Background: Non-small-cell lung cancer remains the leading cause of cancer-related deaths globally, and epidermal growth factor receptor mutations have been identified as crucial drivers of the disease. Encouragingly, epidermal growth factor receptor tyrosine kinase inhibitors have demonstrated promising clinical outcomes. Nonetheless, the emergence of resistance to third-generation EGFR-TKIs like osimertinib and almonertinib is an inevitable challenge. Methods: In this study, we generated almonertinib-resistant cell lines from H-1975 and HCC827 lung cancer cell lines. We utilized various assays, including cell proliferation assays, hematoxylin and eosin staining, and cell cycle assays, to investigate the characteristics of drug-resistant cells. Additionally, we performed RNA transcriptome sequencing to identify differentially expressed genes (DEGs) in almonertinib-resistant cells. To further expand our analysis, we obtained sequencing data of osimertinib-resistant cells from the Gene Expression Omnibus (GEO) dataset and identified DEGs in these cells. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to assess the biological functions and signaling mechanisms associated with DEGs. Furthermore, the survival prognosis and immune cell infiltration of common differentially expressed genes (co-DEGs) in osimertinib-and almonertinib-resistant cells were analyzed, and the expression of a co-DEG (IGFBP7) was verified through quantitative reverse transcriptase polymerase chain reaction (qPCR) and western blotting (WB) assays. Gene knockdown plasmids were constructed for cell transfection, and the invasive ability of resistant cells was assessed using a Transwell assay following the knockdown of IGFBP7. Results: Experimental cell counting kit-8 cytotoxicity studies revealed intriguing findings regarding drug resistance in lung cancer cells. Specifically, the IC50 values and resistance factors of H-1975 and HCC827 cells were found to be 1.9 nM and 833.58 and 2.2 nM and 631.95, respectively. In addition to these quantitative results, comparative observations of the cell morphology and cell cycle revealed significant alterations in drug-resistant cells. Transcriptome sequencing analysis identified 220 DEGs between H-1975 and H-1975/AR and 736 DEGs between HCC827 and HCC827/AR. Interestingly, screening of overlapping DEGs with osimertinib-resistant cells in the GEO database identified some common genes, such as IGFBP7 and RFTN1, which were found to be associated with the improved prognosis of non-small-cell lung cancer by survival analysis. Furthermore, GO analysis and KEGG pathway enrichment analysis revealed different pathway changes in different drug-resistant cells. Survival analysis indicated that a higher expression of co-DEGs (IGFBP7, RFTN1) was associated with a more favorable prognosis. Furthermore, IGFBP7 expression is strongly associated with infiltration levels of CD8+ T cells, Tregs, and macrophage cells in lung adenocarcinoma. Molecular biology experiments confirmed that the mRNA and protein expression level of IGFBP7 were over-expressed in almonertinib-resistance cells. H-1975/AR cells were transfected with si-IGFBP7, and the results of transfection were verified at the mRNA and protein levels. After knocking down gene expression, the IC50 of the cells was 0.3 ± 0.02 µM, which was significantly lower than that of untransfected cells. Additionally, the invasion of cells in the knockdown group was repressed. Conclusions: These findings indicated that almonertinib and osimertinib exhibited distinct resistance mechanisms in vitro, underscoring the need for tailored treatment approaches.

Autoimmune diseases are characterized by irregular immune responses that disrupt self-tolerance. This research explores the effects of the immunomodulatory drug celecoxib on the expression of immune checkpoint receptors in monocyte-derived dendritic cells (DCs). Key receptors, including CTLA-4, VISTA, BTLA, PDL-1, B7H7, and LAG3, play critical roles in initiating and regulating immune responses and maintaining self-tolerance. Previous studies have highlighted the significance of immune checkpoints in preventing autoimmune conditions, with animal research supporting their effectiveness in immunotherapy. Our findings demonstrate that the upregulation of immune checkpoint receptors can enhance the inhibitory functions of DCs, thereby promoting self-tolerance. As a result, tolerogenic DCs present a promising therapeutic avenue for treating autoimmune diseases. Although these results are promising, further trials are required to validate this approach before it can be applied clinically. This study underscores the potential of targeting immune checkpoint receptors as a therapeutic strategy for autoimmune disorders.

Contaminated environments can pose new challenges when new contaminants appear and can select organisms with new genetic and metabolic strategies. The increased presence of Te(IV) in the environment is becoming more important. This highlights how underexplored the investigation of how bacteria molecularly respond to less common environmental contaminants, such as tellurite when compared to other metals/ metalloids. Understanding what tools an organism uses from its genetic pool when responding to a new contaminant requires a multiple-technique approach, such as metabolic tests and differential omics analysis. These analyses provide a full metabolic and phenotypical map of stress response that can include new resistance mechanisms, whether specific or not. This study aimed to determine if Bacillus altitudinis strain 3W19, isolated from a Te(IV) contaminated site, presents specific changes at the proteomic level when exposed to the metalloid. In strain 3W19, growth in the presence of Te(IV) upregulated pathways of amino acid metabolism and membrane transport and downregulated pathways of carbohydrate metabolism. Growth in the presence of Te(IV) also induced the formation of reactive oxygen species and lowered the metabolic activity of the strain. This metal led to the overexpression of the proteins of the ter gene cluster. When compared with other strains, the ter system identified in this strain differed in genomic organization from related Bacillus sp. strains. Together, these strain-specificities can contribute to understanding its Te(IV) resistance phenotype.

MSL1, a scaffold protein of the MSL histone acetyltransferase complex, is crucial for its structural integrity and enzymatic activity. While MSL1 is highly expressed in various tumors, its role in tumor progression and cell death remains unclear. Here, we provide evidence of a negative regulatory relationship between MSL1 and KCTD12 through biochemical assays and knockdown/overexpression studies. Notably, in colon cancer cells, the ferroptosis inducer Erastin significantly suppressed MSL1 expression, leading to KCTD12 upregulation. Moreover, MSL1 promotes Erastin-induced ferroptosis in HCT116 and SW480 cells via the KCTD12-SLC7A11 axis. Consistently, Erastin-induced changes in ROS, GSH, and MDA levels were regulated by this axis, highlighting its role in ferroptosis. These findings offer potential therapeutic targets and a theoretical foundation for colon cancer treatment.

In humans, vitamin D3 synthesis follows a day-night rhythm due to its UV-B-dependent production.

Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive.

Non-small cell lung cancer (NSCLC) is a major cause of cancer-related mortality worldwide. Understanding molecular mechanisms and identifying potential therapeutic targets are crucial for improving treatment outcomes. This study aims to explore the effect of luteolin on NSCLC progression by regulating WDR72 and to investigate the related molecular mechanisms using cellular and animal models. The study employed a comprehensive set of experiments to evaluate the impact of luteolin and WDR72 on NSCLC cell proliferation and metastasis. Techniques included the CCK- 8 assay, colony formation assay, scratch test, and Transwell assay. Molecular docking experiments were performed to validate the binding interaction between luteolin and WDR72. Experimental groups included OE-WDR72, OE-WDR72 + Luteolin, Control, Control + Luteolin, and sh-WDR72. Western blot analysis was used to examine protein expression related to apoptosis, epithelial-mesenchymal transition (EMT), AKT signaling, and other markers. Additionally, a nude mouse subcutaneous tumor model was established to assess the in vivo tumor-forming ability of NSCLC cells under different treatments. Luteolin significantly inhibited the proliferation, invasion, and migration of NSCLC cell lines (H1299 and A549) and reduced tumor formation in nude mice. Molecular docking demonstrated strong binding affinity between luteolin and WDR72. Overexpression of WDR72 promoted NSCLC cell proliferation and migration, while WDR72 silencing showed the opposite effects. Western blot analysis revealed that WDR72 overexpression increased phosphorylated AKT and Bcl- 2 levels while decreasing caspase- 3. In contrast, silencing WDR72 reduced these protein levels. Luteolin treatment in WDR72-overexpressing cells resulted in decreased phosphorylated AKT, increased apoptosis, and suppressed EMT. Tumor transplantation experiments indicated that tumors in the OE-WDR72 group exhibited the fastest growth, while the sh-WDR72 group showed the slowest growth. Luteolin treatment significantly reduced WDR72 expression, suggesting a regulatory role in NSCLC progression. Luteolin effectively inhibits EMT, invasion, and migration of NSCLC cells by modulating WDR72. WDR72 plays a pivotal role in stimulating the proliferation and metastasis of NSCLC cells. By downregulating WDR72, luteolin suppresses NSCLC progression, potentially through modulation of the PI3 K/AKT/EMT signaling pathway. These findings highlight luteolin as a promising therapeutic agent for NSCLC treatment.

The mechanism by which chondrocytes respond to mechanical stress in joints significantly affects the balance and function of cartilage. This study aims to characterize osteoarthritis-associated chondrocyte subpopulations and key gene targets for regulatory drugs. To begin, single-cell and transcriptome datasets were obtained from the Gene Expression Omnibus (GEO) database. Cell communication and pseudo-temporal analysis, as well as High-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA), were conducted on the single-cell data to identify key chondrocyte subtypes and module genes. Subsequently, Consensus Cluster Plus analysis was utilized to identify distinct disease subgroups within the osteoarthritis (OA) training dataset based on the key module genes. Furthermore, differential gene expression analysis and GO/KEGG pathway enrichment analysis were performed on the identified subgroups. To screen for hub genes associated with OA, a combination of 10 machine learning algorithms and 113 algorithm compositions was integrated. Additionally, the immune and pathway scores of the training dataset samples were evaluated using the ESTIMATE, MCP-counter, and ssGSEA algorithms to establish the relationship between the hub genes and immune and pathways. Following this, a network depicting the interaction between the hub genes and transcription factors was constructed based on the Network Analyst database. Moreover, the hub genes were subjected to drug prediction and molecular docking using the RNAactDrug database and AutoDockTools. Finally, real-time fluorescence quantitative PCR (RT-qPCR) was employed to detect the expression of hub genes in the plasma samples collected from osteoarthritis patients and healthy adults. In the OA sample, there is a significant increase in the proportion of prehypertrophic chondrocytes (preHTC), particularly in subgroups 6, 7, and 9. We defined these subgroups as OA_PreHTC subgroups. The OA_PreHTC subgroup exhibits a higher communication intensity with proliferative-related pathways such as ANGPTL and TGF-β. Furthermore, two OA disease subgroups were identified in the training set samples. This led to the identification of 411 differentially expressed genes (DEGs) related to osteoarthritis, 2485 DEGs among subgroups, as well as 238 intersecting genes and 5 hub genes (MMP13, FAM26F, CHI3L1, TAC1, and CKS2). RT-qPCR results indicate significant differences in the expression levels of five hub genes and their related TFs in the clinical blood samples of OA patients compared to the healthy control group (NC). Moreover, these five hub genes are positively associated with inflammatory pathways such as TNF-α, JAK-STAT3, and inflammatory response, while being negatively associated with proliferation pathways like WNT and KRAS. Additionally, the five hub genes are positively associated with neutrophils, activated CD4 T cell, gamma delta T cell, and regulatory T cell, while being negatively associated with CD56dim natural killer cell and Type 17T helper cell. Molecular docking results reveal that CAY10603, Tenulin, T0901317, and Nonactin exhibit high binding activity to CHI3L1, suggesting their potential as therapeutic drugs for OA. The OA_PreHTC subgroups plays a crucial role in the occurrence and development of osteoarthritis (OA). Five hub genes may exert their effects on OA through interactions with PreHTC cells, other chondrocytes, and immune cells, playing a role in inhibiting cell proliferation and stimulating inflammation, thus having high diagnostic value for OA. Additionally, CAY10603, Tenulin, T0901317, and Nonactin have potential therapeutic effects for OA patients.

Cell division cycle 25 (CDC25) phosphatases serve as crucial regulators of cell cycle phase transitions and essential components of the checkpoint machinery involved in DNA damage response. Emerging evidence indicates the oncogenic potential of CDC25 family members across various cancers. However, comprehensive insights into the expression pattern and function of the CDC25 family in diverse cancers remain unexplored. In our study, we investigated CDC25 family using multiple databases, including gene expression levels, molecular signatures, diagnosis value, and prognostic value in pan-cancer. Furthermore, we focused on melanoma and systematically explored CDC25A expression and its clinical correlations. As a result, the expression of CDC25 family members is significantly abnormal in most cancers, correlating with poorer prognosis. CDC25 family members are differently regulated by DNA methylation and genetic alterations across various cancers. In addition, CDC25 family plays a critical role in the malignant progression of melanoma. Functional investigation reveals that CDC25A inhibition suppresses the proliferation of melanoma cells and sensitizes melanoma cells to chemotherapy and NK cell therapy. In conclusion, our study suggests that CDC25 family may serve as a significant biomarker for diagnosis and prognosis across multiple cancers, with CDC25A as a promising therapeutic target for melanoma.

TACE (Transarterial Chemoembolization) is an essential current treatment for liver cancer. Resistance to doxorubicin, the chemotherapeutic component of TACE, poses a serious problem in this treatment, necessitating a deeper understanding of the underlying resistance mechanisms. Upregulation of the Forkhead box A1 transcription regulator in our model of doxorubicin-resistant liver cancer cell line suggested a role in resistance. To better understand the role of FOXA1 in resistance to doxorubicin, we inhibited its expression using siRNA or its miRNA-212-3p inhibitor then studied the effect on the cancer cell lines survival using SRB assay. The expression of several downstream epithelial-mesenchymal transition genes, namely SLUG, TWIST, CDH1 (E-Cadherin), was determined using quantitative real-time PCR. Our results showed a significant upregulation of FOXA1 and downregulation of miRNA-212-3p in doxorubicin-resistant cells. Manipulation of FOXA1 and miRNA-212-3p expressions restored sensitive cell characteristics. In addition, inhibition of FOXA1 increased apoptosis induction in resistant cells. Changes detected in the tested EMT genes point to progression toward more aggressive behavior in the doxorubicin-resistant liver cancer cell line that was reversed with inhibition of FOXA1. Our results suggest a possible role of FOXA1 and miRNA-212-3p in the development of resistance to chemotherapeutic drugs in liver cancer and the possibility of their use as prognostic and/or therapeutic targets.

WRKY transcription factors are important regulators of plant responses to environmental stresses and hormone signaling. This study analyzes the WRKY gene family in Solanum tuberosum by examining the phylogenetic relationships, expression profiles, and their roles in abiotic stress and hormone responses. Phylogenetic tree was constructed using 322 WRKY genes from four Solanum species: S. tuberosum, S. pennellii, S. pimpinellifolium, and S. lycopersicum. The results revealed conserved and expanded WRKY genes across these species. We then studied the expression of 75 SotuWRKY genes in response to salt, drought, heat stresses, and hormone treatments (IAA, ABA, BABA, GA3, and BAP). Results showed that 19, 25, and 29 genes were regulated under salt, drought, and heat stresses, respectively. Several WRKY genes (e.g. SotuWRKY03 and SotuWRKY24) were also regulated by biotic stresses like Phytophthora infestans infection and hormone treatments, indicating their involvement in plant defense mechanisms. A gene co-expression network was constructed based on gene-to-gene correlations, where SotuWRKY52 was identified as a hub gene, positively regulating six WRKY genes and negatively regulating four. These findings suggest that potato WRKY genes play key roles in regulating stress responses and hormone signaling, potentially enhancing potato resistance to stresses and diseases. This study provides new insights into WRKY transcription factors in S. tuberosum and other Solanum species.

Preeclampsia (PE) is a critical complication of pregnancy that affects 3% to 5% of all pregnancies and has been linked to aberrant placentation, causing severe maternal and fetal illness and death.

Valproic acid (VPA) is an antiepileptic and mood-stabilizing drug with well-established teratogenic risks when taken during pregnancy. While its harmful effects on fetal development are well known, less attention has been given to its impact on placental development and function, despite the placenta's critical role in pregnancy.

Embryonic cancer stem cells (CSCs), referred to as self‑renewable cells, are commonly found in liquid and solid cancers and can also be attributed to tumor onset, resistance, expansion, recurrence and metastasis following treatment. Cancer therapy targeting CSCs using natural bioactive products is an optimal option for inhibiting cancer recurrence, thereby improving prognosis. Several natural compounds and extracts have been used to identify direct or indirect therapy effects that reduce the pathological activities of CSCs. Natural gallic acid (GA) is noted to have anticancer properties for oncogene expression, cycle arrest, apoptosis, angiogenesis, migration and metastasis in various cancers. The present study demonstrated that GA has various anticancer activities in NTERA‑2 and NCCIT human embryonic carcinoma cells. In two types of embryonic CSCs, GA effectively induced cell death via late apoptosis. Furthermore, GA showed the G0/G1 cell cycle arrest activity in embryonic CSCs by inducing the increase of p21, p27 and p53 expression and the decrease of CDK4, cyclin E and cyclin D1 expression. The present study showed that GA inhibited the expression levels of mRNA and protein for stem cell markers, such as SOX2, NANOG and OCT4, in NTERA‑2 and NCCIT cells. The induction of cellular and mitochondrial reactive oxygen species by GA also activated the cellular DNA damage response pathway by raising the phosphorylated‑BRCA1, ATM, Chk1, Chk2 and histone. Finally, GA inhibited CSCs invasion and migration by inhibiting the expression of matrix metalloproteinase by the downregulation of EGFR/JAK2/STAT5 signaling pathway. Thus, it is hypothesized that GA could be a potential inhibitor of cancer emergence by suppressing CSC properties.

Immunotherapy targeting the programmed death-ligand 1 (PD-L1) pathway is a standard treatment for advanced hepatocellular carcinoma (HCC). The Wnt signaling pathway, often upregulated in HCC, contributes to an immunosuppressive tumor microenvironment. This study investigated the impact of Wnt pathway inhibition on PD-L1 expression in HCC and evaluated the potential therapeutic benefit of combining Wnt pathway inhibition with PD-L1 blockade.

Leukemia-secreted extracellular vesicles (EVs) carry biologically active cargo that promotes cancer-supportive mechanisms, including aberrant proliferative signaling, immune escape, and drug resistance. However, how antineoplastic drugs affect EV secretion and cargo sorting remains underexplored.

Elevated plasma homocysteine (Hcy) levels lead to hyperhomocysteinemia, a condition associated with various neurological disorders affecting multiple brain regions, including the hippocampus. In this study, we investigated the effects of exposing cultured rat hippocampal neurons to Hcy concentrations corresponding to mild, moderate, and severe hyperhomocysteinemia. A short 24-hour exposure had minimal effects, whereas prolonged exposure up to 14 days moderately enhanced hippocampal excitability without altering the gene expression of voltage-dependent calcium, sodium, or potassium channels or intracellular calcium levels. These findings suggest that Hcy-induced changes in neuronal excitability may contribute to neuropathologies associated with hyperhomocysteinemia.

Despite exhaustive research efforts, integrated genetic and epigenetic mechanisms contributing to tobacco-induced initiation and progression of lung cancers have yet to be fully elucidated. In particular, limited information is available regarding dysregulation of noncoding RNAs during pulmonary carcinogenesis.

The mammalian circadian timing system is organized in a hierarchy, with the master clock residing in the suprachiasmatic nucleus (SCN) of the hypothalamus and subsidiary peripheral clocks in peripheral tissues. Because of the diversity of peripheral tissues and cell-types in the body, the existence of autonomous clock and identification of its potential entrainment signals need to be empirically defined on a cell type-by-cell type basis. In this study, we characterized the basic circadian clock properties of the adrenal zona glomerulosa cells, or ZG cells. Using isolated adrenal explants from Per2Luc mice, dissociated ZG cells from Per2-dluc rats, and a related human adrenocortical cell line H295R, we showed that ZG cells possess genetically-encoded, self-sustained and cell-autonomous circadian clock. As to the potential entrainment signals, angiotensin II (Ang II) caused phase-dependent phase-shifts of adrenal ZG cells in cultured slices. Ang II treatment also drove initiation (or reset) of circadian clock gene expression in H295R cells with associated immediate up-regulation of PER1 and E4BP4 mRNA expression. We found that the type I Ang II receptor blocker CV11974, one of the most widely used clinical drugs for hypertensive diseases, caused attenuation of the phase resetting of H295R cells. Our in vitro data provide a basis to understand and argue for the adrenal gland ZG cells as a component of autonomous and entrainable peripheral clocks.

Enterotoxigenic Escherichia coli (ETEC) is responsible for piglet diarrhea and causes substantial economic loss in the pig industry. Along with the restriction of antibiotics, natural compounds targeting bacterial virulence factors are supposed to be efficacious and attractive alternatives for controlling ETEC infection. This study aimed to investigate the influence of dihydromyricetin (DMY), a natural flavonoid compound, on the expression of virulence factors of ETEC and intestinal inflammatory injury.