Plant responses to biotic and abiotic stresses are complex processes. Previous studies have shown that the LBD gene family plays important roles in plant growth and development as well as in plant defense against biotic and abiotic stresses. The expression of LBD genes was investigated in walnuts under biotic and abiotic stresses, revealing that LBD38-1 may be a key gene in the plant stress response. This study provides new insights into the roles of LBD genes in plant responses to biotic stress.

High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF-ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.

Tert-butyl phenolic antioxidants (TBP-AOs) are utilized in a variety of consumer products, including food packaging, daily use items, and industrial applications. Their widespread use raises significant concerns regarding potential health risks, particularly endocrine disruption. However, our understanding of many TBP-AOs concerning endocrine systems remains limited, underscoring the need for screening of their hormonal activities and better insight into their adverse outcome pathways (AOPs). Transcriptional activation (TA) assays are crucial experimental tools in the early stages of risk assessment. This study evaluated the estrogenic and androgenic characteristics of 30 TBP-AOs through TA assays in hERα-HeLa-9903 and 22Rv1/MMTV_GR-KO cell lines, respectively, augmented by docking simulation using CB-Dock2. Our findings identified 21 estrogen receptor (ER) agonists, one ER antagonist, and eight androgen receptor (AR) antagonists, with significant correlations between biological activity and docking scores for specific proteins: 1GWR_C4 and 7KBS_C2 for ERα, and 2AM9_C1 for AR. These results enhance our understanding of TBP-AOs' toxicity on the endocrine system and confirm that TA assays and docking are effective methods for evaluating their endocrine activities. This research lays the foundation for future studies on endocrine disruptors, aiming to elucidate the mechanisms underlying molecular initiating events and key events within AOPs for TBP-AOs and other chemicals.

The results of protein thiols reacting with oxidants may be different in the presence or absence of glutathione (GSH). Upon exposure to oxidants, such as Cu2+ and polysulfide, the multiple drug resistant regulator MarR dimer in Escherichia coli is believed to form tetramers linked by disulfide bonds between its Cys80 thiols. We confirmed this observation in the absence of GSH; however, the MarR-Cys80 thiol was primarily glutathionylated in the presence of GSH after MarR was treated with various oxidants, including octasulfur (S8), Cu2+, H2O2, ClO-, and a NO donor. When using S8 as the oxidizing agent, we identified four pathways to induce MarR-Cys80 glutathionylation. Since E. coli contains high concentrations of GSH, MarR is likely glutathionylated instead of forming tetramers inside the cells. When E. coli was exposed to S8, cellular levels of protein glutathionylation were increased and most MarR was glutathionylated, as shown by Western blot and LC-MS analyses. The glutathionylated MarR displayed reduced affinity to its cognate operator, resulting in the expression of its repressed genes. The results highlight the need to consider the wide presence of GSH when investigating protein thiol modification.

Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but its significance in hepatocellular cancer (HCC) has not been reported.

Pancreatic cancer (PC) is one of the most tremendously malignant cancers with a poor prognosis, especially when it advances to metastasis. Besides, PC patients have encountered resistance to recent therapeutic approaches. In recent work, we effectively determined ANKRD22 by re-analyzing RNA-seq datasets from cell lines and human tissues deriving from PC. We demonstrated that ANKRD22 expression was remarkably high in the PC group compared to the normal group at both gene expression and protein levels. ANKRD22 resulted in a worse overall survival (OS) rate of PC patients (HR = 1.7, p = 0.0082). Intriguingly, ANKRD22 was statistically highly expressed in the mutated KRAS group relative to the wildtype group (p < 0.05). Similarly, compared to the wildtype TP53, in the mutated TP53, ANKRD22 also significantly expressed (p < 0.05); their concurrent expression, ANKRD22 and KRAS; ANKRD22 and TP53 exacerbated the survival outcome relative to the co-expression of low ANKRD22 and unaltered genes (p < 0.001; HR > 2.6). We explored the potential pathways and biological processes ANKRD22 might not only contribute to promoting PC, including cell-cycle regulation, E2F1 targets, and apoptosis but also foster the dissemination of PC by involve in invasion and migration processes. In the investigation of drugs that might target ANKRD22, we figured out fostamatinib. Molecular docking and molecular dynamic simulation (MDs) techniques provided extensive insights into the binding mode of ANKRD22 and fostamatinib. ANKRD22 exhibited strong binding affinity (ΔG = -7.0 kcal/mol in molecular docking and ∆Gbind = -38.66 ± 6.09 kcal/mol in MDs). Taken together, ANKRD22 could be a promising theragnostic target that might be inhibited by fostamatinib, thereby suppressing PC growth.

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.

In non-small cell lung cancer (NSCLC), miR-200a plays a significant role in apoptosis. One of the genes involved in this pathway is XIAP, which has been shown anti-apoptotic activity. Research has indicated a significant association between miR-200a and the XIAP gene in this pathway. The present study investigated the expression profiles of miR-200a and the XIAP gene in NSCLC patients compared to normal individuals, as well as cancer cells compared to normal and apoptosis-inducing conditions.

Ovarian cancer (OC) remains the leading cause of mortality among gynecological cancers, mainly because of resistance to platinum-based chemotherapy, particularly cisplatin. This study investigated the potential of quercetin (QU)-loaded solid lipid nanoparticles (SLNs) to address cisplatin resistance in OC cells.

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.

Osteoarthritis (OA) is a widespread, debilitating joint disease associated with articular cartilage degradation. It is driven via mechano-inflammatory pathways, whereby catabolic genes in the cartilage-embedded chondrocytes are presumed up-regulated due to increased shear stress arising from friction at the cartilage surface as joints articulate. The enhanced expression of these cartilage-degrading and inflammatory genes leads to tissue degeneration. However, the nature of the stress, and how the cells within the joint respond to it, are poorly understood. Here we show, in a proof of concept study on a mouse model where surgical joint destabilisation has been carried out to induce OA, that the early up-regulation of the matrix metalloproteinase 3 (Mmp3) gene, a member of the matrix-degrading MMP family, and of the interleukin-1 beta (Il1b) gene, a key mediator of inflammatory response, are significantly suppressed when lipid-based lubricants are injected into the joints. We attribute this to the reduction in frictional stress on the chondrocytes due to the lubricant at the cartilage surface. At the same time, Timp1, a compression but not shear-stress sensitive gene, is unaffected by lubricant. Our results demonstrate that cartilage lubrication modulates catabolic gene regulation in OA, shed strong light on the nature of the chondrocytes' response to shear stress, and have clear implications for novel OA treatments. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a widespread, debilitating joint disease associated with degradation of the articular cartilage, the tissue that covers and protects the joint surfaces as they rotate. Such degradation is due to catabolic enzymes expressed by cartilage-embedded chondrocytes (the only cell type in cartilage) in response to mechanical stress. In this proof-of-concept study in a mouse OA model, we show that reduction of cartilage friction by liposome-based lubricants suppresses the production of the catabolic, OA-related genes in chondrocytes. Our findings provide direct evidence in an animal model that catabolic genes are induced in chondrocytes in a mechanosensitive manner, related to the friction at the cartilage surface, and identify putative novel OA treatments through efficient cartilage lubrication.

Drug-resistant influenza demands novel antiviral treatments. Non-structural protein 1 (NS1) of influenza A virus (IAV) regulates the viral life cycle and host immune response, thus becoming a promising therapeutic target. The atractylenolide (ACT) -Ⅲ exhibits notable anti-IAV efficacy; however, its in vivo anti-IAV activity and the underlying mechanisms need further exploration.

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.