Current medicinal chemistry最新文献

Background: Acute kidney injury (AKI) is a common renal condition associated with various factors, including pre-renal, post-renal, and renal causes, with ischemia- reperfusion being a frequent contributor leading to tubular injury. Early identification of AKI is crucial but remains challenging.

Methods: This study explored the molecular signature of AKI using gene microarray data from the GEO dataset, focusing on identifying ferroptosis-related features through three machine-learning algorithms. We also validated potential biomarkers through a hypoxia/ reoxygenation model.

Results: ROC curves, expression differences, and associations with immune cells were analyzed for the three markers to confirm their potential as AKI biomarkers, each demonstrating strong diagnostic ability. Combining these markers proved more effective.

Conclusion: The combination of AEBP2, MDM2, and NR4A1 as diagnostic biomarkers for AKI not only enhances detection capability but also holds promise as a significant tool in clinical practice, providing patients with diagnostic and therapeutic guidance.

Background: HCC is a malignant tumor with high morbidity and mortality. Fibroblasts play a key role in the tumor microenvironment (TME). However, the transcriptional regulatory mechanisms of fibroblasts remained unclear in HCC.

Aim: The aim of this study was to explore the complex role of fibroblasts in hepatocellular carcinoma (HCC) and to reveal their transcriptional regulatory mechanisms.

Objective: The goal of this study was to discover potential prognostic markers for HCC by analyzing the genetic variations and differentiation process of fibroblasts.

Methods: Single-cell transcriptome data from the non-tumor liver site and primary tumor site of HCC were acquired from GSE149614, processed, and clustered using the Seurat pipeline. The inferCNV algorithm was applied to infer copy number variations (CNVs) in fibroblasts. Subsequently, the mechanism underlying the interaction between fibroblasts and other cells in the TME of HCC was analyzed using CellChat software. The trajectory of cellular differentiation of fibroblasts from normal state to malignant state was examined using Monocle 2. SCENIC analysis was performed to identify key transcription factors (TFs) in fibroblasts and assess their correlation with HCC prognosis. Finally, qRT-PCR and Transwell assays were carried out to analyze the mRNA expression and cell metastasis.

Results: We identified a total of nine different cell types (B cells, cycling cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, macrophages, plasma cells, and T cells) based on the single-cell transcriptomic data of HCC. Among them, fibroblasts were highly enriched at the primary tumor site, and their number increased with advanced stages. In addition, significant deletions were detected on chromosome 6p of fibroblasts, and genes in this region were remarkably enriched in pathways associated with antigen processing and presentation. Intercellular communication showed that epithelial cells regulated fibroblasts the most. The differentiation of fibroblasts was mainly accompanied by a transition from normal to malignant state. Importantly, CEBPD and FOSB, the TFs most associated with the putative timing of fibroblasts, were under-expressed in human hepatocytes and showed a significant correlation with HCC prognosis. Overexpressed CEBPD inhibited HCC cell migration and invasion.

Conclusion: In conclusion, our study revealed that fibroblast recruitment and differentiation, as well as copy number loss at chromosome 6p, were associated with a higher degree of malignancy and immune dysfunction in HCC. The current discoveries provided new insights into the clinical treatment and diagnosis of HCC.

Cardiovascular Diseases (CVDs) are responsible for the highest number of deaths and disabilities globally. Although numerous therapeutic options exist for treating CVDs, most traditional strategies have proven ineffective in halting or significantly slowing disease progression, often leading to unfavorable side effects. Using nanocarriers represents an innovative strategy for treating CVD, enabling the personalized delivery of medications to precise locations within the cardiovascular system. Despite significant advancements in pharmacological treatments, challenges persist in effectively administering drugs to the CV system. Employing nanocarriers represents an innovative strategy for treating CVD, enabling the tailored administration of medications to precise locations within the cardiovascular system. Various studies have determined the future outlook of nanomedicines for clinical applications as nanocarrier design continues to improve, leading to enhanced drug delivery and treatment outcomes. The article focuses on the delivery systems of drugs that are effective strategies for treating cardiovascular diseases. This manuscript also seeks to explore new possibilities for how the emerging concept of nanotherapeutics could revolutionize our traditional diagnostic and treatment methods in the coming years.

Objective: Globally, one of the main causes of cancer-related mortality is Colon Adenocarcinoma (COAD). In this study, a new special Immune Cell Functions (ICF) risk model was constructed using single-cell and bulk RNA sequencing data to develop a new understanding and clinical applications for COAD.

Methods: The immune function gene sets were downloaded from a literature reference, and the COAD single-cell dataset GSE146771 was downloaded from the Tumour Immune Single Cell Hub database. Using Lasso analysis, a multiple gene signature was made from the enrichment scores of immune function gene sets that were enriched in different ways. Robust validation of the signature was then performed in multiple independent cohorts. After that, we built the model using a 10-fold cross-test and evaluated its independence for clinical usage using a nomogram. We also investigated the connection between signature and immune function, genetic variation, immunotherapy, and the cancer immunological microenvironment. Lastly, we used qPCR and immunohistochemistry to examine the expression of the unreported model genes. To find the regulatory functions of unreported model genes, an EdU assay was employed.

Results: First, 20 differentially enriched immune function gene sets were identified. Ten genes can be used as a risk profile to assess the prognosis of colon cancer, according to Lasso regression analysis. Signature performance was stable in both the training cohort and two independent GEO external cohorts, and risk scores were confirmed as independent prognostic factors. At the same time, our risk model continued to be highly predictive across various clinical clusters and clinical characteristics, such as immune checkpoints, tumour genome mutations, and chemotherapeutic drug resistance. Patients in the low-risk group have exhibited a higher chance of benefiting from immunotherapy, according to immunotherapy response research. qPCR and immunohistochemistry analysis have revealed SIRP5 expression as high in COAD tissues, while CMC1 and ASAH1 expression has been found to be low. According to the findings of the functional experiment, SIRP5, CMC1, and ASAH1 may control the ability of CRC cells to proliferate.

Conclusion: In this study, using scRNA-seq and bulk RNA-seq data, we created a risk model to predict the prognosis and effectiveness of immunotherapy in patients with COAD. In addition, we have discovered three model genes (SIRP5, CMC1, and ASAH1) that have not been reported before. These genes have the potential to be novel therapeutic targets in Colorectal Cancer (CRC). These findings suggest that this model could be used to evaluate the prognostic risk and identify potential targets for COAD patient treatment.

Introduction: Infections linked to orthopedic trauma are common complications that place a significant strain on the healthcare system. Immediate identification of the infection and its severity is essential for providing effective treatment.

Method: C-reactive Protein (CRP) is a commonly used inflammatory marker in orthopedic surgery and has proven to be a valuable biomarker for diagnosing and monitoring infections. Specifically, CRP aids in the early identification of postoperative infections. This research work has focused on developing a highly sensitive CRP biosensor using iron oxide nanomaterial-modified dielectric sensors.

Result: Gold Urchin (GU)-conjugated aptamers and antibodies were used as probes and attached to the electrode via amine linkers. The aptamer-GU-antibody-modified electrode detected CRP at concentrations as low as 1 pg/mL, with an R2 value of 0.9942. Furthermore, CRP-spiked serum exhibited an increase in current response at all concentrations of CRP, indicating selective detection of CRP. Additionally, control experiments using complementary sequences of the aptamer, relevant proteins, and non-immune antibodies did not enhance the current responses, confirming the specific identification of CRP.

Conclusion: The sensing strategy has enabled the detection of CRP at its lowest levels, facilitating the identification of infections during orthopedic surgery and subsequent treatment.

The influenza virus, a well-known pathogen that causes respiratory illness, remains an important global health threat because of the significant morbidity and mortality rates of people infected with the virus annually. The influenza virus undergoes frequent antigenic variation, and with the increasing frequency of resistant influenza strains against existing antiviral drugs, there is an urgent need for the development of new anti- influenza treatment strategies. Peptides have the potential to offer high potency, selectivity, and relatively low drug resistance. As such, the design and screening of novel anti- influenza virus peptides with high potency have become increasingly important in an effort to fight global influenza epidemics. Herein, we introduce three approaches to developing anti-influenza virus peptides: discovery from natural products, library construction for antiviral peptide screening, and rational design based on functional regions of influenza viral proteins. This review summarizes recent progress in the discovery and design of anti-influenza virus peptides over the past 20 years.

Aims: To build an innovative telomere-associated scoring model to predict prognosis and treatment responsiveness in acute myeloid leukemia (AML).

Background: AML is a highly heterogeneous malignant hematologic disorder with a poor prognosis. While telomere maintenance is frequently observed in tumors, investigations into telomere-related genes (TRGs) in AML remain limited.

Objectives: This study aimed to identify prognostic TRGs using the least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression, evaluate their predictive value, explore the association between TRG scores and immune cell infiltration, and assess the sensitivity of high-scoring AML patients to chemotherapeutic agents.

Method: Univariate Cox regression analysis was conducted on the TCGA cohort to identify prognostic TRGs and to develop the TRG scoring model using LASSO-Cox and multivariate Cox regression. Validation was performed on the GSE37642 cohort. Immune cell infiltration patterns were assessed through computational analysis, and the sensitivity to chemotherapeutic agents was evaluated.

Results: Thirteen prognostic TRGs were identified, and a seven-TRG scoring model (including NOP10, OBFC1, PINX1, RPA2, SMG5, MAPKAPK5, and SMN1) was developed. Higher TRG scores were associated with a poorer prognosis, as confirmed in the GSE37642 cohort, and remained an independent prognostic factor even after adjusting for other clinical characteristics. The high-score group was characterized by elevated infiltration of B cells, T helper cells, natural killer cells, tumor-infiltrating lymphocytes, regulatory T (Treg) cells, M2 macrophages, neutrophils, and monocytes, along with reduced infiltration of gamma delta T cells, CD4- T cells, and resting mast cells. Moreover, high infiltration of M2 macrophages and Tregs was associated with poor overall survival compared to low infiltration. Notably, high-risk AML patients were resistant to Erlotinib, Parthenolide, and Nutlin-3a, but sensitive to AC220, Midostaurin, and Tipifarnib. Additionally, using RT-qPCR, we observed significantly higher expression of two model genes, OBFC1 and SMN1, in AML tissues compared to control tissues.

Conclusion: This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

Background: Indole is considered the most promising scaffold for anticancer drug design due to its high bioavailability, unique chemical properties, and broad spectrum of pharmacological action.

Objective: Twelve novel thiazole-containing the 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives as sunitinib analogs were designed and synthesized, and their anticancer activity was evaluated against the NCI-60 cancer cell lines.

Method: The thiazole-contained 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives were synthesized using Knoevenagel condensation of 1,3-thiazole-5-carboxylic acid 1. Their anticancer activities were evaluated by NCI-60 one-dose screen assay. The molecular docking studies were performed using AutoDock tools and the AutoDock Vina programs. The ADMETlab 2.0 web server predicted the physicochemical properties of compounds.

Results: Among the synthesized new 5-fluoro-2-oxindole derivatives, compound 3g demonstrated high antitumor activity (GI>70%) against eight types of cancer: leukemia, breast cancer, ovarian cancer, lung cancer, melanoma, CNS cancer, renal cancer, and colon cancer. The most activity was observed against breast cancer (T-47D, GI=96.17%), lung cancer (HOP-92, GI=95.95%), ovarian cancer (NCI/ADR-RES, GI=95.13%), and CNS cancer (SNB-75, GI=89.91%). The molecular docking results of compound 3g demonstrated the possibility of inhibiting VEGF2 receptors as his potential anticancer mechanism. The physicochemical properties predicted for compounds 3f and 3g showed positive results.

Conclusion: Compound 3g demonstrated high in vitro NCI-60 anticancer activity against nine cancer types and showed cell growth inhibition against leukemia, CNS, and breast cancer at 6 - 31% higher than Sunitinib, and may represent the basis for further modification of the thiazole-containing analogs of the anticancer drug Sunitinib.

Pressure ulcers (PUs) are caused by continuous pressure or friction on the skin that damages tissue, especially over bony prominences. A critical factor in the development and progression of PUs is poor nutritional status, which often involves deficiencies in essential nutrients such as proteins, vitamins (A, C, D, E, K, and the B complex), and trace elements (including zinc, selenium, copper, iron, and manganese). These micronutrients are vital for effective wound healing, as they play significant roles in cellular repair, immune function, and tissue regeneration. Laboratory tests for serum albumin, prealbumin, transferrin, retinol-binding protein, and anthropometric measures like height, weight, and body mass index (BMI) are used to evaluate a patient's nutritional status. Screening tools such as the Mini Nutritional Assessment (MNA), Malnutrition Universal Screening Tool (MUST), LPZ questionnaire, and Subjective Global Assessment (SGA) are commonly employed. Emerging evidence from various studies, including in vitro, in vivo, and clinical trials, underscores the importance of personalized nutritional interventions in managing PUs. Unlike generic dietary plans, tailored nutrition that addresses the specific needs of individuals shows greater potential in promoting wound healing and improving clinical outcomes. This synthesis of existing research highlights the critical influence of micronutrients on the healing process of PUs. It suggests that a personalized approach to nutrition, which takes into account individual patient requirements and deficiencies, is likely to be more effective than a one-size-fits- all strategy in the management of these complex wounds.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor characterized by rapid growth, invasive behavior, and resistance to conventional therapies, such as surgery, radiotherapy, and chemotherapy. Despite these interventions, patient survival remains poor due to the tumor's ability to recur and adapt to treatments. The function of GBM-derived exosomes (GBM-exosomes) as essential mediators in tumor growth has drawn attention in recent years. These small extracellular vesicles are involved in the transfer of a variety of molecules, including cytokines, miRNAs, proteins, and DNA, facilitating intercellular communication that promotes GBM cell proliferation, angiogenesis, immune evasion, and resistance to therapies. This review aims to provide an in- -depth examination of the mechanisms through which GBM-exosomes contribute to these pathological processes, as well as to discuss the current methodologies for isolating and characterizing GBM exosomes. Additionally, we explore the potential of exosomes as biomarkers for diagnosis and prognosis and as novel therapeutic targets in the fight against GBM. By improving our understanding of GBM-exosomes, we can pave the way for the development of more effective, personalized treatment strategies that may improve patient outcomes and quality of life.