Corticosterone plays an important role in the stress response, physiological regulation, and development of stress-related psychiatric disorders. Although several studies have demonstrated that chronic corticosterone induces anxiety- or depressive-related behaviors in mice, it remains unclear whether chronic corticosterone administration affects gene expression in the brain during the stress response. This study investigated whether chronic corticosterone administration has a significant effect on stress-related gene expression in the brain. Therefore, mice were chronically treated with corticosterone in drinking water and gene expression was analyzed by quantitative PCR (qPCR). Moreover, restraint stress was acutely applied as a novel stressor in mice chronically treated with corticosterone in the cortex and hippocampus. We initially found that chronic corticosterone administration altered glucocorticoid signaling-mediated gene expression, such as FK506 binding protein 5 (Fkbp5) and glucocorticoid-inducible kinase 1 (Sgk1), in the cortex and hippocampus of mice. Next, we found that restraint stress exposure elevated Fkbp5 expression in the vehicle group; however, chronic corticosterone administration occluded further induction of Fkbp5 expression after restraint stress exposure. In addition, pro-inflammatory cytokines tumor necrosis factor α (Tnfa) and interleukin-1β (Il1b) mRNA expression in the cortex and hippocampus were remarkably enhanced by restraint stress in corticosterone-treated mice, but not in the vehicle group. Collectively, our results demonstrated that chronic corticosterone administration modulates glucocorticoid signaling and uncovered the robust induction of pro-inflammatory cytokines after restraint stress exposure in chronically corticosterone-treated mice. These mechanisms may be involved in the molecular basis for the onset of stress-related mental illnesses.

The clinical use of aminoglycosides often results in injury to vestibular hair cells and subsequent vestibular dysfunction. Thus, clarifying the targets and mechanisms underlying aminoglycoside-mediated damage is of urgent importance. Prostaglandin D2 synthase (Ptgds) is a glycoprotein that plays dual roles in lipid transport regulation and prostaglandin metabolism. However, the role of Ptgds in aminoglycoside-induced vestibular dysfunction remains unclear. This study aimed to explore the function of Ptgds in the utricle and HEI-OC1 cells. Neomycin injury induced high levels of Ptgds expression in utricle explants. Moreover, Ptgds knockdown protected against neomycin injury by enhancing cellular proliferation and viability while suppressing reactive oxygen species production, inflammation, and apoptosis. These findings suggest that Ptgds may serve as a novel therapeutic target for treating vestibular dysfunction caused by aminoglycoside-induced damage.

Neuroblastoma (NB) is a pediatric malignancy from the neural crest, where differentiation plays a key role in prognosis. We investigated cysteine and glycine-rich protein 1 (CSRP1) as a therapeutic target for NB, as it has been linked to differentiation and carcinogenesis in various cancers. Immunohistochemical analysis of archived NB samples showed a significant correlation between CSRP1 expression and differentiation. Ectopic CSRP1 expression in MYCN-amplified BE(2)-M17 cells increased sensitivity to cisplatin, promoted neurite extension, and enhanced differentiation, apoptosis, and chemosensitivity to 13cisRA. Synergistic apoptotic effects were observed with 5-aza-2'-deoxycytidine (DAC) and Poly(I:C) treatments in SK-N-AS cells implanted in xenografts, linked to upregulation of CSRP1, innate immune receptor RIG-I, and caspase-9 activation. CSRP1 expression was significantly higher in mitochondrial DNA-depleted SK-N-AS ρ0 cells, compared to parent SK-N-AS cells. Cisplatin increased CSRP1 expression further in parent cells but not in ρ0 cells. Simultaneous upregulation of caspase-8 was found in both cell types, but increased caspase-9 only in parent cells, suggesting that both intrinsic and extrinsic apoptosis pathways are involved in CSRP1 function depending on the existence of mitochondrial DNA. These findings indicate that CSRP1 is involved in differentiation, determination of apoptosis, and possibly innate immunity in NB, which endows CSRP1 with the potential to enhance the effects of 13cisRA, DAC, and Poly(I:C) in combination therapies for NB.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral and maxillofacial regions. Paeonol, derived from Moutan Cortex, has diverse pharmacological effects including anti-inflammatory and anticancer activities. The N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification is a newly discovered RNA epigenetic mechanism. This study aimed to investigate the role of paeonol in OSCC and its underlying mechanisms of action.

Tyrosine is a prerequisite for melanin biosynthesis and plays a crucial role in the growth and development of melanocytes, but the underlying mechanism is still unclear. In our previous research, we added 10- 9-10- 6 mol/L tyrosine to the melanocytes of black-bone chickens and found that 10- 6 mol/L tyrosine significantly increased the tyrosinase content in melanocytes.

Glucocorticoids are widely used to manage osteoarthritis (OA) symptoms, but long-term safety concerns exist. This study investigates the therapeutic potential of dexamethasone (DEX) and triamcinolone acetonide (TA) in chondrocytes, evaluating their anti-inflammatory effects and potential detrimental actions. This study evaluated the effects of DEX and TA on the expression of pro-inflammatory genes in inflamed chondrocytes. In addition, the effects of DEX treatment on chondrocytes were analyzed using next-generation sequencing, high-resolution mass spectrometry, proliferation and metabolic rate, wound healing capacity and senescence-associated B-galactosidase assays. A single therapeutic dose of DEX (40nM) effectively reduced the expression of inflammatory genes in chondrocytes, while TA showed no such effect. DEX significantly reduced inflammation but also ECM production in inflamed chondrocytes. At 24 h, DEX treatment led to 168 differentially expressed genes (DEGs) compared to untreated inflamed cells, decreasing to 5 DEGs by 48 h, indicating a rapidly diminishing anti-inflammatory effect. Conversely, the difference between DEX-treated and healthy cells increased over time, from 666 DEGs at 24 h to 1317 DEGs at 48 h. Pathway analysis revealed potential disruptions in cell cycle, mitosis, and ECM homeostasis in DEX-treated cells compared to both healthy and inflamed controls. Interestingly, repeated DEX administration at both a therapeutic (40nM) and a high dose (1µM) induced senescence in healthy cells but not in inflamed cells. In contrast, repeated high-dose DEX reduced apoptosis marker Caspase 3/7 in inflamed but not healthy cells. Despite the transient suppression of inflammation achieved with DEX treatment, the observed decrease in ECM production and induction of senescence in healthy chondrocytes at therapeutic doses, along with apoptosis in inflamed cells at higher doses, underscore the need for caution in its intra-articular administration.

Hepatic lipid droplet (LD) accumulation is a hallmark of nonalcoholic fatty liver disease (NAFLD). Although the clinical efficacy of berberine (BBR) in treating NAFLD has been established, the mechanism remains uncertain. This study is to evaluate the effects of BBR on hepatic LDs and investigate the underlying mechanisms. Using high-fat diet-induced obese (DIO) mice as the model for NAFLD, BBR was administered daily by gavage for 4 weeks. Liver tissue was examined for changes in lipid deposition and histology. Transcriptomics was performed to screen differently expressed genes. The potential targets of BBR against NAFLD were then determined by Western Blot and immunostaining. In oleic acid (OA)-induced HepG2 cells, the link between BBR and potential targets was further elucidated through the activation or antagonism of PPARα. The binding of BBR to potential targets was predicted using molecular docking. BBR significantly reduced hepatic steatosis by decreasing LD size rather than number. Transcriptomics with validation demonstrated that BBR modulated the expression of LD-associated proteins CIDEA and PLIN4 in the liver. Further investigations revealed that BBR reversed the abnormal elevation of BSCL2 and PLIN2 in steatotic livers. Finally, we found that BBR reduced LD size in OA-induced HepG2 cells by regulating BSCL2 and PPARα-mediated CIDEA/PLIN4/PLIN2. Notably, BBR could bind well to PPARα and BSCL2. BBR can attenuate hepatic steatosis in DIO mice by reducing LD size through the regulation of LD-associated proteins.

Cryptococcus neoformans is the top-ranked W.H.O. fungal priority pathogen, but tools for generating conditional mutations are limited. Auxin-inducible degron systems permit rapid and effective cellular depletion of a tagged protein of interest upon adding a small molecule. These tools are invaluable, particularly for studying essential genes, which may play important roles in pathogen biology. AID2 is one such system that improves on previous strategies. This system achieves greater sensitivity and specificity through an auxin derivative, 5-Ph-IAA, alongside an OsTIR1F74G mutant. We adapted the AID2 system for C. neoformans by codon optimizing OsTIR1F74G and tested its use in multiple scenarios. We demonstrate that the C. neoformans optimized AID2 system enables effective degradation of proteins, including essential proteins, and can be used to help discriminate essential from nonessential genes. This tool enables the study of unexplored parts of the C. neoformans genome.

As living conditions improve and diagnostic capabilities advance, the incidence of tumors has increased, with cancer becoming a leading cause of death worldwide. Surgery, chemotherapy, and radiotherapy are the most common treatments. Despite advances in treatment options, chemotherapy remains a routine first-line treatment for most tumors. Due to the continuous and extensive use of chemotherapy drugs, tumor resistance often develops, becoming a significant cause of treatment failure and poor prognosis. Recent research has increasingly focused on how long stranded non-coding RNAs (LncRNAs) influence the development of malignant tumors and drug resistance by regulating gene expression and other biological mechanisms during cell growth. Studies have demonstrated that variations in lncRNA expression levels, influenced by both interpatient variability and intratumoral genetic and epigenetic differences, are closely linked to tumor drug resistance. Therefore, this review advocates using lncRNA as a framework to investigate the regulation of genes associated with drug resistance, proposing lncRNA-targeted therapeutic strategies to potentially increase the efficacy of chemotherapy, improve patient outcomes, and guide future research directions.

Platinum-based combination chemotherapy remains the backbone of first-line treatment for patients with advanced epithelial ovarian cancer (EOC). While most patients initially respond well to the treatment, patients with relapse ultimately develop platinum resistance. This study identified FLYWCH-type zinc finger-containing protein 1 (FLYWCH1) as an important regulator in the resistance development process. We showed that the loss of FLYWCH1 promotes platinum resistance in EOC cells, and the low FLYWCH1 expression is correlated with poor prognosis of EOC patients. In platinum-sensitive cells, FLYWCH1 colocalizes with H3K9me3, but this association is significantly reduced when cells acquire resistance. The suppression of FLYWCH1 induces gene expression changes resulting in the deregulation of pathways associated with resistance. In line with its connection to H3K9me3, FLYWCH1 induces gene silencing in a synthetic reporter assay and the suppression of FLYWCH1 alters H3K9me3 at promoter regions and repeat elements. The loss of FLYWCH1 leads to the derepression of LTR and Alu repeats, thereby increasing transcriptional plasticity and driving the resistance development process. Our data highlight the importance of FLYWCH1 in chromatin biology and acquisition of platinum resistance through transcriptional plasticity and propose FLYWCH1 as a potential biomarker for predicting treatment responses in EOC patients.

Lactate, traditionally viewed as a glycolysis byproduct, has emerged as an important mediator influencing immunity, inflammation, and tissue damage. While PM2.5 exposure is known to cause various metabolic disturbances, the role of lactate metabolism in PM2.5-induced lung injury remains unclear. This study aims to elucidate the mechanisms underlying PM2.5-induced lung injury from a metabolic perspective.

The use of nanoparticles as an alternative to traditional fertilizers, aiming at a more efficient use of nutrients, is a recently developed concept that requires a thorough understanding of the processes occurring in the soil-plant system. A crucial aspect in this framework is to decipher the plant responses to the unique characteristics of these materials. In this work, we aim at decoding the transcriptional responses of cucumber and maize roots to FePO4 nanoparticles applied as P and Fe sources, respectively. The results demonstrate that P and Fe supplied as nanoscale salts support plant nutrition with an efficiency comparable to that of ionic forms of the nutrients. This supposition is confirmed by transcriptomic profiles that show no significant upregulation of transcripts typically induced by deficiencies in P and Fe in cucumber and maize plants in which these nutrients were provided by FePO4 nanoparticles. The analysis further revealed that nanoparticles alter the expression of genes involved in root development and stress responses, effect that appeared to be independent on the nutritional status of the plants. Our data further underline the challenge to identify generalizable elements of the impact of nanomaterials on plant species, as responses are intimately linked to the type of nanomaterials and differ among plant species.

Drought stress is one of the most important environmental constraints that negatively affect the growth and production of crops worldwide. Recently, nanotechnology has been increasingly used to improve the tolerance of plants exposed to abiotic stresses such as drought. The present study was designed to investigate the moderating effect of cerium oxide nanoparticles (CeO2 NPs) on alleviating drought stress for the apple cv. 'Red Delicious' on M9 rootstock. Drought stress caused a significant increase in CAT, GPX, APX, and SOD enzyme activities compared to control plants. Drought decreased the content of macro and microelements, and the application of CeO2 NPs led to significant changes in the content of these elements in plants under drought stress. CeO2 NPs significantly reduced chlorophyll damage under high drought levels. In addition, they alleviated the damage caused by drought, which was shown by lower levels of MDA and EL. When these nanoparticles were used during drought stress, they greatly increased the production of abscisic acid and indole-3-acetic acid hormone. In response to drought stress, the expression of DREB1A and DREB1E genes increased. The use of CeO2 NPs in stressful and non-stressful conditions had a positive effect on improving the studied traits of the apple plants and enhancing nutrient levels. Taken together, the findings suggest that CeO2 NPs can be used as promising drought stress-reducing agents in apples. Therefore, understanding the mechanisms of abiotic stress in global horticulture and the role of nanoparticles is essential for developing improved, drought-tolerant crops and the adoption of measures to deal with changing climatic conditions.

Sepsis is a syndrome of organ dysfunction caused by the invasion of pathogenic microorganisms. In clinical practice, patients with sepsis are prone to concurrent acute kidney injury, which has high morbidity and mortality rates. Thus, understanding the pathogenesis of sepsis-associated acute kidney injury is of significant clinical importance. Ferroptosis is an iron-dependent programmed cell death pathway, which is proved to play a critical role in the process of sepsis-associated acute kidney injury through various mechanisms. Epigenetic regulation modulates the content and function of nucleic acids and proteins within cells through various modifications. Its impact on ferroptosis has garnered increasing attention; however, the role of epigenetic regulation targeting ferroptosis in sepsis-associated acute kidney injury has not been fully elucidated. Growing evidence suggests that epigenetic regulation can modulate ferroptosis through complex pathway networks, thereby affecting the development and prognosis of sepsis-associated acute kidney injury. This paper summarizes the impact of ferroptosis on sepsis-associated acute kidney injury and the regulatory mechanisms of epigenetic regulation on ferroptosis, providing new insights for the targeted therapy of sepsis-associated acute kidney injury.

Aluminum (Al) toxicity inhibits plant growth and alters gene expression and metabolite profiles. However, the molecular mechanisms underlying the effects of Al toxicity on peanut plants remain unclear. Transcriptome and metabolome analyses were conducted to investigate the responses of peanut leaves and roots to Al toxicity.

Pterostilbene (PTE, 3,5-dimethoxy-4'-hydroxystilbene) is a naturally occurring polyphenol which has antiepileptic properties, and can be utilized as a prophylaxis in patients with seizures and who are at risk of developing epilepsy. However, the effects of PTE on the gamma-aminobutyric acid (GABA)-mediated (GABAergic) nervous system are poorly understood. This study aimed to evaluate the effects of PTE on the GABAergic neurons.

Deciphering how bacteria respond to antibiotic stress is essential for developing strategies to combat the increasing global antibiotic resistance gene (ARG) crisis. Here, we identified an unprecedented antibiotic resistance operon characterized by a single-domain transcription factor (TF) StnY, which responds to streptonigrin (STN) antibiotic and controls the activation of resistance genes stnK4 and stnG4 in Streptomyces flocculus CGMCC4.1223. To the best of our knowledge, StnY represents the first RHH family TF regulating ARG and it helically wraps around the promoter of the resistance operon in an octameric form. Unlike conventional TFs with distinct effector-binding domains, StnY utilizes its DNA-binding domain to bind the STN effector, facilitating the dissociation of StnY-DNA complex. Consequently, the vicinal oxygen chelates (VOC) family protein StnK4 sequesters STN to prevent cellular damage, while the major facilitator superfamily (MFS) protein StnG4 effluxes STN out of the cell. Furthermore, genome analysis reveals the widespread distribution of RHH-VOC-MFS gene cassettes in actinomycetes, the primary source of antibiotics. This study elucidates function mode of a resistance operon governed by a TF lacking an effector-binding domain, offering new insights into ARG regulation and the potential of ARG-guided antibiotics discovery, highlighting TFs as promising targets for addressing ARG.

Leflunomide's anti-tumor effects have been investigated in various types of tumors; however, its impact on pituitary adenoma, particularly prolactinoma, is unclear. Hence, the current study evaluates the effects of leflunomide on prolactinoma cells in vitro and in vivo and elucidates the potential underlying mechanism(s). Cell Counting Kit-8 results revealed that leflunomide inhibits the proliferation of rat pituitary tumor cell lines (GH3 and MMQ) in a concentration-dependent manner in vitro. However, combination therapy of cabergoline and leflunomide exerted stronger inhibitory effects than cabergoline in MMQ cells in vitro and in vivo. Transcriptomics and gene ontology (GO) analyses identified genes significantly enriched in apoptotic processes and programmed cell death. Protein-Protein Interaction (PPI) networks defined the roles of hub genes (Mdm2, Cdkn1a, Plk2, and Ccng1) in leflunomide-induced cell death. GO and pathway enrichment analyses showed that the combination drug-specific differentially expressed genes were associated with inhibiting protein translation, but were active in gene expression processes. Hence, the anti-proliferative effects of leflunomide on prolactinoma cell lines may be mediated through programmed cell death pathways. Importantly, combining cabergoline with leflunomide effectively enhances the toxic effect of cabergoline, suggesting a potential therapeutic role for leflunomide in drug-resistant prolactinoma.

Eg5, also known as KIF11, is a motor protein essential for establishing a bipolar spindle and ensuring proper chromosome congression during mitosis. It is amplified in various human cancers and serves as a critical oncogene driving tumour progression. However, the role and clinical significance of Eg5 in gastric cancer has remained elusive. In this study, we showed that Eg5 is upregulation in gastric cancer tissues and is negatively associated with patient prognosis. The ablation of Eg5 inhibits the proliferation and migration of gastric cancer cells and suppresses tumour growth in xenograft mice. Mechanistically, Eg5 ablation induces the formation of monopolar spindle, leading to cell apoptosis and consequent inhibition of tumour growth. Furthermore, Arry520 is demonstrated as a potent Eg5 inhibitor which blocks tumour growth by increasing the formation of cell monopolar spindle and inducing apoptosis. Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer.

Retinoblastoma-Binding Protein 4 (RBBP4), belonging to the WD-40 family, is an important member of the Polycomb Repressor Complex 2 (PRC2), the Nucleosome Remodeling and Deacetylation complex (NuRD), and is involved in chromatin remodeling, histone deacetylation, and H3K27 methylation.