The resilience of plants against environmental challenges, particularly salinity and dehydration, is crucial for global food security. This study delves into the intricate interaction between NaCl-induced salinity and Azolla aqueous extract (AAE). In a pot trial, wheat kernels were primed with deionized water or 0.1% AAE for 21 h. Seedlings underwent various treatments; tap water, 250 mM NaCl, AAE priming and spray, and combined AAE with NaCl treatments. Seedlings were analyzed for ionic balance, secondary metabolism, antioxidant efficacy, and molecular response to experimental treatments.

The expression of ubiquitin-like molecule interferon-stimulated gene 15 kDa (ISG15) and its post-translational modification (ISGylation) are significantly activated by interferons or pathogen infections, highlighting their roles in innate immune responses. Over 1100 proteins have been identified as ISGylated. ISG15 is removed from substrates by interferon-induced ubiquitin-specific peptidase 18 (USP18) or severe acute respiratory syndrome coronavirus 2-derived papain-like protease. High ISGylation levels may help prevent the spread of coronavirus disease 2019 (COVID-19). Polyamines (spermidine and spermine) exhibit anti-inflammatory, antioxidant, and mitochondrial functions. However, the relationship between nutrients and ISGylation remains unclear. This study assessed the effects of spermine and spermidine on ISGylation. MCF10A and A549 cells were treated with interferon-alpha, spermine, or spermidine, and the expression levels of various proteins and ISGylation were measured. Spermine and spermidine dose-dependently reduced ISGylation. Additionally, spermidine directly interacted with ISG15 and USP18, enhancing their interaction and potentially reducing ISGylation. Therefore, spermidine may prevent ISGylation-related immune responses.

Curcumin, a plant derived natural product isolated from Curcuma longa. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of curcumin in Cutaneous T cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that primarily affects the skin. The study found that curcumin induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases leading to growth inhibition. Furthermore, Curcumin treatment downregulated the expression of S-phase kinase protein (SKP2) with concomitant upregulation of GADD45A, CDKN1A and CDKN1B. Curcumin also suppresses the expression of anti-apoptotic molecules including XIAP and cIAPs. Curcumin treatment of CTCL cells generates reactive oxygen species (ROS) and depletion of glutathione. Pretreatment of CTCL with N-acetyl cysteine prevented curcumin-mediated generation of ROS and prevention caspase activity. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Molecular docking studies revealed a strong binding affinity of curcumin to the active site of SKP2, primarily involving key residues crucial for its activity. Altogether, our results suggest that targeting SKP2 and GADD45A signaling by curcumin could be an attractive strategy for the treatment of CTCL.

Epithelial-mesenchymal transition (EMT) describes a process by which epithelial cells acquire mesenchymal properties associated with increased migration, invasion, and resistance to therapy. In pancreatic ductal adenocarcinoma (PDAC), targeting the molecular and intercellular communication pathways that drive EMT represents a promising therapeutic strategy. Here, we investigate the effects of combined treatment with gemcitabine (G), paricalcitol (P), and hydroxychloroquine (GPH) in KPC-Luc orthotopic mouse models of PDAC, using single-cell RNA sequencing (scRNA-seq), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and cell-cell communication analysis. GPH treatment reduces EMT, which is associated with the downregulation of the essential gene fibronectin (Fn1). Collagen and Fn1 pathways co-expression decreases in GPH-treated KPC-Luc tumors. Cancer-associated fibroblasts (CAFs) appear dominant in collagen signaling, whereas macrophages mediate Fn1 signaling. GPH treatment reduces the expression interaction strength between ligands and receptors (collagen-integrin and Fn1-Cd44 or Fn1-Sdc4) compared to sham, PH, and G. Altogether, this study presents a comprehensive single-cell resolution map of the molecular and cellular mechanisms by which GPH treatment impairs EMT in PDAC, identifying potential therapeutic targets within the fibronectin and collagen signaling axes.

Pathogenesis of Staphylococcus aureus is largely associated with its biofilm formation, that protects the cells from host immune system and antimicrobial threats. Considering the concern over the emergence of antimicrobial resistant S. aureus strains, this study was aimed to explore an effective alternative therapeutant. Trigonelline, an alkaloid, was evaluated for its antibiofilm and antivirulence activities against S. aureus. Trigonelline efficiently inhibited and eradicated biofilm, and abled to decrease the production of protease and hemolysin, the major virulence factors of S. aureus. Inhibition of biofilm formation and eradication of mature biofilm on the catheter surface suggested its potentiality in clinical application. The observed reduction in biofilm formation and virulence factor production following trigonelline treatment may be attributed to its ability to alter the expression of key regulatory genes such as agrA, sarA, saeR, arlR, icaR, and sigB, which control quorum sensing network and biofilm development. Additionally, molecular docking analysis revealed a substantial binding affinity of trigonelline to these regulatory proteins, further supporting its possible inhibitory mechanism. Thus, trigonelline might be a promising alternative chemical lead to manage biofilm-associated bacterial infections caused by S. aureus.

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.

Cancer cells employ various adaptive mechanisms to withstand stressors, with one notable pathway being the unfolded protein response (UPR), crucial in fostering endocrine resistance within ER-positive breast cancer. Investigating miRNAs within tumors holds promise for identifying key miRNA-gene interactions pivotal for tumor characteristics like proliferation and resistance to treatment. Notably, XBP1 emerges as a pivotal player in UPR within the endoplasmic reticulum, particularly through the inositol-requiring enzyme 1 (IRE1α) - the X-box-binding protein 1 (XBP1) pathway, presenting a compelling target for clinical intervention. In this study, I explore the regulatory role of miR-770-5p in modulating XBP1 expression and its potential as a therapeutic target in luminal breast cancer.

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.

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.