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.

The emergence of carbapenem resistance in gram-negative bacteria such as Escherichia coli is one of the world's most urgent public health problems. E. coli, which encounter a diverse range of niches in host can rapidly adapt to the changes in surrounding environment by coordinating their behavior via production, release and detection of signal molecules called autoinducers through a cell density dependent communication system known as quorum sensing. Here, in this study we investigated whether imipenem, and acyl homoserine lactone quorum sensing signal molecules influence the transcriptional response within lsr and lsrRK operon which are associated with auto inducer-2 mediated quorum sensing in E. coli. Two E. coli isolates carrying blaNDM were treated with 10% SDS for 20 consecutive days, resulting in the successful elimination of the blaNDM encoding plasmid from one isolate. Plasmid was extracted from the isolate and was transformed into recipient E. coli DH5α by electroporation. The native type, plasmid-cured type, transformant, and E. coli DH5α were allowed to grow under eight different inducing conditions and the transcriptional responses of lsr and lsrRK operons were studied by quantitative real-time PCR method.

Triterpenoids are well-known pharmacological components of Sanghuangporus fungi, such as Sanghuangporus lonicericola. This study investigates the inductive effects of paclobutrazol (PBZ) on triterpenoid biosynthesis in the submerged fermentation of S. lonicericola and explores the induction mechanisms via multi-omics and genetic methods. The addition of 100 mg/L PBZ significantly increases the triterpenoid yield by 151.39%. A total of 29 triterpenoids are tentatively identified, of which 18 are newly presented only under PBZ induction. Moreover, 30 genes involved in the MVA pathway and 31 genes encoding cytochrome P450 monooxygenases assumed to be responsible for decoration are identified. Finally, a MYB transcription factor (SlMYB) is identified and found to be downregulated under paclobutrazol induction. Genetic manipulation of SlMYB demonstrates its negative regulatory effect on four putative target genes, including ACAT, MVD, IDI, and FDPS. Electrophoretic mobility gel shift assays verify the direct interactions with the promoters of MVD, IDI, and FDPS. Taken together, PBZ acts as an effective inducer of triterpenoid biosynthesis in S. lonicericola, and the transcription factor SlMYB is negatively regulated.

Gray mold, caused by Botrytis cinerea, poses an escalating threat to ginseng production in China. Excessive application of chemical fungicides has resulted in severe resistance development. To elucidate the resistance mechanism of B. cinerea to pyrimethanil, transcriptomic comparisons were conducted between resistant (HRG21) and sensitive (FSG43) strains following exposure to pyrimethanil for 2 and 6 h. GO and KEGG analyses identified differential expression of genes associated with ABC and MFS transporters as well as methionine biosynthesis. qRT-PCR validation confirmed a marked upregulation of ABC (BcatrA, BcatrB, BcatrD, BcatrO, and Bmr3) and MFS (Bchex1 and BcmfsM2) transporter genes in HRG21, whereas in FSG43, ABC (BcatrA, BcatrB, BcatrD, and BcatrO) and MFS (Bchex1) transporter genes were downregulated. No significant transcriptional changes were observed in Mrr1, a transcription factor gene, following pyrimethanil exposure. Molecular docking analysis identified potential binding sites and interaction targets for five key transporters (BcatrB, BcatrA, BcatrD, Bmr3, and Bchex1). Furthermore, exogenous methionine supplementation partially mitigated pyrimethanil toxicity in FSG43. However, amino acid sequences of enzymes involved in methionine biosynthesis (BcmetC, BcStr2, Bcmet2, Bcmxr1, and Bcmxr2) exhibited no variation between FSG43 and HRG21. The results indicate that BcatrB plays a central role in pyrimethanil resistance, while methionine contributes only marginally to resistance mechanisms.

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.

TNBC is an aggressive metastatic cancer that poses considerable treatment challenges because of its acquired drug resistance towards the existing targeted and hormonal therapies. The epigenetic modulation including HDACs triggers the EMT in TNBC which produces a more aggressive tumor phenotype. Chemotherapy and radiotherapy cause severe side effects which make treatment complex and challenging. To avoid these serious side effects and boost the effectiveness of current anti-cancer medications, plant flavonoids have been investigated.

Metformin is an antidiabetic drug used in type 2 diabetes as well as indicators in polycystic ovary syndrome (PCOS) and cancer. Due to their increase in popularity, high amounts of metformin are being released into aquatic environments. However, the toxic effect of metformin on embryonic development in aquatic organisms remains limited. Therefore, this study aimed to elucidate the lethal embryotoxicity of metformin and determine the underlying molecular pathways influencing embryonic development using a zebrafish model through multi-omics analysis. Metformin was microinjected into zebrafish embryos at the 1-cell stage with varying concentrations (50 mM, 100 mM, 200 mM, 400 mM, and 800 mM). From the results, hatching rates decreased in a dose dependent manner. Fetal malformation and mortality (LC50 = 339.8 mM) increased in a dose dependent manner. In situ hybridization of whole-embryo assays demonstrated that metformin exerts a significant impact on the initial stages of embryonic development, leading to aberrant differentiation of the germ layers, perturbed organogenesis, and delayed development. Furthermore, transcriptomics, metabolomics, and lipidomics were used to study the molecular mechanisms of embryonic toxicity. The results showed that the cell cycle, dorsoventral axis formation, and collecting duct acid secretion pathways were significantly altered in treated embryos. In brief, these results provide useful information on the lethal toxicity mechanism of metformin overdose and provide clues for further studies in humans.

Endocrine-disrupting chemicals (EDCs) in the aquatic environment are an emerging concern and can lead to adverse health effects on humans and aquatic life. EDCsare ubiquitous in several daily use and personal care products and ubiquitous in aquatic ecosystems. The aquatic ecosystems also serve as major sinks of EDCs and have even been found to accumulate in aquatic organisms. Fish are an important sentinel species in the aquatic system and are a reliable indication of environmental water pollution. In the present study, we have assessed the immunotoxicity effects of three important EDCs, i.e., triclosan (TCS), bisphenol A (BPA), and diethyl phthalate (DEP). There is mounting evidence that EDCs impact several physiological systems, including fish immune systems. Hence, to better understand the immune system's complexity, we have investigated how EDCs alter the immune responses and can aggravate immunotoxicity using Labeo catla as a model fish species. The results showed significant upregulation of immune gene expression; exposure to EDCs differentially modulates immunity across the different organs (liver and brain) of Labeo catla. The present study highlighted that endocrine-disrupting compounds (TCS, BPA, and DEP) have a significant immunotoxicity effect in fish and activate several immunological pathways to control the toxic effect and maintain homeostasis. The results also indicate that immune genes can be used as a biomarker for EDC toxicity. However, further studies need to see how immune-disrupting effects happen at actual exposure levels in the environment to EDCs.

Selenium is an indispensable nutrient for plants, and optimizing selenium levels can enhance plant growth and metabolism, leading to improved yield and quality. In comparison to conventional inorganic or organic selenium fertilizers, nano-selenium demonstrates superior safety and enhanced biological activity, making it more suitable for crop production. Although nano-selenium fertilizer is extensively used in various crops, its application in pak choi remains limited. As a vital source of selenium, previous research on pak choi (Brassica chinensis var. pekinensis cv. 'Suzhouqing') has primarily focused on investigating physiological effects with limited exploration of the molecular mechanism. Therefore, this study aims to investigate the impact of nano-selenium on pak choi through an integrated analysis of transcriptome and metabolome. Specifically, we examined the effects of different concentrations of nano-selenium (0, 5, 10 and 20 mg L-1) on the growth and nutritional quality of Suzhouqing. The findings revealed that a low concentration (5 mg L-1) of nano-selenium significantly increased leaf weight and total selenium content, while modulating primary metabolites such as soluble amino acids, proteins, sugars and ascorbic acid. Additionally, it influenced secondary metabolites including glucosinolates, phenolic acids and flavonoids. Consequently, this enhancement in growth performance and nutritional quality was attributed to the regulation of pathways involved in selenocompound metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis by key enzymes such as methionine S-methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase, kynurenine-oxoglutarate transaminase, thioredoxin reductase, phenylalanine ammonian-lyase, 4-coumarate-CoA ligase, flavonoid 3', 5'-hydroxylase, naringenin 3-dioxygenase, flavonol synthase and bifunctional dihydroflavonol 4-reductase. These results provide comprehensive insights into the physiological and molecular mechanisms underlying the influence of nano-selenium on plant growth and nutritional quality. Therefore, they offer a solid theoretical basis and technical support for breeding and cultivation strategies aimed at producing selenium-rich pak choi.

This research aimed to explore the effect of Phyllanthus emblica powder on the growth performance, blood hematology, body composition, serum biochemistry, organ histology, gene expression and resistance of Nile Tilapia (Oreochromis niloticus) against Aspergillus flavus. A total of 240 fish (30.5 ± 2.0 g) were distributed in 12 ponds with 20 fish per pond and fed a basal diet supplemented with 0, 1%, 2% and 3% of P. emblica powder for 60 days. A challenge experiment was performed at the end of the trial. All supplemented groups showed better growth performance (final body weight, weight gain, and specific growth rates) (P < 0.05), while feed intake did not affect (P > 0.05). The feed conversion ratio enhanced by the inclusion of dietary P. emblica (P < 0.05). In terms of body composition, crude lipids decreased, while ash percentages increased after fish were fed with P. emblica (P < 0.05). Liver function decreased significantly, while protein fraction, blood hematology and digestive enzymatic profile (amylase, and lipase) were significantly increased in all treated groups. Fish fed with P. emblica exhibited a higher survival rate and increased resistance to A. flavus compared to the control diet. Diets containing P. emblica improved the histoarchitecture of hepatopancreatic and intestine of Nile Tilapia. The inclusion of P. emblica significantly upregulated the expression of CC chemokine, IL-1β, IL-8, SOD, and GPx genes, with a gradual increase in P. emblica levels in the diet (P < 0.05). In conclusion, dietary supplementation with P. emblica powder may serve as an effective strategy for promoting growth and acting as an immunostimulant in Nile Tilapia aquaculture.

In the leaves of C3 species such as rice (Oryza sativa), mesophyll cells contain the largest compartment of photosynthetically active chloroplasts. In contrast, plants that use the derived and more efficient C4 photosynthetic pathway have a considerable chloroplast compartment in both bundle sheath and mesophyll cells. Accordingly, the evolution of C4 photosynthesis from the ancestral C3 state required an increased chloroplast compartment in the bundle sheath. Here, we investigated the potential to increase chloroplast compartment size in rice bundle sheath cells by manipulating brassinosteroid signaling. Treatment with brassinazole, a brassinosteroid biosynthesis inhibitor, raised leaf chlorophyll content and increased the number but decreased the area of chloroplasts in bundle sheath cells. Ubiquitous overexpression of the transcription factor-encoding BRASSINAZOLE RESISTANT 1 (OsBZR1) increased bundle sheath chloroplast area by up to 45%, but these plants became chlorotic. However, when OsBZR1 expression was driven by a bundle sheath-specific promoter, the negative effects on growth and viability were alleviated while chloroplast area still increased. In summary, we report a role for brassinosteroids in controlling chloroplast area and number in rice and conclude that cell-specific manipulation of brassinosteroid signaling can be used to manipulate the chloroplast compartment in rice bundle sheath cells.