Helium, previously described as "biologically inert", displays great medicinal potential in a number of respiratory ailments via influencing redox signaling. However, whether or how this gas functions in plant biology is still elusive. Here, hydroponic and pot experiments showed that mimicking the responses achieved by nitric oxide (NO)-releasing compound, exogenous helium supply with helium-enriched solution or its fumigation significantly prevented NaCl-induced growth inhibition of alfalfa seedlings. Lower level of Na+/K+ ratio in both root and shoot parts caused by lower efflux of net K+ and higher efflux of net Na+, as well as higher abundances of ion transport genes (SOS1, SOS2, SOS3, NHX1, HKT1, and AKT1) were simultaneously observed. Consistently, reactive oxygen species (ROS) accumulation and oxidative injury were abolished by helium. These were further supported by stimulating antioxidant machinery and reprogramming gene expression related to antioxidant defence and related transcriptional factors (MYB4, WRKY33, ERF8, and ERF11) against salinity toxicity. Further experiments showed that helium supplementation strengthened endogenous NO production by up-regulating the expression of nitrate reductase (NR2) and its enzymatic activity, and NO-based S-nitrosylation was further influenced. Above responses were remarkably impaired by the removal of endogenous NO when its scavenger was added. Overall, these results revealed that helium control of salinity tolerance is partially mediated by a NO signaling cascade governing redox and ion homeostasis reestablishment, two important defense strategies against salinity stress.

Studies have demonstrated that adult male fish exposed to estrogenic endocrine-disrupting compounds (EDCs) exhibit reduced sperm motility and fertility. However, the effects of prepubertal estrogenic EDC exposure on testicular development and subsequent reproductive capacity remain poorly understood. In this study, prepubertal male (XY) tilapia at 30 days after hatching (dah) were exposed to 17β-estradiol (E2) for 60 days, covering the prepubertal period, to investigate its impact on testicular development and fertility at sexual maturity. Morphological and histological analyses revealed that prolonged E2 exposure reduced number of spermatogenic cells, increased testicular cell apoptosis, and significantly decreased the gonadosomatic index in E2-treated XY (E2-XY) fish. Fertility analysis of sexually mature E2-XY fish at 180 dah showed a significant reduction in sperm fertilization capacity compared to Control-XY fish. Sperm quality analysis indicated that E2-XY fish had an increased proportion of immotile sperm and a decreased proportion of progressive sperm. Additionally, the straight-line velocity, curvilinear velocity, and beat frequency of sperm flagella were significantly reduced in E2-XY fish sperm. Scanning electron microscopy (SEM) and immunofluorescence analysis revealed a significant reduction in flagellum length in E2-XY sperm compared to Control-XY sperm. Transcriptome sequencing of 180 dah E2-XY testes demonstrated a significant downregulation of genes associated with motor activity, microtubule binding, microtubule motor activity, and dynein complex formation. Specifically, the expression of kinesin and dynein axonemal heavy chain gene family members was significantly reduced. qPCR and Western blot (WB) assays confirmed that the expression of kinesin family members (kifc1, kif2c, kif11, kif16b, kif17, kif20a, kif20ba, kif20bb, kif22) and dynein heavy chain domain-containing protein family members (dnah2, dnah5, dnah7, dnhd1), which are involved in flagellar movement and assembly, was significantly decreased in E2-XY testes compared to Control-XY testes. These findings demonstrate that prepubertal E2 exposure downregulates genes critical for sperm flagella formation and motility in tilapia, resulting in shortened flagella, reduced motility, and irreversible fertility impairment, in contrast to the recoverable fertility observed in adult fish following exposure to estrogenic EDCs. This study provides novel insights into the mechanisms underlying reduced fertility in male fish exposed to estrogenic EDCs.

Breast cancer, the most prevalent malignant tumour in women, is characterised by high metastatic potential and frequent recurrence, both of which significantly impact patient prognosis following metastasis. To address this challenge, identifying novel therapeutic target combinations is critical for improving metastatic breast cancer treatment. This study investigates the mechanism by which asparaginyl endopeptidase (AEP) regulates breast cancer metastasis. Bioinformatics analysis revealed a potential interaction between AEP and CD74, which was subsequently confirmed through co-immunoprecipitation (co-IP) experiments. Further investigations demonstrated that AEP activates ERK pathway phosphorylation via CD74 regulation, thereby enhancing epithelial-mesenchymal transition (EMT) progression and promoting breast cancer cell migration. Compared to controls, dual inhibition of AEP and CD74 effectively reduced EMT markers and the migratory capacity of cancer cells in vitro. Subsequent in vivo experiments showed that this combinatorial strategy significantly suppressed breast cancer lung metastasis in mice without observable toxicity. These findings elucidate the molecular mechanism through which AEP promotes metastasis via CD74 regulation, while validating the therapeutic efficacy and safety of dual AEP/CD74 targeting. This study provides a novel conceptual framework and potential therapeutic targets for metastatic breast cancer intervention.

Sphingosine-1-phosphate receptor 3 (S1PR3) has been implicated in promoting tumor progression in various cancers. However, the role and molecular mechanisms of S1PR3 in oral squamous cell carcinoma (OSCC) remain poorly understood. The aims of this study were to investigate the function of S1PR3 in OSCC progression and its potential as a therapeutic target.

Alfalfa (Medicago sativa L.) has the benefits of high yield and nutritional value as a sustainable forage. However, the water deficit significantly limits its growth and yield performance. Nitric oxide (NO) is a signal molecule that can enhance plant tolerance. The majority of previous studies focus on the role of exogenous NO in plant tolerance. However, the underlying mechanism of endogenous NO in alfalfa drought tolerance remains largely unexplored.

Phytohormones play pivotal roles in regulating floral development and secondary metabolite synthesis in saffron (Crocus sativus L.).

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.