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.

Methamphetamine (METH) abuse and HIV infection are major public health concerns worldwide. While both METH and HIV- 1 Tat proteins can induce neurotoxicity and synergistic effects on the nervous system, the mechanisms by which they act synergistically remain unclear. Our recent research shows that neuroinflammation plays an important role in neurotoxicity induced by METH and HIV- 1 Tat proteins, but the regulatory mechanism has not been clarified. Tripartite Motif Containing 13 (TRIM13) is a protein known to regulate the inflammatory response through ubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6). This study investigated the role of TRIM13 and TRAF6 in the inflammatory response of U- 87 MG cells induced by METH and HIV- 1 Tat proteins. U- 87 MG cells were treated with 2 mM METH and/or 100 nM HIV- 1 Tat protein. Western blot (WB), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) experiments were employed to elucidate the role of TRIM13 and TRAF6. The results demonstrated that METH and HIV- 1 Tat protein could synergistically induce an inflammatory response in U- 87 MG cells. Furthermore, the knockdown of TRIM13 significantly enhanced this inflammatory response, while the inhibition of TRAF6 significantly weakened it. Additionally, the study revealed that TRIM13 could degrade TRAF6 via ubiquitination. In conclusion, this study suggests that TRIM13 regulates TRAF6 ubiquitination to dampen the inflammatory response of U- 87 MG cells induced by METH and HIV- 1 Tat proteins. These findings highlight TRIM13 and TRAF6 as potential targets for therapeutic intervention in the context of METH and HIV- 1 Tat protein-induced inflammatory responses and neurotoxic effects.

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.

Salinity stress is one of the major environmental factors drastically affecting crop productivity all over the world. At a biochemical level, salinity stress results in the production and accumulation of osmoprotectants, which serve as a mechanism for survival. The halophyte Pandanus odorifer (Forssk.) Kuntze grows in the wild, mainly along the seashore in the tropical and subtropical Pacific Oceans. Previously, we reported that the upregulated expression of asparagine synthetase (PoASN1) (EC 6.3.5.4) and the accumulation of the osmolyte asparagine conferred salt tolerance to the P. odorifer. Here, we focused on understanding the PoASN1 gene structure, enzymatic characteristics, regulatory mechanism and function via its overexpression in E. coli and Oryza sativa. In this study, expression analysis revealed that the PoASN1 gene was inducible only beyond 500 mM NaCl. Remarkably, overexpression of PoASN1 resulted in enhanced salinity survival of E. coli (up to 500 mM) and rice (up to 250 mM) because of osmolyte glycine betaine and asparagine, respectively, implying that glutamine-hydrolyzing PoASN1 plays a critical function in salinity tolerance.

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.

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.

Ovarian cancer (OV) is the leading cause of death among gynecological malignancies. This study aimed to investigate the influence of Icariside II on OV in vitro and in vivo and to elucidate whether Icariside II induces ferroptosis in OV cells by regulating SLC7A11 expression.

Metastatic breast cancer (BC) is the main cause of cancer-related mortality in women worldwide. HR + /HER2- BC patients are treated with endocrine therapy (ET), but therapeutic resistance is common. The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with ET was approved for metastatic BC patients and extended the median progression-free survival to 24 months. This therapy is not always effective, and in every patient, resistance ultimately occurs, but the underlying resistance mechanisms remain unclear. To address this gap, we explored circulating tumour cells (CTCs) as biomarkers to assess treatment response and resistance in metastatic HR + /HER2- BC patients receiving CDK4/6i plus ET.

The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT.

Seed germination represents a pivotal phase in crop production, exhibiting pronounced sensitivity to abiotic stresses. In this study, wheat seeds of the 'Ningchun 4' variety were subjected to treatments involving zinc (Zn) chloride and iron (Fe) chloride, both individually and in combination. The impacts of these treatments on Fe and Zn accumulation, starch mobilization, antioxidant responses, and nitric oxide (NO) metabolism during seed germination were thoroughly examined. Individual application of Fe or Zn significantly inhibited and delayed wheat seed germination, which was accompanied by elevated levels of starch, sucrose, and soluble sugars, as well as increased reactive oxygen species and malondialdehyde concentrations. Concurrently, total amylase and α-amylase activities were downregulated, while antioxidant enzyme activities and the expression of TaCAT, TaAPX, and TaGR were upregulated. Seeds treated solely with Fe exhibited excessive Fe accumulation, heightened Fe2+ content, and diminished Zn content. Conversely, these trends were reversed in seeds treated with Zn alone. Furthermore, reduced NO levels were associated with downregulated nitrate reductase and nitric oxide synthase activities, alongside decreased expression of their corresponding genes in response to Fe exposure. Notably, the above effects induced by Zn alone were less severe compared to those induced by Fe stress. Importantly, the addition of Zn (100 µM or 250 µM) significantly alleviated the detrimental effects of Fe on several parameters in germinating seeds. The results from NO fluorescent probe staining corroborated the quantitative NO measurements across different treatments. In conclusion, an appropriate concentration of Zn effectively promoted the germination of Fe-stressed wheat seeds by mitigating Fe accumulation, attenuating oxidative damage, and enhancing starch mobilization during seed germination.

Further study of the mechanism of glucocorticoid (GC)-induced osteoblast (OB) apoptosis is highly important for the prevention and treatment of GC-induced osteoporosis and osteonecrosis. Serine/arginine-rich splicing factor 1 (Srsf1) expression was downregulated in a dose-dependent manner during GC-induced OB apoptosis. Knockdown of Srsf1 significantly promotes GC-induced OB apoptosis, while overexpression of Srsf1 significantly inhibits GC-induced OB apoptosis. Mechanistically, GC induces the up-regulation of histone deacetylase 4 (Hdac4) in OB, and inhibits the expression of transcription activator forkhead box C1 (Foxc1) by reducing the levels of histone H3 lysine 9 acetylation (H3K9ac) and H3K27ac in the promoter region of Foxc1, thereby down-regulating Srsf1. Next, SRSF1 regulates GC-induced OB apoptosis by regulating Bcl-2 modifying factor (Bmf) alternative splicing. From the perspective of alternative splicing, this study demonstrates that Srsf1 and its regulatory mechanism may serve as a new target for the prevention and treatment of GC-induced osteoporosis and osteonecrosis.

Cadmium (Cd) is a toxic heavy metal whose contamination in soil threatens food safety, agricultural production, and human health. To date, phytoremediation is a low-cost and environmentally friendly method for eliminating Cd contamination. In this study, we report a gene from ramie (Boehmeria nivea) that encodes a dehydration responsive element binding (DREB) factor associated with plant tolerance to Cd, namely BnDREB1. The open reading frame of BnDREB1 comprises 873 bp encoding 290 amino acids and includes a characteristic AP2 domain. Its cloned promoter sequence contains various hormone and stress responsive elements. Quantitative RT-PCR analysis showed that BnDREB1 is expressed in different organs of ramie. Treatments with polyethylene glycol (PEG), abscisic acid (ABA), and Cd upregulated the expression of BnDREB1. Confocal microscopic analysis revealed that BnDREB1 is mainly localized in the nucleus. Overexpression of BnDREB1 in Arabidopsis thaliana increased the tolerance of transgenic plants to Cd, thereby protecting plant growth from its toxicity. Biochemical analysis revealed that overexpression of BnDREB1 reduced the levels of Cd induced malonaldehyde and hydrogen peroxide, inhibited the reduction of Cd caused soluble protein contents, increased the Cd accumulation, and enhanced Cd translocation in transgenic plants. Taken together, these findings suggest that BnDREB1 is an appropriate candidate gene for phytoremediation of Cd-contaminated soil .

Acute myeloid leukemia is a hematological malignancy characterized by acquired genomic aberrations. Mutations in the FMS-like tyrosine kinase 3 gene cause constitutive activation of downstream signaling pathways, thereby driving disease progression and conferring a poor prognosis. Gilteritinib, a tyrosine kinase inhibitor, is a promising treatment for FMS-like tyrosine kinase 3-mutated acute myeloid leukemia. However, gilteritinib resistance remains a significant concern, and its underlying mechanisms are not yet understood.