Design and synthesis of oridonin derivatives as cytotoxic agents.

Oridonin is one of the ent-kaurane diterpenes that have been studied extensively for various bioactivities. In an effort to expand natural scaffold-based library as anticancer agents, we have designed and synthesised a number of novel oridonin derivatives and evaluated their bioactivities on a panel of human cancer cell lines (HCT116, A375, MCF-7, HepG2, and A549). Compound 4b bearing a 4-fluorophenyl moiety was found to be the most active compound with an IC50 value of 0.3 µM against MCF-7 cells, which was 7.4-fold more active than oridonin. This study could provide some insightful information for further synthesis of oridonin derivatives as anticancer agents.

Association Between Endometriosis and Prognosis of Ovarian Cancer: An Updated Meta-Analysis.

Objective: Increased risk of ovarian cancer (OC) among endometriosis patients has been proposed. However, the association between endometriosis and prognosis of OC remains controversial. This study evaluated whether endometriosis had influence on the survival outcomes of OC through a meta-analysis. Methods: Relevant studies were retrieved from PubMed, Embase, and Web of Science databases and were evaluated using the Newcastle-Ottawa Quality Assessment Scale. Effect size was presented as hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity test evaluation was performed using Cochran's Q test and I2 statistics. Publication bias was determined using Egger's test. Statistical analysis was performed using Stata 12.0 software. Results: Twenty-one studies involving 38641 patients were included. For the total OC, there were significant differences in overall survival (OS) [HR (95% CI)=0.67 (0.55, 0.80), P<0.001] and progression-free survival (PFS) [HR (95% CI)=0.58 (0.42, 0.81), P=0.001] between endometriosis-associated ovarian cancer (EAOC) and non-EAOC patients in the random-effects models (P<0.05). For ovarian clear cell cancer, there were significant differences in terms of OS [HR (95% CI)=0.63 (0.48, 0.83), P=0.001] and PFS [HR (95% CI)=0.67 (0.52, 0.87), P=0.002] between EAOC and non-EAOC patients in the fixed-effects models (P>0.05). Subgroup analysis suggested no significant differences between EAOC and non-EAOC in OS and PFS in the univariate analysis per subgroup, and PFS in the American subgroup (P>0.05). Conclusion: EAOC patients tended to have better OS and PFS than non-EAOC patients. Conducting higher quality prospective cohort studies with large sample sizes is recommended to confirm the authenticity of the current study's results. Systematic Review Registration: https://inplasy.com/inplasy-2022-3-0109/.

Circ_ROBO2/miR-149 Axis Promotes the Proliferation and Migration of Human Aortic Smooth Muscle Cells by Activating NF-κB Signaling.

Atherosclerosis is the leading global cause of mortality. The occurrence of coronary artery disease (CAD) is regulated by a diversity of pathways, including circRNAs. However, the potential mechanisms of circRNAs in CAD remain unclear. Here, qRT-PCR was used to examine the expressions of miR-149 and circ_ROBO2. Their influences on cell proliferation, migration, and apoptosis were measured by CCK-8, trans-well, and flow cytometry assays, respectively. The protein levels of p-IκBα and NF-κB p65 were examined using western blot. The molecular interactions were validated using dual luciferase reporter and RNA pull-down assays. The expression patterns of circ_ROBO2 and miR-149 in CAD patients and PDGF-BB-treated human aortic smooth muscle cells (HASMCs) were upregulated and downregulated, respectively. Knockdown of circ_ROBO2 could markedly inhibit the capabilities of proliferation and migration, enhance the apoptotic rate, and suppress NF-κB signaling in PDGF-BB-treated HASMCs. Mechanistically, circ_ROBO2 acted as a sponge of miR-149 to activate TRAF6/NF-κB signaling. Rescue studies demonstrated that neither silencing miR-149 nor activation of NF-κB signaling obviously abolished the biological roles of circ_ROBO2 knockdown in PDGF-BB treated-HASMCs. This discovery elucidated a functional mechanism of circ_ROBO2 in CAD, suggesting that circRNAs serve a vital role in the progression of CAD.

Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism.

The cardiac and hematopoietic progenitors (CPs and HPs, respectively) in the mesoderm ultimately form a well-organized circulation system, but mechanisms that reconcile their development remain elusive. We found that activating transcription factor 3 (atf3) was highly expressed in the CPs, HPs, and mesoderm, in zebrafish. The atf3 -/- mutants exhibited atrial dilated cardiomyopathy and a high ratio of immature myeloid cells. These manifestations were primarily caused by the blockade of differentiation of both CPs and HPs within the anterior lateral plate mesoderm. Mechanistically, Atf3 targets cebpγ to repress slc2a1a-mediated glucose utilization. The high rate of glucose metabolism in atf3 -/- mutants inhibited the differentiation of progenitors by changing the redox state. Therefore, atf3 could provide CPs and HPs with metabolic adaptive capacity to changes in glucose levels. Our study provides new insights into the role of atf3 in the coordination of differentiation of CPs and HPs by regulating glucose metabolism.

Role of Noncoding RNA in Pulmonary Arterial Hypertension and Potential Drug Therapeutic Target.

Pulmonary arterial hypertension (PAH) is a devastating disease without effective drugs available for its treatment. An in-depth exploration of the pathogenesis of PAH, as well as inquiry into potential therapeutic targets, remains an urgent issue. Non-coding RNAs (ncRNAs) have arisen as key players in malignant tumors, cardiovascular diseases and more recently in PAH progression and development. Network pharmacology is a new discipline based on system biology, which can predict potential therapeutic targets in diseases regulated by multiple genes. In this review, we discuss the current knowledge of ncRNAs and network pharmacology regulated genes involved in PAH, as well as the search for potential drug targets for PAH.

The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors.

Vasculogenic defects of great vessels (GVs) are a major cause of congenital cardiovascular diseases. However, genetic regulators of endothelial precursors in GV vasculogenesis remain largely unknown. Here we show that Stat4, a transcription factor known for its regulatory role of pro-inflammatory signalling, promotes GV vasculogenesis in zebrafish. We find stat4 transcripts highly enriched in nkx2.5+ endothelial precursors in the pharynx and demonstrate that genetic ablation of stat4 causes stenosis of pharyngeal arch arteries (PAAs) by suppressing PAAs 3-6 angioblast development. We further show that stat4 is a downstream target of nkx2.5 and that it autonomously promotes proliferation of endothelial precursors of the mesoderm. Mechanistically, stat4 regulates the emerging PAA angioblasts by inhibiting the expression of hdac3 and counteracting the effect of stat1a. Altogether, our study establishes a role for Stat4 in zebrafish great vessel development, and suggests that Stat4 may serve as a therapeutic target for GV defects.