Current medicinal chemistry最新文献

Cervical cancer remains a significant global health concern, making it essential to investigate new treatment options continuously. This page provides an overview of the latest advancements and best practices in detection and intervention, including Pap smears, colposcopy, biopsy, immunotherapy, targeted therapies, chemotherapy, radiation therapy, and surgery. Surgical techniques such as radical hysterectomy and minimally invasive procedures have advanced to enhance patient outcomes and quality of life. Simultaneously, radiation therapy methods have been refined to maximize tumour control while reducing adverse effects. Chemotherapy remains vital, with new drugs and combination regimens demonstrating improved tolerance and efficacy. Immunotherapy, notably immune checkpoint inhibitors, has shown promise in advanced stages of cervical cancer. Additionally, targeted therapies that focus on specific biochemical pathways offer the potential for personalized treatment approaches. This review critically assesses ongoing research, evaluates existing data, and emphasizes the opportunities and challenges of each therapeutic approach. Ultimately, integrating these diverse treatment strategies is the key to enhancing patient outcomes.

Background: Necroptosis is a modifiable form of cell death mainly dependent on RIPK3 and MLKL. The association between necroptosis and inflammation has been a key focus of research. An increasing number of studies have shown that necroptosis plays an important role in inflammatory diseases, such as inflammatory bowel disease.

Methods: Articles published up to 2023 were searched on the Web of Science. VOSviewer, CiteSpace, Gephi, and Microsoft Office Excel were used for bibliometric analysis and visualisation. In addition, journal impact factors and journal partitions were obtained through the Web of Science.

Results: A total of 3011 articles were included in this study. The number of publications and citations in the field increased year by year. China had the highest number of publications. Cell Death & Disease published the most papers in the field. P. Vandenabeele is one of the most important scholars in this field. The most cited reference was "Molecular Mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death".We found substantial evidence that acute kidney injury, sepsis, cancer, and other diseases are closely related to necroptosis. In addition, we found that inhibitors of necroptosis have great potential in the treatment of inflammatory diseases.

Conclusion: This is the first bibliometric analysis of studies related to necroptosis in inflammatory diseases. Our results provide an overview of basic and influential research, providing a basis for the identification of valuable research directions. Furthermore, this work offers general insight into the role of necroptosis in inflammatory human diseases.

Introduction: Copine-3 (CPNE3) is a conservative calcium-dependent phospholipid-binding protein belonging to the copines protein family. CPNE3 has been implicated in the development and progression of several diseases, including cancer.

Method: Herein, we investigated the molecular mechanisms through which CPNE3 regulates the migration of lung adenocarcinoma (LUAD) cells in vitro. Western blotting and immunohistochemical assays showed that CPNE3 is widely distributed in LUAD tissues and cell lines and that CPNE3 downregulation promotes the migration of human LUAD A549 cells.

Results: Stable isotope labelling with amino acids in cell culture, which is a quantitative proteomics approach coupled with bioinformatic analyses, revealed that CPNE3 regulates SQSTM1/p62 and vimentin expression, indicating that CPNE3 may mediate epithelial-mesenchymal transition (EMT). CPNE3 silencing by siRNA upregulated vimentin levels but downregulated E-cadherin levels in the A549 cells.

Conclusion: Furthermore, SQSTM1/p62 knockdown enhanced migratory ability and EMT progression in CPNE3-silenced A549 cells. Overall, CPNE3 knockdown was found to promote EMT by inhibiting SQSTM1/p62 signalling and facilitating cell migration. Our findings highlight the role of CPNE3 as a tumour suppressor, providing deeper insights into its carcinogenic roles in LUAD.

Background: Metabolic Syndrome (MS) is a cluster of conditions that significantly increase the risk of infertility in women. Granulosa cells are crucial for ovarian folliculogenesis and fertility. Understanding molecular alterations in these cells can provide insights into MS-associated infertility.

Objective: This study aimed to investigate Differentially Expressed Genes (DEGs) and Proteins (DEPs) in granulosa cells from female patients with MS-associated infertility.

Method: Transcriptome and proteome analyses were integrated to compare granulosa cells from three MS patients with infertility to three control subjects. RNA sequencing and quantitative proteomics analyses were conducted, followed by differential expression analysis, Gene Set Enrichment Analysis (GSEA), and Protein-protein Interaction (PPI) network construction. Functional enrichment of overlapping DEGs and DEPs and potential drug-protein interactions were also explored. Hub genes identified by PPI were validated via quantitative Polymerase Chain Reaction (qPCR) and western blot assays.

Results: Principal Component Analysis (PCA) demonstrated a distinct separation between MS and control groups, indicating significant differences in gene and protein expression. A total of 1,046 upregulated and 23 downregulated DEGs, along with 222 upregulated and 412 downregulated DEPs, were identified in the MS group. GSEA highlighted enrichment in processes, like the cell cycle and immune response. Venn diagram revealed 71 overlapping DEGs and DEPs, mainly related to immune regulation. Key hub proteins and potential therapeutic candidates were identified, with hub genes upregulated at the mRNA level, but downregulated at the protein level in granulosa cells of MS patients.

Conclusion: The integrative analyses revealed significant molecular alterations in granulosa cells from MS patients with infertility. Identified DEGs, DEPs, and hub proteins suggested potential therapeutic targets and pathways for addressing MS-associated infertility.

Background: Resistance to lenvatinib poses a serious threat to the therapy of patients with Hepatocellular Carcinoma (HCC). The mechanism by which HCC develops resistance to lenvatinib is currently unknown.

Objective: The aim of this study was to identify key genes and pathways involved in lenvatinib resistance in HCC using bioinformatic analysis and experimental validation.

Methods: Differentially expressed genes (DEGs) were identified from the GSE186191 gene expression profile, comparing HCC cell lines with lenvatinib-resistant HCC cell lines. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were then carried out using DAVID. A protein-protein interaction network was constructed to visualize DEGs and identify hub genes. The expression and prognostic significance of these hub genes were further examined. Additionally, genomic enrichment analysis (GSEA) was utilized to investigate the potential functions of key genes. Following this, the presence of AHSG was validated in both the original Huh7 cells and the lenvatinib-resistant Huh7 (Huh7LR) cells resistant to lenvatinib through the utilization of quantitative real-time PCR (qRT-PCR).

Results: A total of 232 DEGs were identified between HCC cell lines and those that are resistant to lenvatinib. These DEGs were significantly associated with arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and mucin-type O-glycan biosynthesis. Three hub genes, including AHSG, C6, and ORM1, were identified. The low expression of AHSG showed a poorer prognosis in HCC. GSEA demonstrated a significant correlation between low AHSG expression and pathways involving fatty acid metabolism, ribosome function, glycine, serine, and threonine metabolism, peroxisome activity, and bile acid biosynthesis. The expression of AHSG was notably reduced in Huh7LR cells (p = 0.006) compared to Huh7 cells.

Conclusion: Diminished AHSG expression is strongly associated with lenvatinib resistance in HCC, suggesting that it may have implications for developing effective strategies to overcome this resistance.

Objective: This study aims to investigate the effect of Gallic Acid (GA) on the alleviation of chemotherapy-induced bone marrow suppression, with a comparison to Diyu sheng bai tablets (DYSB) and RhG-CSF.

Methods: A mouse model of bone marrow suppression was established in BALB/c mice using intraperitoneal injections of cyclophosphamide (CTX). All procedures were performed after obtaining ethical clearance from the institutional animal ethics committee. Mice were treated with low (100 mg/kg/d), medium (200 mg/kg/d), and high (400 mg/kg/d) doses of Gallic Acid (GA) to mitigate CTX-induced bone marrow suppression. In parallel, mice in the positive control group were also treated with DYSB and RhG-CSF at their respective standard doses (DYSB: 100 mg/kg/day, RhG-CSF: 125 mg/kg/day). The efficacy of GA in alleviating chemotherapy-induced bone marrow suppression was evaluated through blood cell counts, immune organ (thymus and spleen) indices, bone marrow nucleated cell (BMNC) counts, cell cycle analysis, apoptosis, histopathology of bone marrow and spleen, and analysis of splenic hematopoietic factors.

Results: CTX induced a decrease in peripheral blood cells and BMNC counts, reduced spleen and thymus indices, and diminished abnormal pathology of bone marrow and spleen, as well as decreasing disturbances in hematopoietic factors. GA was able to alleviate these abnormalities in the bone marrow. It modulated cell proliferation and apoptosis, adjusted the proportion of cells in the G0/G1 phase, and reduced apoptosis in femoral bone marrow.

Conclusion: Gallic Acid (GA) alleviates chemotherapy-induced bone marrow suppression by improving immune organ function, promoting bone marrow cell recovery, and inhibiting apoptosis. These findings support GA as a potential adjunct therapy for chemotherapy, with promising clinical applications.

Background: This study investigates the potential effects of elemene injection on pancreatic cancer using network pharmacology and experimental validation.

Methods: GEO database were used to acquire genes which are differentially expressed between pancreatic cancer tissue and normal tissue. The vigorous energetic ingredients were identified in research and the object genes were obtained from BATMAN-TCM. The key targets and signaling pathways of elemene injection were identified using compound- target network analysis, protein-protein interaction network analysis, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. in vitro experiments were carried out to confirm the accuracy of the network pharmacology predictions.

Results: Two hundred and eleven target genes that may be involved in Elemene's impact on pancreatic cancer were identified. Bioinformatics analysis was conducted to determine the two active mixtures and one key target. GO and KEGG enrichment analyses indicated that elemene injection exerts therapeutic effects on pancreatic cancer, regulating the cell adhesion by ECM-receptor interaction pathway. The experiments verified that elemene injection suppressed the growth and movement of pancreatic cancer cell lines Panc02 and MiaPaca-2 and the mechanism is related to regulating ECM-receptor interaction pathway-related genes. FN1 was identified as core targets by bioinformatics analysis. The FN1 was downregulated by elemene injection and was validated by QPCR and Western Blot.

Conclusion: The findings of the current study emphasized that elemene injection might control cell attachment, decrease metastasis, and suppresses pancreatic cancer progress. FN1 might be a therapeutic target for pancreatic cancer.

Aims: The purpose of this study was to investigate the prognostic significance of cholesterol uptake genes in predicting the survival of breast cancer patients.

Background: Cholesterol plays a crucial role in the homeostasis of tumor cells. It is known that cholesterol levels can influence important parameters of the disease, such as sensitivity to therapy, progression, and metastasis of cancer. Previous studies suggest that breast cancer subtypes exhibit differences in metabolism.

Objective: The objectives of this study were to determine whether cholesterol uptake genes have prognostic significance for overall survival in breast cancer patients, evaluate if this prognostic significance varies between breast cancer subtypes, and identify differences in the expression of cholesterol uptake genes among these subtypes.

Methods: Data from mRNA sequencing of tumors from the Cancer Genome Atlas (TCGA) portal were analyzed. Tumors were classified into molecular subtypes, and the prognostic significance of cholesterol uptake gene expression levels was evaluated for each subtype. DESeq2 and Fisher's test were used to assess differences in gene expression.

Results: High expression levels of genes involved in de novo cholesterol synthesis were associated with poor prognosis for the Basal-like and Luminal A breast cancer subtypes. The prognostic significance of low-density lipoprotein receptor (LDLR), LDLR adapter protein 1 (LDLRAP1), and proprotein convertase subtilisin/kexin type 9 (PCSK9), which are responsible for exogenous cholesterol uptake, varied across subtypes. Specifically, low expression of LDLR was associated with a favorable prognosis for the luminal A (OR = 2.17; FDR = 0.0048) and luminal B (OR = 2.21; FDR = 0.015) subtypes but indicated poor prognosis in the basal-like subtype (OR = 0.48; FDR = 0.05). No genes were significant for prognosis prediction in the HER2-positive subtype. The HER2+ subtype exhibited higher expression of cholesterol uptake genes compared to the basal-like subtype based on the analysis of tumor mRNA sequencing (OR = 6.45, p-value = 3.07E-05). This finding was also confirmed through the study of publicly available single-cell sequencing data (OR = 40.3, p-value = 2.19e-07), which may contribute to the differences in their prognostic significance.

Conclusion: The prognostic significance of cholesterol uptake gene expression varies among breast cancer subtypes. Precise fitting of biomarkers into breast cancer subtypes may aid in more accurate patient stratification and improve treatment approaches.

Background: Sarcopenia, an aseptic chronic inflammatory disease, is a complex and debilitating disease characterized by the progressive degeneration of skeletal muscle. PANoptosis, a novel proinflammatory programmed cell death pathway, has been linked to various diseases. However, the precise role of PANoptosis-related features in sarcopenia remains uncertain.

Methods: According to the intersection of differentially expressed genes (DEGs) in the sarcopenia dataset GSE167186 and the PANoptosis gene set, we classified patients into PANoptosis-related subtypes (PANRS) using consensus clustering. The DEGs of PANRS were intersected with weighted gene co-expression network analysis (WGCNA). Proteinprotein interaction network and cytoHubba algorithms were employed to further identify potential genes related to PANoptosis. The most characteristic genes were selected using LASSO regression and validated by ROC curve analysis, followed by relevant immune infiltration analysis. Additionally, small-molecule drug screening was performed using Cmap. The relative expression levels of hub genes in sarcopenia were confirmed by PCR. Finally, single-cell analysis and GSEA were used to examine the distribution and function of hub genes.

Results: Thirty-five candidate genes were identified through WGCNA and PANRS. Machine learning and ROC curve analysis revealed three core genes: LTBP2, ETS2, and H3.3B, all of which were up-regulated in patients with sarcopenia (p<0.01). Immune infiltration analysis indicated that these three diagnostic genes were linked to the activation of NK cells and macrophages. Single-cell analysis demonstrated that LTBP2 was mainly localized in fibroblasts, while ETS2 and H3.3B exhibited a uniform distribution. Enrichment analysis indicated that the three hub genes were predominantly associated with the inhibition of energy metabolism.

Conclusion: In this study, the hub genes LTBP2, ETS2, and H3.3B associated with PANoptosis in sarcopenia were successfully identified through a combination of bioinformatics and experimental verification methods. This establishes a foundation for new candidate diagnostic and therapeutic targets for sarcopenia.

Objective: LGALS3BP exhibits differential expression in various types of tumors. This study aimed to analyze its potential diagnostic and prognostic value in Triple- negative Breast Cancer (TNBC).

Methods: We conducted a comprehensive analysis of LGALS3BP's differential expression and its association with patient survival outcomes using data from public databases. To further validate these findings, Immunohistochemistry (IHC) experiments were performed to confirm the differential expression of LGALS3BP protein in TNBC. Additionally, we also investigated the relationship among LGALS3BP, tumor immune infiltration, and drug sensitivity.

Results: Results indicated LGALS3BP to be significantly upregulated in TNBC, with its high expression correlating with improved survival outcomes. Furthermore, LGALS3BP expression correlated with immune cell infiltration. Notably, high LGALS3BP expression may confer a greater likelihood of benefiting from immunotherapy.

Conclusion: LGALS3BP may serve as a diagnostic and prognostic biomarker for TNBC.