Design, synthesis and antifungal activity of novel α-methylene-γ-butyrolactone derivatives containing benzothiophene moiety.

BACKGROUND: The discovery of agricultural fungicide candidates from natural products is one of the key strategies for developing environment friendly agricultural fungicides with high efficiency, high selectivity and unique modes-of-action. Based on previous work, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing benzothiophene moiety were designed and synthesized. RESULTS: The majority of the proposed compounds displayed moderate to considerable antifungal efficacy against the tested pathogenic fungi and oomycetes, some exhibiting broad spectrum antifungal activity. Notably, compounds 2 (3-F-Ph) and 7 (4-Cl-Ph) showed excellent antifungal activity against Rhizoctonia with half maximal effective concentration (EC50) values of 0.94 and 0.99 mg L-1, respectively, comparable to the commercial fungicide tebuconazole (EC50 = 0.96 mg L-1), and also displayed significant inhibitory effects against V alsa mali with EC50 values of 2.26 and 1.67 mg L-1, respectively - better than famoxadone and carabrone. The in vivo protective and curative effects against R. solani of compound 2 were 57.2% and 53.7% at 100 mg L-1, respectively, which were equivalent to tebuconazole (51.6% and 52.4%). Further investigations found that compound 2 altered the ultrastructure of R. solani cell, significantly increased the relative conductivity of the cells, and reduced the activity of complex III in a dose-dependent manner. Molecular docking results showed that compound 2 matched well with the Qo pocket. CONCLUSION: The results revealed that MBL derivatives containing benzothiophene moiety are promising antifungal candidates and provide a new backbone structure for further optimization of novel fungicides. © 2024 Society of Chemical Industry.

GSDMD-mediated pyroptosis: a critical mechanism of diabetic nephropathy.

Pyroptosis is a recently identified mechanism of programmed cell death related to Caspase-1 that triggers a series of inflammatory reactions by releasing several proinflammatory factors such as IL-1ß and IL-18. The process is characterised by the rupture of cell membranes and the release of cell contents through the mediation of gasdermin (GSDM) proteins. GSDMD is an important member of the GSDM family and plays a critical role in the two pathways of pyroptosis. Diabetic nephropathy (DN) is a microvascular complication of diabetes and a major cause of end-stage renal disease. Recently, it was revealed that GSDMD-mediated pyroptosis plays an important role in the occurrence and development of DN. In this review, we focus on two types of kidney cells, tubular epithelial cells and renal podocytes, to illustrate the mechanism of pyroptosis in DN and provide new ideas for the prevention, early diagnosis and molecular therapy of DN.

Increased index of microcirculatory resistance in older patients with heart failure with preserved ejection fraction.

OBJECTIVE: To study the coronary microvascular function in older patients with heart failure with preserved ejection fraction (HFpEF) using an invasive pressure-temperature sensor guidewire. METHODS: Patients undergoing echocardiography and cardiac catheterization examinations for exertional dyspnea and a positive stress test were retrospectively enrolled from January 2014 to November 2017, and were allocated into the control group or HFpEF group. The HFpEF group was secondary divided into two groups according to the age of 65. Comparing the clinical features and values obtained in examinations between the three groups, multivariate regression analysis was used to analyze the predictors of left ventricle end diastolic pressure (LVEDP). RESULTS: There were 87 patients enrolled in this study. The older HFpEF patients (n = 32) were more likely to be female; and had the most comorbidities, such as diabetes mellitus, atrial fibrillation, and chronic kidney dysfunction (CKD) with a low estimated glomerular filtration rate (eGFR), and had a similar hypertensive prevalence as the adult HFpEF group (n = 24), whose mean LVEDP and index of microcirculatory resistance (IMR) were highest in comparison to the adult HFpEF patients and controls (n = 31). The coronary flow reserve (CFR) in the older HFpEF and adult HFpEF groups was similarly reduced. In the regression analysis, the IMR linearly correlated to LVEDP, and was the only independent predictor of LVEDP. CONCLUSIONS: An increased IMR and reduced CFR were characteristics of microvascular dysfunction in older HFpEF patients. The IMR independently had a positive linear correlation with LVEDP. Microvascular rarefaction might be a subsequent pathological progression in the development of HFpEF.

Genetic polymorphisms of UTS2 rs2890565 Ser89Asn in coronary heart disease and myocardial infarction in Chinese population.

OBJECTIVE: Atherosclerosis plays a key role in the inducibility and persistence of coronary heart disease. Clinical evidence, in vitro and in vivo studies have implicated Urotensin II (U-II/UTS2) in the development of atherosclerosis and coronary artery disease, contributing to the (patho) physiological regulation of cardiovascular homeostasis in humans. Increased U-II plasma levels have been reported in patients with atherosclerosis and coronary heart disease. Considering these, our objective was to evaluate possible role of the UTS2 gene polymorphisms (Thr21Met and Ser89Asn) in the genetic susceptibility to coronary heart disease and myocardial infarction in a Chinese population. METHODS: A case-control study was designed to compare the distribution of alleles and genotypes between case group (subjects with myocardial infarction, n=409) and control group (subjects with coronary heart disease, n=830). The detection of UTS2 gene polymorphisms was achieved with PCR-RFLP technique. RESULTS: We did not identify statistically significant differences between the myocardial infarction and coronary heart disease groups, neither with regard to the frequency of genotype/variant at the Ser89Asn locus nor at the Thr21Met locus. When stratified by sex, differences in genotype distribution of polymorphism Ser89Asn were only seen in female subjects in both additive tested inheritance model (OR=0.257, 95% CI: 0.074-0.896, P=0.033) and recessive tested inheritance model (OR=0.280, 95% CI: 0.082-0.955, P=0.042). For subjects with myocardial infarction, we identified statistically significant differences between the ST-segment elevation myocardial infarction and non ST-segment elevation myocardial infarction groups. Differences in genotype distribution of polymorphism Ser89Asn not Thr21Met were seen in both additive tested inheritance model (OR=0.202, 95% CI: 0.049-0.833, P=0.027) and recessive tested inheritance model (OR=0.208, 95% CI: 0.052-0.835, P=0.027). When stratified by sex, differences in genotype distribution of polymorphism Ser89Asn were only seen in male subjects in both additive tested inheritance model (OR=0.208, 95% CI: 0.049-0.890, P=0.034) and recessive tested inheritance model (OR=0.197, 95% CI: 0.047-0.824, P=0.026). CONCLUSIONS: Ser89Asn (S89N) polymorphisms of the UTS2 gene were significantly associated with coronary heart disease and myocardial infarction in Chinese population. Additionally, we demonstrated that Genotype Asn89Asn may imply a potential benefit role for myocardial infarction.

Up-regulating relaxin expression by G-quadruplex interactive ligand to achieve antifibrotic action.

Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.

The formation and stabilization of a novel G-quadruplex in the 5'-flanking region of the relaxin gene.

It has been reported that binding of STAT3 protein to the 5'-flanking region of the relaxin gene may result in downregulation of the relaxin expression. There is a Guanine(G)-rich segment located in about 3.8 Kb upstream of the relaxin gene and very close to the STAT3's binding site. In our study, NMR spectroscopy revealed the formation of G-quadruplex by this G-rich strand, and the result was confirmed by ESI mass spectrometry and CD spectroscopy. The theoretical structure of RLX G-quadruplex was constructed and refined by molecular modeling. When this relaxin G-quadruplex was stabilized by berberine(ΔTm = 10°C), a natural alkaloid from a Chinese herb, the gene expression could be up-regulated in a dose-dependent manner which was proved by luciferase assay. This result is different from the general G-quadruplex function that inhibiting the telomere replication or down-regulating many oncogenes expression. Therefore, our study reported a novel G-quadruplex in the relaxin gene and complemented the regulation mechanism about gene expression by G-quadruplexes.

Angiopoietin-1/Tie2 signaling pathway inhibits lipopolysaccharide-induced activation of RAW264.7 macrophage cells.

Angiopoietin-1 (Ang1) is a ligand for the endothelial-specific tyrosine kinase receptor Tie2 and has been shown to play an essential role in embryonic vasculature development. There have been many studies about the anti-inflammatory effects of Ang1, most of which focus on endothelium cells. In the present study, we explore the role of Ang1-Tie2 signaling in the activation of macrophages upon lipopolysaccharide (LPS) stimulation. We found that Tie2 receptor is expressed on macrophages and Ang1 could inhibit LPS-induced activation of macrophages, as evidenced by cell migration and TNF-alpha production, specifically through Tie2 receptor. We further investigated the mechanism and found that Ang1-Tie2 could block LPS-induced activation of NF-kappaB which has been shown to be necessary for macrophage activation with LPS treatment. Thus, we described, for the first time, the role of Ang1-Tie2 signaling in macrophage activation and the possible mechanisms in response to immune stimulation.