Considering the different behaviour of cells in response to diseases in different conditions and sex hormone-dependent cancers, we addressed the possible effect of the sex of the source of these cells from adipose tissue on prostate cancer cells. In this in vitro study, we evaluated the effects of male and female MSC Conditioned Media (MCM, FCM) on prostate cancer cells. The assessment included Hoechst dye staining, a scratch-wound assay, a colony formation assay, and a flow cytometric analysis of apoptosis and the cell cycle. We also performed real-time PCR to examine various genes, including apoptosis-related genes, epithelial-mesenchymal transition (EMT) genes, angiogenesis-related genes, and cell growth and survival biomarkers. Our results indicated that the IC50 values were 50% and 75% media in MCM and FCM in each of the three prostate cancer cell lines, respectively. An evaluation of gene expression revealed that in all three prostate cancer cell lines, treatment with MCM was more effective than FCM in reducing the expression of N-Cadherin and Vimentin, EGFR and BCL2 genes (p < 0.001). Furthermore, the MCM significantly increased the expression of BAX and E-Cadherin genes (p < 0.001) in the PC3 cell line. MCM proved to be more effective than FCM in reducing the expression of the epithelial-mesenchymal transition pathway, EGFR gene, and Apoptosis Regulator (BCL2) in the PC3 cell line. Due to its potential in regenerative medicine and cell therapy, this approach may serve as an effective treatment option for advanced prostate cancer.

The effects of hyaluronan (HA) in cancer are widely studied; however, the role of different molecular weight HA is poorly understood. Identifying novel proteins regulated by different molecular weight HA may highlight novel therapeutic targets. Proteomics analysis was performed to identify novel proteins regulated by different molecular weight HA (27, 183 and 1000 kDa) in ES-2 ovarian cancer cells over-expressing Notch3 intra-cellular domain. Our analyses identified sphingosine kinase 1 (SPHK1), a novel protein regulated by 183- and 1000-kDa HA. Utilising online databases and high-grade serous ovarian cancer (HGSOC) patient tissue microarray cohorts, we assessed the relationship between SPHK1 expression and ovarian cancer metastasis, recurrence and patient outcome. We assessed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on SPHK1 expression in ovarian cancer cells and HGSOC patient tissues using ex vivo tissue explant assays. SPHK1 was significantly increased in ovarian cancer compared to normal tissues, elevated in metastatic and recurrent HGSOC tissues and associated with poor patient outcome. 4-MU significantly inhibited SPHK1 expression in ovarian cancer cells (ES-2, CaOV3 and A2780) and HGSOC patient tissues. This study highlights a link between HA and SPHK1 expression in ovarian cancer. Our findings confirm an adverse effect on ovarian cancer prognosis. SPHK1 constitutes a novel promising target against ovarian cancer that warrants further investigation.

An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced 64Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using 64Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.

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.

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.

Per-and polyfluoroalkyl substances (PFAS) are a pervasive family of synthetic compounds with a wide range of reported health effects. Epigenetic clocks, DNA methylation-based predictors of chronological and biological age, are promising biomarkers for characterizing biological aging in humans. The potential impact of PFAS exposure on epigenetic aging in the general US population remains unclear. In the 1999-2000 National Health and Nutrition Examination Survey (NHANES) cycle (N = 262), eleven PFASs were measured in serum and DNA methylation was measured in blood with the EPICv1 array. Seven epigenetic clocks and their respective epigenetic age acceleration (EAA) measures were calculated. Survey-design weighted generalized linear regression models were used to test adjusted associations between individual log2-transformed PFAS concentrations and EAA stratified by sex. Among male participants, doubling of PFNA concentrations was associated with greater EAA across several clocks including the Horvath clock (beta = 1.48, 95 % CI: 0.35, 2.61), Skin&Blood clock (beta = 1.27, 95 % CI: 0.21, 2.32), and PhenoAge (beta = 1.43, 95 % CI: 0.41, 2.44), and doubling of PFOS exposure was associated with greater Skin&Blood EAA (beta = 1.14, 95 % CI: 0.04, 2.24). When considering cell-adjusted EAA measures, each of these associations among male participants remained significant, and PFOSA was associated with decreased PhenoAge EAA (beta = -0.84, 95 % CI: -1.49, -0.18) and GrimAge2 EAA (beta = -0.81, 95 % CI: -1.51, -0.11) among female participants. In summary, we found evidence of sex-specific associations between PFAS exposure and epigenetic aging in a sample of older adults representative of the general US population.

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.

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.

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.

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.

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.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with limited treatment options and high relapse rates due to chemoresistance and the presence of cancer stem cells (CSCs). This study explores the molecular profile and invasive properties of two TNBC cell lines, MDA-MB-231 (Basal-Like 1; BL1 subtype) and HCC1806 (BL2 subtype), as well as their chemotherapy-resistant derivatives (doxorubicin and paclitaxel). Both cell lines exhibited CD44+ and CD24-/low profiles with significant differences in epithelial-mesenchymal transition (EMT) markers. Chemoresistant variants exhibited significant changes in CSC markers, EMT genes, and ALDH activity, particularly the upregulation of CD133, suggesting its role in chemoresistance. Analysis of embryonic pathways revealed a prominent role of Sonic Hedgehog signaling, particularly in the BL2 subtype. Resistant models also exhibited increased Notch receptor expression. This study also examined novel polyamine compounds with an amino-pyridine structure. These compounds showed significant cytotoxicity against both sensitive and resistant TNBC cells, enhancing the efficacy of standard chemotherapeutics (paclitaxel and doxorubicin). Additionally, they reduced stem-like properties and self-renewal capacity of CSCs. This comprehensive characterization of TNBC cell lines and their chemoresistant variants underscores the molecular heterogeneity of TNBC and highlights potential therapeutic targets and strategies to enhance treatment efficacy and overcome resistance.

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.

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.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis being one of the primary characteristics. Elemene, a natural product derived from Curcuma wenyujin, has been approved for treating advanced and metastasis HCC patients. However, the molecular mechanism of elemene in HCC is still unclear.

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).

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.

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.

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.

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.