41. Unveiling the effect of chia seeds and matcha tea on growth performance, metabolism, carcass characteristics, and gene expression on New Zealand rabbits.
作者: Amira Abdalla Abdelshafy Mohamed.;Ahmed S H Soliman.;Shymaa Sobhy Mourad.
来源: Sci Rep. 2025年15卷1期16491页
Novel of hematopoietic system and hepatic system under the usage of antioxidant plants such as chia seeds and matcha green tea were critical sites in this study which promoted by crucial health of New-Zealand white (NZW) rabbits as a model for mammalia and eukaryotic cell. Our study investigated the effect of chia seeds and matcha green tea on the liver. Eighteen NZW rabbits average weighed of 547.08gm with an average age of 30 days were divided into three groups, control, chia seeds powder group 0.150gm/L, and matcha green tea group 0.075 gm/L. The weekly treatments were weighted from weaning age to marketing age about nine weeks were the experimental period. At the end of this experiment, we studied growth performance, metabolism, carcass characteristics, and some gene expression related to the growth factor family, hepatic metabolism, lipid profile, iron storage, and one of the endoplasmic reticulum stress receptors of NZW rabbits. The data in this study reported that final body weight increased significantly (P < 0.05) in the matcha group compared to the control, carcass trait and dressing parts were increased significantly in comparison to control. However, Red blood cell count, hemoglobin concentration, and ferritin increased in matcha groups in comparison to control while there is no difference significant between chia and control. Cortisol and insulin in plasma were decreased significantly in chia and matcha compared to control. IRP1, APOA2, IGF1, A1BG, and SLC27A5 were up-regulated in matcha tea groups compared to control while, SLC27A5 was down-regulated in chia groups and Leptin and GRP78 were showed down-regulated in chia and matcha groups. This study offers new insights into the role of chia seeds and matcha tea in physiological and biological processes in the liver and achieved a vital and healthy biological body and reduces the incidence of cancer.
42. Unraveling the molecular mechanisms of paclitaxel in high-grade serous ovarian cancer through network pharmacology.
High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of epithelial ovarian cancer, often diagnosed at advanced stages with a poor prognosis. Paclitaxel (PTX), a standard chemotherapeutic agent for HGSOC, exerts cytotoxic effects on cancer cells and modulates the tumor microenvironment. This study aimed to elucidate the molecular mechanisms of PTX in HGSOC using bioinformatics, machine learning, network pharmacology, and molecular docking, to identify potential diagnostic biomarkers and therapeutic targets. We identified differentially expressed genes (DEGs) between HGSOC and normal ovarian tissues using the GSE54388 dataset from the Gene Expression Omnibus database. The intersection of these DEGs with PTX targets, identified from the Swiss Target Prediction database, yielded 15 overlapping genes. These genes were analyzed via protein-protein interaction (PPI) network analysis to identify significant interaction relationships. Kaplan-Meier survival analysis was then performed to assess the prognostic significance of these genes. Their protein expression patterns in HGSOC tissues were validated using the Human Protein Atlas (HPA) database. Functional enrichment analysis was conducted using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. A combined diagnostic model was developed using LASSO regression and validated in two independent external datasets (GSE26712 and GSE12470). Molecular docking experiments were conducted to confirm the binding affinity of PTX to key proteins. Immune infiltration analysis was performed to assess the tumor microenvironment, revealing significant differences in immune cell composition between normal and tumor tissues. A total of 2267 DEGs were identified, with 15 overlapping genes related to PTX targets. After PPI network analysis, Kaplan-Meier survival analysis, and HPA validation, five key genes (AURKA, CBX7, CCNA2, HSP90AA1, and TUBB3) were identified as associated with HGSOC progression. The combined diagnostic model demonstrated high accuracy in distinguishing HGSOC from normal tissues, with AUC values of 0.9892 and 0.9465 in the GSE26712 and GSE12470 validation datasets, respectively. Molecular docking confirmed stable binding of PTX to these key proteins, suggesting their role in PTX's therapeutic effects. Immune infiltration analysis revealed significant differences in immune cell composition between normal and tumor tissues, highlighting the potential impact of these genes on the tumor microenvironment. In summary, our findings provide a theoretical basis for improving clinical diagnosis and elucidating the underlying mechanisms of HGSOC.
43. Inhibition of Purine Metabolism Promotes the Differentiation of Neuroblastoma Driven by MYCN.
作者: Yufeng Jiang.;Hui Xiao.;Yi Yang.;Guoyu Chen.;Yingwen Zhang.;Xiaoyu Wu.;Qi Zhang.;Qingyi Huang.;Hongxiang Gao.;Yali Han.;Anan Zhang.;Dapeng Jiang.;Liang Zheng.;Yanxin Li.;Yijin Gao.
来源: Cancer Med. 2025年14卷9期e70953页
Neuroblastoma (NB), the common extracranial solid tumor in children, is associated with a poor prognosis, particularly in high-risk patients. MYCN amplification stands as the most prominent molecular hallmark within this high-risk subgroup. However, MYCN protein is considered "undruggable" due to its lack of a conventional enzymatic binding pocket and its predominant nuclear localization, which precludes targeting by standard small-molecule inhibitors or antibody-based therapeutics. Consequently, current therapeutic strategies have achieved limited efficacy against MYCN-driven NB. Notably, MYCN not only orchestrates diverse metabolic reprogramming pathways in tumors but also exerts a pivotal influence on cellular differentiation. To overcome this therapeutic barrier, we seek to elucidate the contribution of purine metabolism to stemness maintenance in MYCN-amplified NBs and to discover novel small-molecule inhibitors capable of inducing differentiation in high-risk NBs.
44. Discovery of drug transporter inhibitors tied to long noncoding RNA in resistant cancer cells; a computational model -in silico- study.
作者: Mohanad Diab.;Amel Hamdi.;Feras Al-Obeidat.;Wael Hafez.;Ivan Cherrez-Ojeda.;Muneir Gador.;Gowhar Rashid.;Sana F Elkhazin.;Mahmad Anwar Ibrahim.;Tarek Farag Ismail.;Samar Sami Alkafaas.
来源: Front Immunol. 2025年16卷1511029页
Chemotherapeutic resistance is a major obstacle to chemotherapeutic failure. Cancer cell resistance involves several mechanisms, including epithelial-to-mesenchymal transition (EMT), signaling pathway bypass, drug efflux activation, and impairment of drug entry. P-glycoproteins (P-gp) are an efflux transporter that pumps chemotherapeutic drugs out of cancer cells, resulting in chemotherapeutic resistance. Several types of long noncoding RNA (lncRNAs) have been identified in resistant cancer cells, including ODRUL, MALAT1, and ANRIL. The high expression level of ODRUL is related to the induction of ATP-binding cassette (ABC) gene expression, resulting in the emergence of doxorubicin resistance in osteosarcoma. lncRNAs are observed to be regulators of drug transporters in cancer cells such as MALAT1 and ANRIL. Targeting P-gp expression using natural products is a new strategy to overcome cancer cell resistance and improve the sensitivity of resistant cells toward chemotherapies. This review validates the inhibitory effects of natural products on P-gp expression and activity using in silico molecular docking. In silico analysis showed that Delphinidin and Asparagoside-f are the most significant natural product inhibitors of p-glycoprotein-1. These inhibitors can reverse multi-drug resistance and induce the sensitivity of resistant cancer cells toward chemotherapy based on in silico molecular docking. It is important to validate that pre-elementary docking can be confirmed using in vitro and in vivo experimental data.
45. Ethanol extract from Ziziphus nummularia stem inhibits MCF-7 breast cancer cell proliferation through TP53 regulating kinase (TP53RK)-mediated p53 activation: In silico and genes expression investigations.
作者: Berna Elya.;Rosmalena Rosmalena.;Ajeng M Fajrin.;Aryo Tedjo.;Nur A Ramadanti.;Norma N Azizah.;Najihah Bm Hashim.
来源: Narra J. 2025年5卷1期e1382页
The p53 signaling pathway plays a critical role in regulating the cell cycle, apoptosis, and senescence, making it a key target in cancer research. The aim of this study was to investigate the effects of an ethanol extract from the stem of Ziziphus nummularia on the proliferation and expression of genes involved in the p53 pathway in MCF-7 breast cancer cells. To achieve this, real-time quantitative PCR (RT-qPCR) was used to evaluate the mRNA expression of downstream genes linked to cell cycle and senescence, including CycE or CCNEl, RBLl, and E2F1. Molecular docking simulations using Molegro Virtual Docker (MVD) were also performed to assess the potential inhibitory activity of metabolite compounds from Z. nummularia stem against p53-regulating kinase (TP53RK). The results showed that the IC50 value of Z. nummularia stem ethanol extract against MCF-7 cells was 38.27 ± 0.72 μg/mL. The results also revealed a reduction in the expression of downstream genes linked to cell senescence and the cell cycle: CycE or CCNE1 (p = 0.011), RBL1 (p = 0.008), and E2F1 (p = 0.005), which was observed through RT-qPCR analysis of mRNA expression. This fact indicated that the inhibitory effects on proliferation by the ethanol extract of Z. nummularia stem might occur via pathways associated with cell senescence and cell cycle arrest. Molecular docking results of metabolite compounds from Z. nummularia stem suggested that squalene (Rerank score -112.70 kJ/mol), and nummularine B (Rerank score -110.68 kJ/mol) had potential as TP53RK inhibitors. These Rerank scores were smaller compared to the Rerank score of adenyl-imidodiphosphate (AMP-PNP), which was the native ligand of TP53RK, as confirmed by molecular dynamics analysis. These in silico results were confirmed by the decrease in p21 (CDKN1A) mRNA expression. In conclusion, the anti-proliferative effects of the ethanol extract from Z. nummularia stem on breast cancer cells occurred by affecting cell cycle-related genes and inhibiting apoptosis protection mediated by overexpression of p21 (CDKN1A) through p53 activity.
46. Do guard cells have single or multiple defense mechanisms in response to flg22?
作者: Zalán Czékus.;András Kukri.;Atina Martics.;Boglárka Pollák.;Árpád Molnár.;Attila Ördög.;Györgyi Váradi.;László Galgóczy.;Rebeka Papp.;Liliána Tóth.;Katalin Ágnes Kocsis.;Nóra Faragó.;Nikolett Bódi.;Mária Bagyánszki.;Gabriella Szalai.;Kamirán Áron Hamow.;Péter Poór.
来源: Physiol Plant. 2025年177卷3期e70249页
Bacterial flagellin (flg22) induces rapid and permanent stomatal closure. However, its local and systemic as well as tissue- and cell-specific effects are less understood. Our results show that flg22 induced local and systemic stomatal closure in intact tomato plants, which was regulated by reactive oxygen- and nitrogen species, and also affected the photosynthetic activity of guard cells but not of mesophyll cells. Interestingly, rapid and extensive local expression of Ethylene response factor 1 was observed after exposure to flg22, whereas the relative transcript levels of Defensin increased only after six hours, especially in systemic leaves. Following local and systemic ethylene emission already after one and six hours, jasmonic acid levels increased in the local leaves after six hours of flg22 treatment. Using immunohistochemical methods, significant defensin accumulation was found in the epidermis and stomata of flg22-treated leaves and above them. Immunogold labelling revealed significant levels of defensins in the cell wall of the mesophyll parenchyma and guard cells. Furthermore, single cell qRT-PCR confirmed that guard cells are able to synthesise defensins. It can be concluded that guard cells are not only involved in the first line of plant defense by regulating stomatal pore size, but can also defend themselves and the plant by producing and accumulating antimicrobial defensins where phytopathogens can penetrate.
47. Betulinic Acid Delays Turnip Mosaic Virus Infection by Activating the Phytosulfokine Signalling Pathway in Nicotiana benthamiana.
作者: Meirong Xiang.;Pengyue Wang.;Keda Han.;Jianjian Liu.;Ziting Huang.;Chaonan Wang.;Xinxin Jing.;Jiao Du.;Bingjian Sun.;Honglian Li.;Chao Zhang.;Pengbai Li.
来源: Mol Plant Pathol. 2025年26卷5期e70092页
Plant viral diseases pose a significant threat to agricultural production, and the availability of effective drugs against viral diseases remains limited. In this study, we discovered that betulinic acid (BA), a pentacyclic triterpenoid derived from plants, delays infection by turnip mosaic virus (TuMV) in Nicotiana benthamiana. Transcriptomic analysis revealed that BA treatment specifically induced the expression of N. benthamiana phytosulfokine 3 (NbPSK3), a plant pentapeptide hormone with diverse functions, while TuMV infection suppressed its expression. Further study demonstrated that NbPSK3 positively regulates antiviral defence against TuMV infection. Disruption of PSK signalling by targeting the membrane-bound PSK receptors (PSKRs) promoted viral infection. Additionally, exogenous sulphonated PSK (active form) treatment significantly delayed infection by TuMV in N. benthamiana compared to unmodified PSK peptides (dPSK, inactive form) or control treatments, while silencing the receptor NbPSKR1 abolished the ability of PSK to inhibit TuMV infection. Moreover, the inhibition of TuMV infection by BA is dependent on the PSK-PSKR signalling pathway. Overall, these findings not only underscore the potential of BA as a promising and environmentally friendly agent for modulating plant viral diseases but also emphasise the role of the PSK signalling pathway in promoting at least partial resistance to TuMV, which might have interest for crop breeding.
48. Novel proteolysis-targeting chimera targeting RAD51 for the treatment of triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. RAD51 is associated with homologous recombination repair (HRR), a crucial DNA repair mechanism. This paper reports the development and efficacy of a novel targeted RAD51 degrader compound, TRD2, for treating TNBC. TRD2 is synthesized by linking a RAD51 binder to the ligand of the E3 ligase cereblon (CRBN). The results showed that TRD2 effectively reduces the RAD51 protein levels in TNBC cells and exhibits potent anticancer effects in vitro and in vivo. Mechanistic studies showed that TRD2 induces RAD51 ubiquitination and subsequent proteasomal degradation by binding to CRBN. Furthermore, TRD2 demonstrated significant tumor growth inhibition in a mouse xenograft model of TNBC. These findings highlight the potential of TRD2 as a promising therapeutic approach in TNBC, leveraging Proteolysis-targeting chimera (PROTAC) technology to degrade the overexpressed RAD51 protein selectively. The study emphasizes the importance of targeting DNA damage repair core proteins and suggests that TRD2 could overcome challenges posed by resistance to conventional therapies. Nevertheless, additional experiments will be needed to validate these observations and explore the potential impacts on other proteins and cancer types. Overall, this research introduces a novel strategy for TNBC treatment, addressing the limitations of current therapeutic options.
49. Inhibition of autophagy by esketamine attenuates hypoxia/reoxygenation injury in cardiomyocytes via inhibition of Ca2+/CaMKKβ/AMPK/mTOR pathway by down-regulation of transient receptor potential vanilloid 1 expression.
This research sought to determine the influence of esketamine (ESK) on hypoxia/reoxygenation (H/R) injury in cardiomyocytes by blocking autophagy via the transient receptor potential vanilloid type 1 (TRPV1)/ Ca2+/ calmodulin-dependent protein kinase β (CaMKKβ)/ adenosine monophosphate (AMP)-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway. H9c2 cardiomyocytes were hypoxic for 4 h and reoxygenated for 6 h. H9c2 cells were pretreated with ESK (30 μg/ml) before hypoxia. H9c2 cells were transfected with plasmid vectors that interfered with TRPV1 or CaMKKβ, and the success of the transfections was verified by RT-qPCR. Cell viability was detected by MTT assay; apoptosis was detected by flow cytometry; intracellular Ca2+ concentration ([Ca2+]i) was assessed using fluorescent dye Fluo-3 AM/Pluronic F127, and LC3-I, LC3-II, Beclin-1, and CaMKKβ/AMPK/mTOR-related proteins were detected by Western blot. In results: ESK treatment inhibited H/R-induced cell injury, cellular autophagy, and [Ca2+]i elevation. Induction of autophagy or [Ca2+]i elevation attenuated the ameliorative effect of ESK on H/R-induced cell injury. Upregulating TRPV1 attenuated We conclude that ESK-induced protection against H/R injury, as well as reduced the effect on the CaMKKβ/AMPK/mTOR pathway. ESK attenuates H/R cardiomyocyte injury by hindering autophagy through the TRPV1/Ca2+/CaMKKβ/AMPK/mTOR pathway.
50. The promoter regions of CBDAS and PT genes of cannabinoid biosynthesis in Cannabis sativa respond to phytohormones and stress-related signals.
作者: Mohd Fayaz.;Tsering Angmo.;Kajal Katoch.;Aasim Majeed.;Maridul Kundan.;Mir Abdul Wajid.;Koushik Pal.;Prashant Misra.
来源: Planta. 2025年261卷6期135页
The functional characterization of promoter regions of CBDAS and PT genes of cannabinoids biosynthesis suggests that multiple factors including tissue-specific, phytohormones, and stress-related signals modulate their activity. Cannabis sativa L. has tremendous potential as a future crop for producing clinically important cannabinoid metabolites. While the cannabinoid biosynthetic pathway is largely known, the mechanistic details about its regulation are less understood. Decrypting the environmental and developmental factors regulating cannabinoid biosynthesis pathway may prove beneficial in pathway engineering and molecular breeding programs. Functional characterization of the promoter regions of key cannabinoid biosynthesis genes can provide useful insights into their transcriptional regulation. This study, therefore, is focused to uncover the role of different phytohormones and abiotic factors in influencing the activity of CsCBDAS and CsPT1 promoters through the development of promoter-GUS fusion expressing transgenic lines of Nicotiana tabacum. Spatial analysis across different tissues revealed that CsCBDAS and CsPT1 promoters drive a high level of GUS staining in leaf and flowers of the transgenic lines. A strong GUS staining was detected in the glandular trichomes of both tobacco transgenic lines. The results showed that out of the five hormones, three (IAA, GA3, and SA) and four (IAA, GA3, SA, and ABA) caused significant activation of CsCBDAS and CsPT1 promoters, respectively. While the light, heat, cold, salt, and wound stress induced promoter activity of both CsCBDAS and CsPT1, the drought stress was found to induce the activity of CsCBDAS promoter only. Validation of the expression patterns of these genes under different conditions in C. sativa through qRT-PCR suggested that phytohormones and abiotic factors may influence the cannabinoid biosynthesis in C. sativa by modulating their promoter activity.
51. Mapping the molecular signature of ABA-regulated gene expression in germinating barley embryos.
作者: Ewa Sybilska.;Bahareh Sadat Haddadi.;Luis A J Mur.;Manfred Beckmann.;Szymon Hryhorowicz.;Joanna Suszynska-Zajczyk.;Monika Knaur.;Andrzej Pławski.;Agata Daszkowska-Golec.
来源: BMC Plant Biol. 2025年25卷1期619页
Abscisic acid (ABA) regulates key plant processes, including seed germination, dormancy, and abiotic stress responses. While its physiological role in germination is well-documented, the molecular mechanisms are still poorly understood. To address this, we analyzed transcriptomic and metabolomic changes in ABA-treated germinating barley (Hordeum vulgare) embryos. To map ABA-responsive gene expression across embryonic tissues, we employed the Visium Spatial Transcriptomics (10× Genomics). This approach, which remains technically challenging to be applied in plant tissues, enabled the precise localization of gene expression across six embryo regions, offering insights into tissue-specific expression patterns that cannot be resolved by traditional RNA-seq.
52. Tryptophan-induced transcriptomic changes in the European Seabass are highly dependent on neuroendocrine-immune conditions.
作者: Diogo Peixoto.;Inês Carvalho.;Diego Robledo.;Marina Machado.;Patricia Pereiro.;Antonio Figueras.;Rita Azeredo.;Benjamín Costas.
来源: Sci Rep. 2025年15卷1期16340页
In European seabass (Dicentrarchus labrax), dietary tryptophan (TRP) surplus has a notable modulatory effect on the hypothalamic-pituitary-interrenal axis under chronic stress and acute inflammation, affecting cortisol levels and neuroendocrine- and immune-related gene expression. A transcriptomic approach (RNA-seq) was applied to head-kidney samples of fish submitted to confinement stress and/or acute inflammation to uncover the biological mechanisms behind these effects. Undisturbed seabass fed dietary TRP supplementation showed an up-regulation of various innate immune functions, contrasting previous studies which indicated mainly a TRP regulatory role. Upon bacterial injection, TRP-fed fish showed a transcriptomic profile similar to their counterparts fed on control diet, indicating TRP's inability to modulate immune mechanisms under bacterial challenge. Under confinement stress, TRP-fed fish exhibited a molecular profile similar to unstressed control fish, highlighting TRP's role in mitigating stress. However, combining dietary TRP supplementation with confinement stress and immune stimulation by bacterial inoculation resulted in a unique molecular profile. Stressed fish fed TRP did not show the restorative effect of immune stimulation on carbohydrate metabolism and showed downregulated genes related to glycolysis and glycogenolysis. Additionally, transcription upregulation in these fish after bacterial injection included terms related to serine and steroid metabolism (carboxyl ester lipase 2), indicating tryptophan-induced changes in lipid mobilization in the head-kidney, potentially affecting cortisol synthesis and other hormones.
53. Quercetin Induces Apoptosis Through Downregulating P4HA2 and Inhibiting the PI3K/Akt/mTOR Axis in Hepatocellular Carcinoma Cells: An In Vitro Study.
作者: Junli Zhang.;Jiayi Guo.;Ying Qian.;Lianchen Yu.;Junrao Ma.;Biao Gu.;Weichun Tang.;Yi Li.;Hongwei Li.;Wenjuan Wu.
来源: Cancer Rep (Hoboken). 2025年8卷5期e70220页
Quercetin is a natural product with multiple activities, which possesses a promising antitumor effect on malignancies. The involvement of proline 4-hydroxylase II (P4HA2) in collagen synthesis is crucial in the growth of tumor cells. Apoptosis is a programmed cell death requisite for the stability of the intracellular environment. However, the relationship between quercetin and cell apoptosis, as well as the impact of P4HA2 in this connection, has not yet been specified in hepatocellular carcinoma(HCC).
54. Artesunate Enhances Sensitivity of Renal Cancer Cells to Sunitnib by Mediating Tripartite Motif Containing 24-Induced Ubiquitination of Paired Box 6.
作者: Zelin Cui.;Jianhua Wen.;Guanglin Yang.;Liwei Wei.;Hao Chen.;Qiyue Zhao.;Shubo Yang.;Jiayin Yu.;Yichen Huang.;Shuting Tan.;Qizhou Mo.;Min Qin.;Jiwen Cheng.
来源: Chem Biol Drug Des. 2025年105卷5期e70116页
This research aims to elucidate the mechanistic role of artesunate (ART) in enhancing the sensitivity of renal cell carcinoma (RCC) to sunitinib. To establish sunitinib-resistant RCC cell lines (786-O R and Caki-1 R), cells were treated with different concentrations of sunitinib and ART. The viability of the cells was measured through the cell counting kit-8 (CCK-8) assay. Tripartite motif-containing 24 (TRIM24) and paired box 6 (PAX6) expression were suppressed with lentiviral vectors, quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) analysis. TRIM24-PAX6 interaction was examined through co-immunoprecipitation (Co-IP) and deubiquitination assays. Additional assays included colony formation, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, WB detection of phosphorylated histone H2AX (γ-H2AX) for DNA damage, epithelial-mesenchymal transition (EMT) marker analysis, sphere formation, and stemness marker assessments. In vivo drug resistance was tested using a mouse subcutaneous xenograft model. ART enhanced sunitinib sensitivity in resistant RCC cells, reducing colony formation, inducing apoptosis, elevating γ-H2AX, and upregulating TRIM24. ART enhances sunitinib sensitivity in RCC cells by upregulating TRIM24 expression, which facilitates the ubiquitination of PAX6. This process leads to the suppression of EMT and stem cell-like transitions in RCC cells.
55. Disruption of PPARG Activity and CPT1A Regulation by Bisphenol A: Implications for Hepatic Lipid Metabolism.
Bisphenol A (BPA) is a widely used industrial chemical with potential endocrine-disrupting effects on metabolic processes. This study investigates the impact of BPA on hepatic function and transcriptional regulation in mouse livers and AML12 cells. Male mice were exposed to low (5 g/kg) and high (50 g/kg) doses of BPA for six weeks. Transcriptomic analysis was performed on liver tissues, and histological examinations were conducted. AML12 cells were treated with varying BPA concentrations, and PPARG transcriptional activity was assessed using a luciferase reporter assay. Additionally, molecular docking, molecular dynamics (MD) simulations, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), MM-PBSA calculations, and multi-species protein structure comparative analysis were employed to analyse the interaction between BPA and PPARG. Transcriptomic analysis revealed a decrease in differentially expressed genes with higher BPA doses, with low-dose exposure significantly downregulating hepatic Cpt1a mRNA levels. Histological examination indicated lipid vacuole formation at high doses without collagen deposition. BPA consistently inhibited PPARG activity in both MCF7 cells and mouse livers. BPA exposure disrupts hepatic lipid metabolism and PPARG activity, highlighting its role as an endocrine disruptor. Further research is needed to elucidate the long-term effects of BPA on liver health.
56. Exogenous melatonin enhances drought tolerance and germination in common buckwheat seeds through the coordinated effects of antioxidant and osmotic regulation.
作者: Zemiao Tian.;Jiadong He.;Zhanyu Wang.;Zhuo Zhang.;Muriel Quinet.;Yu Meng.
来源: BMC Plant Biol. 2025年25卷1期613页
Drought stress is a major constraint on seed germination and crop productivity, particularly for drought-sensitive crops like common buckwheat (Fagopyrum esculentum). Exogenous melatonin has emerged as a promising strategy to mitigate drought stress by enhancing plant physiological and biochemical responses. However, its specific roles in regulating antioxidant defenses, osmotic adjustment, and plant compounds biosynthesis during buckwheat seed germination under drought stress remain poorly understood.
57. NPS-2143 suppresses malignant phenotypes of retinoblastoma cells involved in regulating NF-κB pathway.
NPS-2143, as a CaSR allosteric antagonist, performs an important role in diverse cancers. However, the function and mechanism of NPS-2143 in human retinoblastoma have not been reported. Cell viability was evaluated by using cell counting kit-8, flow cytometry was used for apoptosis detection and western blotting was carried out to detect the expression of target genes. Small interference RNA (siRNA) was used to reduce CaSR expression. Bortezomib was used to suppress the NF-κB pathway. NPS-2143 (16.5 µM) suppressed the proliferation of Y-79 cells, and increased the apoptosis of Y-79 cells. NPS-2143 treatment inhibited the protein patterns of p-P65 NF-κB and p-IκBα. Additionally, si-CaSR transfection obviously decreased the proliferation of Y-79 cells, and increased the apoptosis of Y-79 cells. Moreover, the protein patterns of p-P65 NF-κB and p-IκBα were obviously decreased after si-CaSR transfection. Bortezomib treatment increased the apoptosis of Y-79 cells, and CaSR overexpression suppressed the apoptosis of Y-79 cells. The whole data indicated that NPS-2143 inhibited the viability of Y-79 cells, and induced apoptosis by modulating the NF-κB signaling pathways. Therefore, NPS-2143 has potential anti-retinoblastoma effect.
58. BiDAC-dependent degradation of plasma membrane proteins by the endolysosomal system.
作者: Sammy Villa.;Qumber Jafri.;Julia R Lazzari-Dean.;Manjot Sangha.;Niclas Olsson.;Austin E Y T Lefebvre.;Mark E Fitzgerald.;Katrina Jackson.;Zhenghao Chen.;Brian Y Feng.;Aaron H Nile.;David Stokoe.;Kirill Bersuker.
来源: Nat Commun. 2025年16卷1期4345页
The discovery of bifunctional degradation activating compounds (BiDACs) has led to the development of a new class of drugs that promote the clearance of their protein targets. BiDAC-induced ubiquitination is generally believed to direct cytosolic and nuclear proteins to proteolytic destruction by proteasomes. However, pathways that govern the degradation of other classes of BiDAC targets, such as integral membrane and intraorganellar proteins, have not been investigated in depth. In this study we use morphological profiling and CRISPR/Cas9 genetic screens to investigate the mechanisms by which BiDACs induce the degradation of plasma membrane receptor tyrosine kinases (RTKs) EGFR and Her2. We find that BiDAC-dependent ubiquitination triggers the trafficking of RTKs from the plasma membrane to lysosomes for degradation. Notably, functional proteasomes are required for endocytosis of RTKs upstream of the lysosome. Additionally, our screen uncovers a non-canonical function of the lysosome-associated arginine/lysine transporter PQLC2 in EGFR degradation. Our data show that BiDACs can target proteins to proteolytic machinery other than the proteasome and motivate further investigation of mechanisms that govern the degradation of diverse classes of BiDAC targets.
59. Twist1 Regulates the Immune Checkpoint VISTA and Promotes the Proliferation, Migration and Progression of Pancreatic Cancer Cells.
Pancreatic cancer is one of the deadliest malignant tumours worldwide. Despite the developments in the treatments of pancreatic cancer, survival rates remain at a low level, and the mechanisms underlying the aggressive course of the cancer are not fully understood. VISTA is an immune checkpoint and has recently become a significant target in cancer treatment; however, the roles of VISTA in the development of pancreatic cancer have largely remained unknown. Histone deacetylase inhibitors (HDACi) have been reported to reverse the epithelial-mesenchymal transition (EMT) and may enhance the efficacy of anti-PD-1 therapy. The PD-L1/PD-1 immune checkpoint targeted by this therapy shares structural similarity with VISTA. Moreover, combination therapy of vorinostat and anti-PD-1 has been shown to significantly reduce tumour growth by suppressing the transcription factor c-Myc. Therefore, in this study, we aim to investigate the genes that are associated with EMT and explore the potential mechanism involving Twist1, a proto-oncogene, and VISTA in pancreatic cancer. We also sought to determine the synergistic effects of an HDACi, vorinostat, in combination with Twist1-siRNA on VISTA expression in pancreatic cancer cells' viability and proliferation. Our results revealed that Twist1 blockade in combination with vorinostat in pancreatic cancer cells suppresses EMT-associated genes and the immune checkpoint VISTA compared to treatments administered alone. As a result, identifying the genes associated with EMT in pancreatic cancer and understanding the role of Twist1 in this process is a crucial step to contribute to the identification of new targets for pancreatic cancer treatment and the improvement of existing treatment strategies.
60. Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer.
作者: Yuanhang Yu.;Jin Hu.;Wenwen Wang.;Hao Lei.;Zihan Xi.;Peiyi Zhang.;Ende Zhao.;Chong Lu.;Hengyu Chen.;Chunping Liu.;Lei Li.
来源: Sci Adv. 2025年11卷19期eadr3173页
Dysregulation of deubiquitination is essential for cancer growth. However, the role of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain- and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis of TNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m6A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy for TNBC.
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