metabolic pathway, in the biosynthesis of plant bioactive compounds remains to be elucidated. In this study, we investigated the effects of exogenous 2KGA on ASA biosynthesis and secondary metabolite accumulation in the non-heading Chinese cabbage (Brassica campestris [syn. B. rapa] ssp. chinensis cv. Shanghai bok choy). The findings revealed a dose-dependent relationship between ASA accumulation in plants and 2KGA dose, with high expression levels of the L-gulono-1,4-lactone oxidase (GLO) gene, which is crucial for 2KGA to enhance ASA biosynthesis. The ASA content of GLO-deficient (At5g11540, At5g46750) plants showed no response to exogenous 2KGA treatment. Moreover, changes in the levels of total phenolics and total flavonoids were significantly positively correlated with ASA content. Metabolomics and transcriptomics analyses revealed that the increase in ASA content induced by 2KGA and the subsequent feedback effects influenced major metabolic pathways, including the citric acid cycle, amino acid metabolism, and photosynthesis, as well as varied expression of 30 transcription factors. These findings suggest that exogenous 2KGA has the potential to modulate energy and precursor metabolic pathways by interacting with plant ASA anabolism, thereby facilitating growth and enhancing bioactive compound accumulation. Our study provides novel insights into the role of 2KGA in the biosynthesis of bioactive compounds in plants.

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system. Conventional treatment includes maximal safe surgical resection combined with radiotherapy and chemotherapy.

Arsenic is a neurotoxin associated with cognitive impairment following long-term exposure, while Neurotrophin-3 (NT-3) is essential for the survival and development of neurons. This study aims to explore the protective effects of NT-3 on arsenic-caused cognitive impairment and neuronal damage, as well as clarify the underlying mechanisms. In vivo and in vitro results indicated that sodium arsenite impaired cognitive function, reduced neuronal density, and induced apoptosis, which was accompanied by the down-regulation of NT-3 and the PI3K/AKT pathway. Overexpression of NT-3 in HT-22 cells mitigated apoptosis triggered by arsenic and partially restored PI3K/AKT pathway activity. Thus, our findings suggest that NT-3 may counteract the arsenic neurotoxicity by activating PI3K/AKT.

Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H2O2) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H2O2, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells in vivo. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.

Exogenous IAA applying within 32 days after herbaceous peony bud germination induces a 6-h transient stem change: first bending then upright. This process correlates with the degradation of cell wall substances like cellulose and pectin. Herbaceous peony (Paeonia lactiflora) holds a growing presence in the cut flower market. A vital criterion for selecting cut herbaceous peonies is the uprightness of their stems, which is largely determined by cell wall materials (CWMs). Our previous study indicated that applying indole-3-acetic acid (IAA) during the development process could enhance the stem straightness of herbaceous peonies at the flowering stage. Interestingly, in certain development phases, after IAA application, the stems were observed to first bend and then regain an upright position within hours (transient changes), yet the underlying mechanism remains unclear. This study aimed to identify the stages during which these transient changes occur and elucidate the role of CWMs in terms of their contents, enzyme activities, metabolites, and gene expression. The results showed that IAA-induced transient changes were most prevalent in the first three stages. The accumulated cellulose, pectin, and lignin in the IAA-treated group were consumed as the stem regained their upright position. Cinnamyl-alcohol dehydrogenase, β-glucosidase, and pectin methylesterase played key degradation roles. Combined metabolome and transcriptome analyses revealed that differential metabolites and differentially expressed genes were enriched in pathways such as glycolysis/gluconeogenesis, xylan biosynthesis process, secondary cell wall biogenesis, and lignin catabolism. The cellulose synthesis gene CESA2, decomposition gene CEL5, and pectin decomposition gene At1g48100 deserved further investigation. This study provides support for clarifying the mechanism by which IAA regulates stem uprightness of P. lactiflora and serves as a reference for selection and cultivation of herbaceous peony cut flowers.

Expression of many bacterial genes is regulated by cis- and trans-acting elements in their 5' upstream regions (URs). Cis-acting regulatory elements in URs include upstream ORFs (uORFs), short ORFs that sense translation stress that manifests as ribosomes stalling at specific codons within the uORF. Here, we show that the transcript encoding the Escherichia coli TopAI-YjhQ toxin-antitoxin system is regulated by a uORF that we name 'toiL'. We propose that in the absence of translation stress, a secondary structure in the UR represses translation of the topAI transcript by occluding the ribosome-binding site. Translation repression of topAI leads to premature Rho-dependent transcription termination within the topAI ORF. At least five different classes of ribosome-targeting antibiotics relieve repression of topAI. Our data suggest that these antibiotics function by stalling ribosomes at different positions within toiL, thereby altering the RNA secondary structure around the topAI ribosome-binding site. Thus, toiL is a multipurpose uORF that can respond to a wide variety of translation stresses.

Pancreatic cancer (PC) has a poor prognosis and limited response to therapies. Combinatorial approaches, such as natural product-based therapies, can enhance anticancer efficacy while minimizing side effects. This study evaluated M. sativa's anticancer properties and its potential as adjunctive therapy with Gemcitabine (GEM) to sensitize PANC-1 cells to chemotherapy.

Omaveloxolone is a synthetic oleanane triterpene with considerable antitumor activity. It induces human glioblastoma (GBM) cell death in vitro and in vivo, but the underlying mechanism remains to be determined. In this study, GBM cell lines (GBM8401 and U-87 MG cells) were exposed to different concentrations of omaveloxolone (0, 600, 800 and 1000 nM). A cell viability assay was conducted using the PrestoBlue Cell Viability Reagent. Three-dimensional microscopy revealed changes in cell morphology. Cell cycle, apoptosis and mitochondrial membrane potential were tested using flow cytometry. The expression levels of cell cycle-related proteins and genes were determined through Western blotting and next-generation sequencing, respectively. The results indicated that omaveloxolone had significant selective cytotoxicity against human GBM cells and suppressed the migration and invasion of these cancer cells. It also caused cell cycle arrest through the downregulation of cell cycle-related genes, including cell division cycle 20 homologue (CDC20), as revealed by next-generation sequencing. In a xenograft tumour model, omaveloxolone decreased tumour volume and CDC20 expression. Taken together, these findings suggest that omaveloxolone is a potential drug candidate for GBM treatment by promoting GBM cell death through the downregulation of CDC20 expression.

Cadmium is one of the most toxic heavy metal pollutants in the world, seriously affecting crop growth and human health. 2,4-Epibrassinolide (BRs) has been proven to promote plant growth, enhance abiotic stress resistance and improve crop quality and yield. In this study, adzuki bean (V. angularis) cultivar 'Zhen Zhuhong' was grown hydroponically in 1/2 Hoagland nutrient solution with 0, 1, and 2 mg L-1 cadmium chloride (CdCl2), and then treated with 0 or 1 μM BR at the V1 stage. Compared with Cd stress, ascorbic acid content, peroxidase (POD, EC 1.11.1.7), catalase (CAT, EC 1.11.1.6) and superoxide dismutase (SOD, EC1.15.1.1) activities in adzuki Cd-stressed bean roots under BR treatment were increased by 30.63%, 41.83%, 51.49%, and 29.48%, which alleviated intracellular ROS accumulation and DNA oxidative damage. In addition, proline content and free amino acid content in BR-treated adzuki bean seedling roots under Cd stress increased by 30.37% and 35.96%, which was conducive to maintaining cell membrane homeostasis and improving root activity. RNA-seq and real-time quantitative reverse transcription PCR analyses revealed that BR treatment regulates the absorption, transport, and accumulation processes of Cd2+ in adzuki bean seedling roots, reducing the nonspecific accumulation of Cd2+ within cells and alleviating the toxic effects of Cd on root cells. BR treatment enhances the DNA damage repair in the roots of adzuki beans under Cd stress by reducing the extent of DNA oxidative damage, and effectively promoting the transition of cells from the G1 phase to the S phase.

Common carp is one of the most economically important freshwater fish species globally. Ammonia exposure, a frequent challenge in aquaculture, can lead to significant economic losses. This study investigated the impact of un-ionized ammonia (UIA) exposure on the expression profiles of three key genes in common carp fry: interleukin-1 beta (IL-1β), corticotropin-releasing hormone (CRH), and leptin a1 (Lep-a1). These genes are crucial indicators of immune response, stress regulation, and appetite control, respectively. Fish were exposed to 0.7 mg/L of UIA, and gene expression was analysed in liver and gill tissues at five time points (12 h, 2-, 4-, 7-, and 14-days of exposure) using quantitative real-time PCR (RT-qPCR).