Current Medicinal Chemistry - Volume 32, Issue 23, 2025

Systemic arterial hypertension is a serious chronic health problem caused by multiple factors. It is a major risk factor for Cardiovascular Diseases (CVDs), including heart failure, coronary heart disease, and myocardial infarction. Hypertension can be effectively treated with inhibitors of the Angiotensin Converting Enzyme (ACE), such as captopril, enalapril, and lisinopril. However, these drugs are associated with significant adverse reactions (e.g., persistent coughing, skin rashes, and angioedema).

Considering the recent insights obtained by our group into the antihypertensive effect of boroxazolidones, the aim of the current contribution was to design and synthesize a series of these compounds derived from α-amino acids and evaluate them (in silico and in vitro) as inhibitors of ACE and acetylcholinesterase (AChE).

The best candidates were examined for their in vivo antihypertensive activity to regulate high blood pressure in male spontaneously hypertensive rats. Although boron-containing compounds were once thought to be toxic in any medical context, they have increasingly been used as antibiotics, antiseptics, and antineoplastic agents. BXZ-His, BXZ-Lys, BXZ-Orn, BXZ-Phe, and BXZ-Pro were selected in silico as promising ACE and AChE inhibitors. After synthesis, these molecules were tested in vitro as ACE and AChE inhibitors, finding that most were effective at micromolar concentrations. The two best candidates, BXZ-Lys and BXZ-His, were evaluated in vivo with spontaneously hypertensive rats.

BXZ-Lys significantly decreased systolic, diastolic, and mean blood pressure, being more potent than a common ACE inhibitor, captopril.

Future research is required to elucidate the mechanism of action of this antihypertensive effect.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. With an increasing number of patients, NAFLD has been identified as a risk factor for Hepatocellular Carcinoma (HCC). The precise pathophysiology of NAFLD-related HCC has not been completely understood recently.

We analyzed the hub genes related to NAFLD and HCC to predict the risk of NAFLD progressing to HCC.

Two datasets of NAFLD were used to identify differentially expressed genes. Lasso-Cox regression analysis was performed to determine a gene model to predict the risk of the progression from NAFLD to HCC. Three validation datasets were analyzed to evaluate the performance of the gene model, including normal and NAFLD with fibrosis, NAFLD with fibrosis and NAFLD-related HCC, and normal and NASH-related HCC.

Seven genes, including COL1A1, TIPM1, VCAN, FOS, CD79A, CXCL9, and VWF, were identified as the hub genes, and then a gene model was constructed. By calculating, the area under the receiver operating characteristic curves (AUCs) for risk prediction were 0.97, 0.886, and 0.751 in the three validation datasets, respectively. Gene set enrichment analysis indicated that the MAPK, TGFβ, p53, PPAR, insulin signaling pathways, and fatty acid metabolism were significantly upregulated in the high-risk group. GTPase activity and intrinsic apoptotic signaling pathway had significant upregulation in the low-risk group.

The seven hub genes may predict the risk of NAFLD developing into HCC by mediating the potential molecular mechanism, which could be used as biomarkers for predicting the progression, diagnosis, and treatment of NAFLD.

The aims of this study are to discover dysregulated adipocytokine signaling pathway and pyroptosis-related genes to predict neonatal hypoxic-ischemic encephalopathy (HIE) occurrence.

HIE is an important cause of infant death and long-term neurological sequelae. Current treatment options for HIE are relatively limited and the pathogenesis of HIE remains to be fully explored. This study investigated the alterations of adipocytokine signaling pathway and pyroptosis in neonatal HIE.

To reveal the alterations of adipocytokine signaling pathway and pyroptosis relevant to HIE occurrence.

Data on neonatal HIE were downloaded from the Gene Expression Omnibus (GEO) database. Pathway analyses of single-sample gene set enrichment analysis (ssGSEA) and GSEA were performed on the adipocytokine signaling pathway and pyroptosis. Proportions of immune cells in a single sample were also calculated by ssGSEA and CIBERSORT algorithm. The relationship between the adipocytokine signaling pathway and pyroptosis was analyzed according to Pearson correlation analysis.

The activities of KEGG pathways changed after the occurrence of HIE, and adipocytokine signaling pathway was activated with related overexpressed genes. For the three energy metabolisms, carbohydrate metabolism was enhanced; lipid metabolism showed increased fatty acids metabolism and decreased ability of fatty acids synthesis; metabolic levels of phosphate and phenylalanine in amino acid metabolism were elevated. Enhanced pyroptosis and relevant overexpressed genes were accompanied by increased immune cells. A positive connection between adipocytokine signaling pathway and pyroptosis was observed.

These results indicated that the adipocytokine signaling pathway may promote HIE occurrence by upregulating the expression of pyroptosis-related genes, providing a novel mechanism for HIE.

This study was to explore the relationship between plasma exosomes and Acute myocardial infarction (AMI).

Acute myocardial infarction (AMI) is one of the most common cardiovascular complications. Recent studies have shown that exosomes play a crucial role in the development and progression of cardiovascular diseases. However, there is a lack of relevant research on the relationship between plasma exosomes and AMI.

This study was designed to explore the relationship between plasma exosomes and AMI.

This retrospective study collected the basic clinical data of patients with AMI (n = 10), stable angina pectoris (SAP, n = 10), and noncoronary heart disease (CON, n = 10) at the Department of Cardiovascular Medicine at Taizhou Hospital (Zhejiang, China, 2021.01 to 2021.12). Proteomics was used to systematically screen the differential proteins of plasma exosomes in patients with clinical AMI, SAP, and CON. Then, the results were further verified using parallel reaction monitoring (PRM).

Five of all the differentially expressed proteins (DEPs) were quantified by PRM. Compared with the CON group, heparin cofactor 2 (SERPIND1), mannan-binding lectin serine protease 1 (MASP1), ficolin-2 (FCN2), and α1-Microglobulin/bikunin precursor (AMBP) were upregulated in patients with AMI and SAP, with a higher expression in AMI than in SAP. Additionally, human leukocyte antigen (HLA-C) was downregulated in both exosomes and plasma.

The expression of four plasma exosome biomarkers in AMI and SAP patients was higher than that in noncoronary heart disease (NCHD) patients. HLA-C was downregulated in both exosomes and plasma, showing a potential to serve as a new candidate target for the detection and therapy of AMI.

Cyclin-dependent kinase 1 (CDK1) regulates the cell cycle and is highly expressed in most tumors. CDK1 expression has been associated with poor disease prognosis. This study aimed to identify the prognostic value of CDK1 in pan-cancer and investigate the association between CDK1 expression and immune cell infiltration.

CDK1 expression and its correlation with prognosis in pan-cancer were analyzed using online databases. Immune infiltration was assessed by ESTIMATE and CIBERSORT algorithms. We then evaluated the relationship between CDK1 expression and tumor mutational burden (TMB), microsatellite instability (MSI), or tumor-infiltrating immune cells. In addition, we performed the co-expression analysis of immune-related genes and GO analysis with CDK1 expression in pan-cancer. Finally, we compared the CDK1 expression profile with the immune-related genes in 30 pairs of clinical gastrointestinal tumor samples.

Our analysis demonstrated overexpression of CDK1 in most tumor tissues, especially in gastrointestinal tumors. The high expression of CDK1 was associated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), and sarcoma (SARC). Besides, CDK1 expression was significantly associated with TMB in 22 cancer types and MSI in 8 cancer types as well as greater frequencies of MSI-high (MSI-H) status and high tumor mutational burden (TMB-H) in uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), sarcoma (SARC), rectum adenocarcinoma (READ), mesothelioma (MESO), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD). In addition, CDK1 expression correlated with immune cell infiltrating levels, such as M0, M1, or M2 macrophages, memory CD4 T cells, T follicular helper cells, and naive B cells. Our data showed that CDK1 was remarkably correlated with 47 immune-related and immune checkpoint genes in many cancer types. Furthermore, CDK1 was up-regulated in gastrointestinal tumor samples, especially in gastric cancer and intestinal cancer. CDK1 was positively correlated with IDO1 in gastric cancer and PD-1 in intestinal cancer.

Taken together, our data demonstrated the roles of CDK1 in oncogenesis and metastasis in pan-cancer. Thus, CDK1 is a potential prognostic biomarker and a target for tumor immunotherapy.