Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

BACKGROUND: Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. OBJECTIVE: The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. PATIENTS AND METHODS: We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. RESULTS: We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. CONCLUSION: The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

Roles of TRPM7 in ovarian cancer.

Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.

eIF3a sustains non-small cell lung cancer stem cell-like properties by promoting YY1-mediated transcriptional activation of ß-catenin.

Cancer stem cells (CSCs) are the leading cause of recurrence and poor prognosis in non-small cell lung cancer (NSCLC). Eukaryotic translation initiation factor 3a (eIF3a) participates in many tumor development processes, such as metastasis, therapy resistance, and glycolysis, all of which are closely associated with the presence of CSCs. However, whether eIF3a maintains NSCLC-CSC-like properties remains to be elucidated. In this study, eIF3a was highly expressed in lung cancer tissues and was linked to poor prognosis. eIF3a was also highly expressed in CSC-enriched spheres compared with adherent monolayer cells. Moreover, eIF3a is required for NSCLC stem cell-like traits maintenance in vitro and in vivo. Mechanistically, eIF3a activates the Wnt/ß-catenin signaling pathway, promoting the transcription of cancer stem cell markers. Specifically, eIF3a promotes the transcriptional activation of ß-catenin and mediates its nuclear accumulation to form a complex with T cell factor 4 (TCF4). However, eIF3a has no significant effect on protein stability and translation. Proteomics analysis revealed that the candidate transcription factor, Yin Yang 1 (YY1), mediates the activated effect of eIF3a on ß-catenin. Overall, the findings of this study implied that eIF3a contributes to the maintenance of NSCLC stem cell-like characteristics through the Wnt/ß-catenin pathway. eIF3a is a potential target for the treatment and prognosis of NSCLC.

CircRNAs in tumor immunity and immunotherapy: Perspectives from innate and adaptive immunity.

Tumor immunotherapy is a new therapeutic approach that has been evolving in the last decade and has dramatically changed the treatment options for cancer. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) with high stability, tissue-specific and cell-specific expression. There is growing evidence that circRNAs are involved in the regulation of both adaptive and innate immunity. They play important roles in tumor immunotherapy by affecting macrophage, NK and T cell function. The high stability and tissue specificity make them ideal candidate biomarkers for therapeutic effects. CircRNAs also represent one of promising targets or adjuvant for immunotherapy. Investigations in this field progress rapidly and provide essential support for the diagnosis, prognosis and treatment guidance of cancers in the future. In this review, we summarize the role of circRNAs on tumor immunity from the viewpoint of innate and adaptive immunity, and explore the role of circRNAs in tumor immunotherapy.

Association of variations in the CAT and prognosis in lung cancer patients with platinum-based chemotherapy.

PURPOSE: To explore the relationship between ATM, ATR and CAT polymorphisms and prognosis of lung cancer patients received platinum-based chemotherapy. METHODS: 404 patients with lung cancer who received platinum-chemotherapy were enrolled and DNA typing was performed. Cox regression analysis and stratification analyses was performed to assess relationships between OS and PFS with SNPs genotypes. The prognosis of lung adenocarcinomaand squamous cell carcinomapatients was analyzed with The Cancer Genome Atlas (TCGA) database according to the grouping of CAT expression. RESULTS: CAT rs769217 was significantly related to PFS of patients with lung cancer who received platinum-chemotherapy. In the Additive model, rs769217 was associated with PFS (HR = 0.747, 95% CI = 0.581-0.960, p = 0.023). In the Dominant model, CT and TT genotypes led to lung cancer progression 0.738 times more than CC genotype. In stratification analyses of association between CAT rs769217 polymorphisms and PFS, the HR of patients at stage IV in additive model was 0.73, and HR was 0.745 (p = 0.034) in dominant model. For OS analyses, HR was 0.672 in the older lung cancer patients (>55 years old) in additive model. Meanwhile, in the Dominant model, it was found that the older patients with CT and TT genotypes had better prognosis, and the risk of death after receiving platinum-based chemotherapy was 0.692 times that of patients with CC genotype (p = 0.037). TCGA data shows that LUAD patients with high CAT expression have longer OS (p = 0.020). CONCLUSION: CAT rs769217 is significantly related to PSF of platinum-based chemotherapy in lung cancer patients and may be a biomarker for predicting the prognosis of lung cancer patients with platinum-based chemotherapy.

Effects of Glycolysis-Related Genes on Prognosis and the Tumor Microenvironment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common and deadly malignancy worldwide. Current treatment methods for hepatocellular carcinoma have many disadvantages; thus, it is urgent to improve the efficacy of these therapies. Glycolysis is critical in the occurrence and development of tumors. However, survival and prognosis biomarkers related to glycolysis in HCC patients remain to be fully identified. Methods: Glycolysis-related genes (GRGs) were downloaded from "The Molecular Signatures Database" (MSigDB), and the mRNA expression profiles and clinical information of HCC patients were obtained from TCGA. Consensus clustering was performed to classify the HCC patients into two subgroups. We used the least absolute shrinkage and selection operator (LASSO) regression analysis to construct the risk signature model. Kaplan-Meier (K-M) survival analysis was performed to evaluate the prognostic significance of the risk model, and the receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy. The independent prediction ability of the risk model was validated by univariate and multivariate Cox regression analyses. The differences of immune infiltrates and relevant oncogenic signaling between different risk groups were compared. Finally, biological experiments were performed to explore the functions of screened genes. Results: HCC patients were classified into two subgroups, according to the expression of prognostic-related GRGs. Almost all GRGs categorized in cluster 2 showed upregulated expressions, whereas GRGs in cluster 1 conferred survival advantages. GSEA identified a positive correlation between cluster 2 and the glycolysis process. Ten genes were selected for risk signature construction. Patients were assigned to high-risk and low-risk groups based on the median risk score, and K-M survival analysis indicated that the high-risk group had a shorter survival time. Additionally, the risk gene signature can partially affect immune infiltrates within the HCC microenvironment, and many oncogenic pathways were enriched in the high-risk group, including glycolysis, hypoxia, and DNA repair. Finally, in vitro knockdown of ME1 suppressed proliferation, migration, and invasion of hepatocellular carcinoma cells. Conclusion: In our study, we successfully constructed and verified a novel glycolysis-related risk signature for HCC prognosis prediction, which is meaningful for classifying HCC patients and offers potential targets for the treatment of hepatocellular carcinoma.

Pan-cancer analyses identify DCBLD2 as an oncogenic, immunological, and prognostic biomarker.

Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2) is a two-domain transmembrane protein-coding gene located on chromosome 3, the protein expressed by which acts as the membrane receptor of semaphorin and vascular endothelial growth factor during the development of axons and blood vessels. Although several research evidences at the cellular and clinical levels have associated DCBLD2 with tumorigenesis, nothing is known regarding this gene from a pan-cancer standpoint. In this study, we systematically analyzed the influence of DCBLD2 on prognosis, cancer staging, immune characteristics, and drug sensitivity in a variety of cancers based on a unified and standardized pan-cancer dataset. In addition, we performed GO enrichment analyses and KEGG analyses of DCBLD2-related genes and DCBLD2-binding proteins. Our results showed that DCBLD2 is a potential oncogenic, immunological as well as a prognostic biomarker in terms of pan-cancer, and is expected to contribute to the improvement of tumor prognosis and the development of targeted therapy.

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer.

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

Integrative analysis of expression profile indicates the ECM receptor and LTP dysfunction in the glioma-related epilepsy.

BACKGROUND: Seizures are a common symptom in glioma patients, and they can cause brain dysfunction. However, the mechanism by which glioma-related epilepsy (GRE) causes alterations in brain networks remains elusive. OBJECTIVE: To investigate the potential pathogenic mechanism of GRE by analyzing the dynamic expression profiles of microRNA/ mRNA/ lncRNA in brain tissues of glioma patients. METHODS: Brain tissues of 16 patients with GRE and 9 patients with glioma without epilepsy (GNE) were collected. The total RNA was dephosphorylated, labeled, and hybridized to the Agilent Human miRNA Microarray, Release 19.0, 8 × 60 K. The cDNA was labeled and hybridized to the Agilent LncRNA + mRNA Human Gene Expression Microarray V3.0, 4 × 180 K. The raw data was extracted from hybridized images using Agilent Feature Extraction, and quantile normalization was performed using the Agilent GeneSpring. P-value < 0.05 and absolute fold change > 2 were considered the threshold of differential expression data. Data analyses were performed using R and Bioconductor. RESULTS: We found that 3 differentially expressed miRNAs (miR-10a-5p, miR-10b-5p, miR-629-3p), 6 differentially expressed lncRNAs (TTN-AS1, LINC00641, SNHG14, LINC00894, SNHG1, OIP5-AS1), and 49 differentially expressed mRNAs play a vitally critical role in developing GRE. The expression of GABARAPL1, GRAMD1B, and IQSEC3 were validated more than twofold higher in the GRE group than in the GNE group in the validation cohort. Pathways including ECM receptor interaction and long-term potentiation (LTP) may contribute to the disease's progression. Meanwhile, We built a lncRNA-microRNA-Gene regulatory network with structural and functional significance. CONCLUSION: These findings can offer a fresh perspective on GRE-induced brain network changes.

Construction of m6A-Related lncRNA Prognostic Signature Model and Immunomodulatory Effect in Glioblastoma Multiforme.

Background: Glioblastoma multiforme (GBM), the most prevalent and aggressive of primary malignant central nervous system tumors (grade IV), has a poor clinical prognosis. This study aimed to assess and predict the survival of GBM patients by establishing an m6A-related lncRNA signaling model and to validate its validity, accuracy and applicability. Methods: RNA sequencing data and clinical data of GBM patients were obtained from TCGA data. First, m6A-associated lncRNAs were screened and lncRNAs associated with overall survival in GBM patients were obtained. Subsequently, the signal model was established using LASSO regression analysis, and its accuracy and validity are further verified. Finally, GO enrichment analysis was performed, and the influence of this signature on the immune regulation response and anticancer drug sensitivity of GBM patients was discussed. Results: The signature constructed by four lncRNAs AC005229.3, SOX21-AS1, AL133523.1, and AC004847.1 is obtained. Furthermore, the signature proved to be effective and accurate in predicting and assessing the survival of GBM patients and could function independently of other clinical characteristics (Age, Gender and IDH1 mutation). Finally, Immunosuppression-related factors, including APC co-inhibition, T-cell co-inhibition, CCR and Check-point, were found to be significantly up-regulated in GBM patients in the high-risk group. Some chemotherapeutic drugs (Doxorubicin and Methotrexate) and targeted drugs (AZD8055, BI.2536, GW843682X and Vorinostat) were shown to have higher IC50 values in patients in the high-risk group. Conclusion: We constructed an m6A-associated lncRNA risk model to predict the prognosis of GBM patients and provide new ideas for the treatment of GBM. Further biological experiments can be conducted on this basis to validate the clinical value of the model.

Association of variations in the Fanconi anemia complementation group and prognosis in Non-small cell lung cancer patients with Platinum-based chemotherapy.

PURPOSE: To explore the associations between FANC (FANCA, FANCC, FANCE, FANCF, and FANCJ) single nucleotide polymorphisms (SNPs) and prognosis of non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy. METHODS: According to the inclusion criteria, we selected 395 DNA samples from NSCLC patients for genotyping and combined with clinical data for Cox regression analysis and stratification analyses to assess relationships between overall survival (OS) and progression free survival (PFS) with SNPs genotypes. RESULTS: The results revealed that patients with FANCE rs6907678 TT genotype have a longer OS than TC and CC genotype (Additive model: P = 0.004, HR = 1.696, 95% CI = 1.186-2.425). In stratification analyses, Longer PFS is found in female, age ≤ 55 years old and non-smoking patients with FANCE rs6907678 TT genotype, and patients with TT genotypes were significantly had longer OS in male, age ＞55 years old, non-smoking, squamous cell carcinoma and stage IV stratification. CONCLUSION: Our data demonstrates that patients with FANCE rs6907678 TT genotype are contributed to better prognosis. FANCE rs6907678 may be used as a clinical biomarker for predicting the prognosis of NSCLC patients with platinum-based chemotherapy.

eIF3a Regulates Colorectal Cancer Metastasis via Translational Activation of RhoA and Cdc42.

Tumor metastasis is the major cause of tumor relapse and cancer-associated mortality in colorectal cancer, leading to poor therapeutic responses and reduced survival. eIF3a was previously described as an oncogene. However, its role in colorectal cancer progression and metastasis has not yet been fully investigated. In this study, the expression specificity and predictive value of eIF3a were investigated in clinical samples. The effects of eIF3a on cell proliferation and migration were verified in vivo and in vitro, respectively. The underlying molecular mechanism was revealed by western blotting, immunofluorescence, RNA-binding protein immunoprecipitation, and dual-luciferase reporter gene assays. The results showed that eIF3a was significantly overexpressed in tumor tissues compared with adjacent normal tissues. High eIF3a expression was correlated with tumor metastasis and overall survival. Downregulation of eIF3a obviously inhibited the proliferation and motility of malignant cells in vitro and in vivo. Mechanistically, eIF3a regulates Cdc42 and RhoA expression at the translation level, which further affects pseudopodia formation and actin cytoskeleton remodeling. Taken together, eIF3a accelerates the acquisition of the migratory phenotype of cancer cells by activating Cdc42 and RhoA expression at the translational level. Our study identified eIF3a as a promising target for inhibiting colorectal cancer metastasis.

eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response.

OBJECTIVES: The individual differences and pervasive resistance seriously hinder the optimization of irinotecan-based therapeutic effectiveness. Eukaryotic translation initiation factor 3a (eIF3a) plays a key role in tumour occurrence, prognosis and therapeutic response. This study focused on the role of eIF3a in irinotecan-induced DNA damage response. MATERIALS AND METHODS: The cck8 cell viability and clone survival analyses were used to test the regulatory role of eIF3a on irinotecan sensitivity in HT29 and CACO2 cell lines in vitro. This regulatory role was also verified in vivo by conducting subcutaneous xenograft model. Irinotecan-induced DNA damage, cell cycle arrest and apoptosis were tested by flow cytometry analysis, TUNEL staining, western blot and comet assays. The immunofluorescence, co-IP, luciferase reporter assay, RIP and flow cytometric analyses were carried out to investigate the underline mechanism. RESULTS: We demonstrated that eIF3a continuously activates ATM/ATR signal by translationally inhibiting PPP2R5A, a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair complete. Suppression of PPP2R5A resulted in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity. CONCLUSIONS: Our study suggested eIF3a with a high potential to influence phenotypic functions, which may contribute substantially to the early identification of susceptible individuals and the provision of personalized medication to irinotecan-treated patients.

eIF3a R803K mutation mediates chemotherapy resistance by inducing cellular senescence in small cell lung cancer.

Drug resistance in small cell lung cancer (SCLC) significantly affects the efficacy of chemotherapy treatment. However, due to the lack of tumor tissue samples, especially serial tumor samples during chemotherapy, the mechanism of chemotherapy resistance has not been fully studied. Circulating tumor DNA, which can be obtained in a noninvasive manner, can complement tumor sampling approaches for research in this field. We identified an SCLC patient with acquired drug resistance from 52 SCLC patients for whom follow-up data were available. By comparing somatic mutations in circulating tumor DNA before and after chemotherapy, for the first time, we found that the somatic mutation eIF3A R803K may be related to acquired chemotherapy resistance. Then, the association between the eIF3A R803K mutation and chemotherapy resistance was confirmed by samples from 254 lung cancer patients receiving chemotherapy. We found that the eIF3a R803K mutation weakened the proliferation ability of tumor cells but increased their resistance to chemotherapy. Further studies revealed that the eIF3A R803K mutation promotes cellular senescence. In addition, fisetin showed a synergistic effect with chemotherapy in eIF3A R803K mutant cells. These results suggest that the eIF3A R803K somatic mutation has the potential to predict chemotherapy resistance in SCLC. Moreover, the eIF3A R803K mutation promotes chemotherapy resistance by inducing senescence. Furthermore, a senolytic drug, fisetin, can reverse chemotherapy resistance mediated by the eIF3A R803K mutation.

Non-Coding RNA Polymorphisms (rs2910164 and rs1333049) Associated With Prognosis of Lung Cancer Under Platinum-Based Chemotherapy.

Purpose: Lung cancer is the largest cause of cancer deaths in the world. Platinum-based chemotherapy is a foundation of first-line chemotherapy. However, the prognosis of lung cancer treated with platinum-based chemotherapy is still a challenge. Single nucleotide polymorphism of non-coding RNA has the potential to be a biomarker, but its effectiveness has yet to be comprehensively assessed. In this study, we explored the association between polymorphisms of non-coding RNA and prognosis of lung cancer patients receiving platinum-based chemotherapy. Materials and Methods: For 446 lung cancer patients receiving platinum-based chemotherapy, 22 single nucleotide polymorphisms of microRNA and long noncoding RNA were genotyped by MALDI-TOF mass spectrometry. Cox regression analysis, Kaplan-Meier method, and long-rank test have been performed to assess the association of overall and progression-free survival with polymorphisms. Results: In the additive and dominant models, genetic polymorphism of ANRIL rs1333049 (G > C) was significantly associated with progression-free survival. Additive model: CC vs GC vs GG [HR = 0.84, p = 0.021, 95% CI (0.73-0.97)]; Recessive model: CC vs GG + GC [HR = 0.77, p = 0.026, 95% CI (0.61-0.97)]. In the dominant model, compared with the CC genotype patients, lower risk of death [HR = 0.81, p = 0.036, 95% CI (0.66-0.99)] and lower risk of progression [HR = 0.81, p = 0.040, 95% CI (0.67-0.99)] have been observed on the patients with CG or GG genotype in miR-146A rs2910164. Conclusion: Our research demonstrated the potential of using ANRIL rs1333049 (G > C) and miR-146A rs2910164 (C > G) as biomarkers to support the prediction of a better prognosis for lung cancer patients receiving platinum-based chemotherapy.

The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

Metabolomics of Artichoke Bud Extract in Spontaneously Hypertensive Rats.

Hypertension adversely affects the quality of life in humans across modern society. Studies have attributed increased reactive oxygen species production to the pathophysiology of hypertension. So far, a specific drug to control the disease perfectly has not been developed. However, artichoke, an edible vegetable, plays an essential role in treating many diseases due to its potent antioxidant activities. The objective of this study is to evaluate the effect of artichoke bud extract (ABE) on heart tissue metabolomics of hypertensive rats. Spontaneously hypertensive rats and Wistar-Kyoto (WKY) rats were divided into six groups, then exposed to different doses comprising ABE, Enalapril Maleate, or 1% carboxylmethyl cellulose for 4 weeks. Their blood pressures were recorded at 0, 2, 3, and 4 weeks after the start of the test period. Thereafter, all rats were anesthetized, and blood was collected from their cardiac apexes. Then, we measured the levels for 15 kinds of serum biochemical parameters. An established orthogonal partial least square-discriminant analysis model completed the metabolomic analysis. Hypertensive rats in the ABE group exhibited well-controlled blood pressure, relative to those in the model group. Specifically, artichoke significantly lowered serum levels for total protein (TP), albumin (ALB), and uric acid (UA) in the hypertensive rats. This effect involved the action of eight metabolites, including guanine, 1-methylnicotinamide, p-aminobenzoic acid, NAD, NADH, uridine 5'-monophosphate, adenosine monophosphate, and methylmalonic acid. Collectively, these findings suggest that ABE may play a role in affecting oxidative stress and purine, nicotinate, and nicotinamide metabolism.