YAP-galectin-3 signaling mediates endothelial dysfunction in angiotensin II-induced hypertension in mice.

BACKGROUND: Vascular endothelial dysfunction is regarded as an early event of hypertension. Galectin-3 (Gal-3) is known to participate in various pathological processes. Whilst previous studies showed that inhibition of Gal-3 effectively ameliorates angiotensin II (Ang II)-induced atherosclerosis or hypertension, it remains unclear whether Ang II regulates Gal-3 expression and actions in vascular endothelium. METHODS: Using techniques of molecular biology and myograph, we investigated Ang II-mediated changes in Gal-3 expression and activity in thoracic aortas and mesenteric arteries from wild-type and Gal-3 gene deleted (Gal-3-/-) mice and cultured endothelial cells. RESULTS: The serum level of Gal-3 was significantly higher in hypertensive patients or in mice with chronic Ang II-infusion. Ang II infusion to wild-type mice enhanced Gal-3 expression in the aortic and mesenteric arteries, elevated systolic blood pressure and impaired endothelium-dependent relaxation of the thoracic aortas and mesenteric arteries, changes that were abolished in Gal-3-/- mice. In human umbilical vein endothelial cells, Ang II significantly upregulated Gal-3 expression by promoting nuclear localization of Yes-associated protein (YAP) and its interaction with transcription factor Tead1 with enhanced YAP/Tead1 binding to Gal-3 gene promoter region. Furthermore, Gal-3 deletion augmented the bioavailability of nitric oxide, suppressed oxidative stress, and alleviated inflammation in the thoracic aorta of Ang II-infused mice or endothelial cells exposed to Ang II. CONCLUSIONS: Our results demonstrate for the first time that Ang II upregulates Gal-3 expression via increment in YAP nuclear localization in vascular endothelium, and that Gal-3 mediates endothelial dysfunction contributing to the development of hypertension.

Synthesis of Chiral 2,3-Dihydrofurans via One-Pot Pd-Catalyzed Asymmetric Allylic Cycloaddition and a Retro-Dieckmann Fragmentation Cascade.

An efficient method for the enantioselective synthesis of 2,3-dihydrofurans bearing a quaternary stereocenter has been developed via Pd-catalyzed asymmetric allylic cycloaddition and a retro-Dieckmann Fragmentation cascade. The asymmetric allylic cycloaddition of vinylethylene carbonates with 3-cyanochromone followed by base-assisted retro-Dieckmann fragmentation proceeded smoothly via a one-pot process to produce chiral 3,4-disubstituted 2,3-dihydrofurans in high yields with excellent enantioselectivities.

Pd-Catalyzed regio- and stereoselective allylic substitution of vinylethylene carbonates with 1,2,4-triazoles.

N 1-Substituted 1,2,4-triazoles are ubiquitous skeletons in medicinal agents, agrochemicals, and organic materials. Herein, an efficient and practical method for the synthesis of N1-allylated 1,2,4-triazoles via Pd-catalyzed allylic substitution of vinylethylene carbonates (VECs) with 1,2,4-triazoles has been developed. By using a catalyst generated in situ from Pd2(dba)3·CHCl3 and DPPE under mild conditions, the process allows rapid access to N1-allylated 1,2,4-triazoles bearing diverse functionalities in high yields with excellent N1-selectivities, linear-selectivities, and Z-stereoselectivities.

Tandem arylation and regioselective allylic etherification of 2,3-allenol via Pd/B cooperative catalysis.

An efficient method for the construction of arylated allylic ethers was developed via three-component tandem arylation and allylic etherification of 2,3-allenol with aryl iodides and alcohols. In the cooperative catalytic system of a palladium complex and triethylborane, the process allows rapid access to functionalized 1-arylvinylated 1,2-diol derivatives in good to high yields with complete branch-selectivities. The synthetic utility of the present process was demonstrated by the late-stage functionalization of a drug molecule, the gram-scale synthesis and the elaboration of the products.

Enantioselective Construction of Tertiary C-O Bond via Allylic Substitution of Vinylethylene Carbonates with Water and Alcohols.

An efficient method for the enantioselective construction of tertiary C-O bond via asymmetric allylic substitution of racemic vinylethylene carbonates with water and alcohols has been developed. Under the cooperative catalysis system of an in situ generated chiral palladium complex and boron reagent in mild conditions, the process allowed rapid access to valuable tertiary alcohols and ethers in high yields with complete regioselectivities and high enantioselectivities. This protocol represented the first example of direct enantioselective formation of a tertiary C-O bond with water as an oxygen donor. The synthetic utilities of the process have been demonstrated by the elaboration of the products into key intermediates of biologically relevant agents, and chiral tertiary cyclic ethers could also be provided through the sequential reactions of the allylic etherification and ring-closing metathesis.

CTRP9 regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and migration via TGF-ß1/ERK1/2 signaling pathway.

Hypoxia is an important risk factor for pulmonary arterial remodeling in pulmonary arterial hypertension (PAH). Vascular remodeling in hypoxia-induced PAH is driven by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). The purpose of the present study was to explore the expression of CTRP9 in rats model of hypoxia-induced PAH and investigate the effects of CTRP9 on HPASMCs function in vitro and determine the underlying mechanisms. We established a rat model of hypoxic PAH, which showed a downregulation of CTRP9 expression. In HPASMCs cultured under the condition of hypoxia, treatment with CTRP9 notably restrained cell proliferation responses to hypoxia accompanied with decreased two biomarkers of cell proliferation Ki-67 and PCNA. Meanwhile, CTRP9 strikingly promoted hypoxia-mediated cell apoptosis as reflected by upregulation of Bax and downregulation of Bcl-2, as well as enhanced Caspase 3 activity. Additionally, CTRP9 treatment dramatically prevented the migratory potential by declined the expression of MMP-2 and MMP-9. Moreover treatment with CTRP9 augmented hypoxia-mediated differentiation by elevating the expression level of differentiation markers α-SMA and SM22. Mechanistically, anti-proliferative effects conferred by CTRP9 are mediated through suppression of TGF-ß1/ERK1/2 pathway. Collectively, we identified CTRP9 as a novel mediator of PASMC growth in hypoxia-mediated PAH, indicating that CTRP9 in the pulmonary vasculature may be an underlying mechanism in the development of hypoxia-induced PAH. Our study, for the first time, established that CTRP9 plays a protective role of CTRP9 in pulmonary vascular remodeling, pointing to its potential clinical value for patients with PAH.

Palladium-catalyzed enantioselective decarboxylative cycloaddition of vinylethylene carbonates with isocyanates.

An efficient method for the enantioselective construction of ß-substituted ß-vinylglycinol derivatives through palladium-catalyzed decarboxylative cycloaddition of vinylethylene carbonates with isocyanates was developed. By using a palladium complex generated in situ from [Pd2 (dba)3]⋅CHCl3 (dba=dibenzylideneacetone) and (S)-Segphos as a catalyst under mild reaction conditions, the process provided 4-substituted-4-vinyloxazolidin-2-ones in high yields with a high level of enantioselectivity. The stereochemical outcome of the reaction was explained by DFT calculations and the synthetic utility of the process was demonstrated by the gram-scale transformation and formal synthesis of MK-0731 as a kinesin spindle protein inhibitor.

N-[4-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methylphenyl]-N'-[2-(dimethylamino)] benzoylurea induces cell-cycle arrest and apoptosis in human cancer cells.

N-[4-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methylphenyl]-N'-[2-(dimethylamino)]benzoylurea (SUD) is a novel synthesized benzoylurea derivative. We selected several human cancer cell lines to investigate whether SUD can inhibit the growth of cancer cells. We selected the liver cell line L-02 to investigate the effect of SUD on the normal cells. Flow cytometric analysis was used to detect the effect of SUD on cell cycle, Hoechst 33258 staining was used to evaluate the apoptosis induced by SUD, real-time fluorescence quantitative PCR was used to investigate the expression of the cell cycle-relevant and apoptosis-relevant genes, a reactive oxygen species (ROS) assay was used to observe the production of ROS, and western blotting was used to determine the level of cell cycle-relevant and apoptosis-relevant proteins. According to the results of the MTT assay, the growth of human cancer cell lines was significantly inhibited by SUD treatment in a time-dependent and concentration-dependent manner; however, the growth of human normal cells was not significantly inhibited by SUD treatment. The results of flow cytometric analyses showed that SUD induced cell-cycle arrest at the G2-phase in MCF-7 cells and at the G1-phase in BGC-823 cells. The results of Hoechst 33258 staining showed that SUD induced apoptosis in MCF-7 and BGC-823 cells. The results of the ROS assay showed that the production of ROS was increased by SUD in MCF-7 and BGC-823 cells. Our research suggests that the growth-inhibitory effect of SUD on MCF-7 cells was related to G2-phase arrest, which was associated with the upregulated expression of p53 and Chk1 proteins, and downregulation of the cyclin B1 gene, cdc25a, and cyclin-dependent kinase 1 (CDK1) proteins; the growth-inhibitory effect of SUD on BGC-823 cells was related to G1-phase arrest, which was associated with upregulation of the p53 gene and Chk1 protein and downregulation of cdc25a protein and the CDK4 gene. SUD also induced apoptosis in MCF-7 and BGC-823 cell lines through the mitochondrial pathway in a p53-dependent manner.

Effect of miR-503 Down-Regulation on Growth and Invasion of Esophagus Carcinoma and Related Immune Function.

BACKGROUND MicroRNA (miR) has been proved to be an important biomarker for tumors because it can regulate occurrence, progression, invasion, and metastasis of cancer. A previous study has shown the involvement of miR-503 in multiple gastrointestinal tumors. Its detailed role and immune regulatory function in esophagus carcinoma, however, remains unknown. This study thus investigated the effect of miR-503 in regulating growth, proliferation, and invasion of esophagus cancer and its influence on cytokine secretion. MATERIAL AND METHODS Esophagus carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were transfected with miR-503 inhibitor. MTT assay was used to quantify the cell proliferation, and a Transwell chamber was used to evaluate cell invasion. Release of cytokines, including interleukin-2 (IL-2), IL-4, IL-10, and interferon-γ (IFN-γ), was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS MiR-503 expression was significantly elevated in esophagus carcinoma cells (p<0.05). The specific inhibition of miR-503 expression remarkably suppressed proliferation and invasion of tumor cells. It can also down-regulated IL-2 and IFN-γ expression and facilitate secretion of IL-4 and IL-10 when compared to the control group (p<0.05 in all ceases). CONCLUSIONS The inhibition of miR-503 can effectively inhibit tumor progression and improve immune function, suggesting its potency as a novel drug target for esophagus cancer treatment.

[m-Nisodipine inhibited 5-HT-induced proliferation of rat PASMCs through Rho/ROCK signal pathway].

This paper is to report the exploration of the activation of Rho/ROCK signal pathway in 5-HT-induced proliferation of rat pulmonary artery smooth muscle cells (PASMCs) and the inhibitory effect of m-Nis on this pathway. PASMCs were cultured with the explant technique. MTT assay was used to explore the proliferation of PASMCs after 5-HT treated for different time and the intervening effect of m-Nis. RT-PCR and Western blot were used respectively to explore the mRNA expression of RhoA, ROCK1 and the protein expression of p-MYPT1 in 5-HT-treated PASMCs and intervening effect of m-Nis. The results of MTT assay suggested that 5-HT (1 µmol · L(-1)) treatment for 12-72 h significantly induced the proliferation of rat PASMCs (P<0.05 or P < 0.01), which were inhibited by m-Nis (1 x 10(-5), 1 x 10(-6), l x 10(-7), 1 x10(-8) mol · L(-1)) in dose-dependent manners (P < 0.05 or P < 0.01). Similarly, the mRNA expression of RhoA, ROCK1 and the protein expression of p-MYPT1 were also inhibited by m-Nis in different degrees (P < 0.05 or P < 0.01). Thus, the results of this study suggested that Rho/ROCK pathway played an important role in 5-HT-induced proliferation of rat PASMCs, m-Nis inhibited 5-HT-induced proliferation obviously, which may be related to the blockage of Rho/ROCK signal pathway.

Palladium-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates with Michael acceptors: construction of vicinal quaternary stereocenters.

An efficient method for the diastereo- and enantioselective construction of vicinal all-carbon quaternary stereocenters through palladium-catalyzed decarboxylative cycloaddition of vinylethylene carbonates with activated Michael acceptors was developed. By using a palladium complex generated in situ from [Pd2(dab)3]⋅CHCl3 and a phosphoramidite ligand as a catalyst under mild reaction conditions, the process provides multifunctionalized tetrahydrofurans bearing vicinal all-carbon quaternary stereocenters in high yields with a high level of absolute and relative stereocontrol.

Palladium-catalyzed decarboxylative cycloaddition of vinylethylene carbonates with formaldehyde: enantioselective construction of tertiary vinylglycols.

An efficient method for the enantioselective construction of tertiary vinylglycols through a palladium-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates with formaldehyde was developed. By using a palladium complex generated in situ from [Pd2(dba)3]⋅CHCl3 and a phosphoramidite ligand as a catalyst under mild reaction conditions, the process allows conversion of racemic 4-substituted 4-vinyl-1,3-dioxolan-2-ones into the corresponding 1,3-dioxolanes, as methylene acetal protected tertiary vinylglycols, in high yields with good to excellent enantioselectivities.

Synthesis of polyvinylethylene glycols (PVEGs) via polyetherification of vinylethylene carbonate by synergistic catalysis.

An efficient and controllable polyetherification of vinylethylene carbonate (VEC) using diols as initiators is developed. By using a synergistic catalysis with palladium and boron reagents under mild conditions, the polymerization process enables the regioselective production of a series of polyvinylethylene glycols (PVEGs) bearing pendent vinyl groups in high yields with accurate molecular weight control and narrow molecular weight distribution. The utility of PVEGs is demonstrated by the production of functional polyurethanes and post-polymerization modification via thiol-ene photo-click chemistry.

The relationship between pre-operative right ventricular longitudinal strain and low-cardiac-output syndrome after surgical aortic valve replacement.

Objectives: This study was performed to investigate the relationship between right ventricular free wall longitudinal strain (RVFWSL) and low cardiac output syndrome (LCOS) after surgical aortic valve replacement (SAVR) and to further explore its association with readmission within 2 years in patients who developed LCOS after SAVR. Methods: This single-center retrospective observational study involved consecutive patients who underwent SAVR at our hospital from May 2018 to June 2020. Preoperative echocardiography was obtained within 3 days before SAVR. The longitudinal strain of the right ventricle was analyzed using the right ventricle as the main section, and the RVFWSL and right ventricular four-chamber longitudinal strain (RV4CSL) were obtained. The primary observation was the occurrence of LCOS. The secondary prognostic indicators were mainly the readmission rates within 2 years. Results: In total, 146 patients were finally included in this study. The RVFWSL was significantly lower in the LCOS group than in the No-LCOS group (16.63 ± 2.10) vs. (23.95 ± 6.33), respectively; P < 0.001). The multivariate regression analysis showed that the RVFWSL was associated with LCOS (odds ratio, 1.676; 95% confidence interval, 1.258-2.232; P < 0.001). The receiver operating characteristic curve showed that the cut-off value for RVFWSL to predict LCOS was less than -18.3, with an area under the curve of 0.879, sensitivity of 100%, and specificity of 80.47%. The multivariate regression analysis showed that LCOS was an independent risk factor for readmission within 2 years in patients undergoing SAVR. Conclusion: Patients with RVFWSL (<-18.3%) may be an increased risker for LCOS after SAVR. The occurrence of LCOS after SAVR is Yong-jian Zhang a risk factor for readmission within 2 years. Right ventricular function monitoring may have some predictive value for the postoperative prognosis in patients undergoing SAVR.

Left epigastric isolated tumor fed by the inferior phrenic artery diagnosed as ectopic hepatocellular carcinoma: A case report.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most frequent cancers and the main cause of cancer-related death worldwide. Ectopic HCC, an extremely rare type of HCC, exhibits a wide range of clinical signs and radiographic features, making preoperative identification challenging. CASE SUMMARY: A 47-year-old man underwent routine abdominal color ultrasonography, which identified an asymptomatic tumor in the left upper abdomen. The patient had no history of hepatitis, did not drink alcohol, and had no family history of cancer. Abdominal contrast-enhanced computed tomography (CT) revealed a heterogeneously enhanced lesion between the spleen and stomach that had invaded the diaphragm, with blood supplied by the left inferior phrenic artery. The patient underwent laparoscopic surgery, and HCC was identified by postoperative pathology. Additionally, specific immunohistochemical staining was performed to assess the molecular biological characteristics of the HCC. The patient underwent two rounds of hepatic arterial interventional chemotherapy after surgery. Abdominal plain and enhanced magnetic resonance imaging and lung CT 3 mo postoperatively revealed no signs of local recurrence or distant metastasis. CONCLUSION: This asymptomatic ectopic HCC case described achieved an excellent result due to early detection, radical resection, and systematic surveillance.

Pd-Catalyzed Asymmetric Three-Component Allenol Carbopalladation and Allylic Cycloaddition Cascade: A Route to Functionalized Tetrahydrofurans.

The first Pd-catalyzed asymmetric three-component reaction of 2,3-allenol, aryl iodides, and 2-arylmethylenemolononitriles has been developed via an allenol carbopalladation and an allylic cycloaddition cascade. This process allows rapid access to substituted tetrahydrofurans bearing diverse functional groups in good yields with high diastereoselectivities and excellent enantioselectivities. The concise total synthesis of a lignan, (-)-2-episesaminone, has been achieved by the elaboration of a functionalized tetrahydrofuran obtained from this reaction.

Route to Chiral Tetrahydrofuran Acetals via Pd-Catalyzed Asymmetric Allylic Cycloaddition of Vinyl Epoxides with ß-Keto Enol Ethers.

An efficient method for the synthesis of functionalized chiral tetrahydrofuran (THF) acetals via Pd-catalyzed asymmetric allylic cycloaddition has been developed. With a palladium catalyst coordinated by a chiral phosphine ligand, the protocol is enabled to combine readily available vinyl epoxides and ß-keto enol ethers to produce THF acetals bearing three stereocenters in a broad substrate scope with uniformly high levels of enantio- and diastereoselectivity.

Stereoselective Total Synthesis of Formosanol, Tsugacetal, and Methyl ß-Conidendral.

The first enantioselective total synthesis of aryltetralin lignan acetals, (-)-formosanol, (+)-tsugacetal, (+)-methyl ß-conidendral, and their enantiomers have been accomplished on the basis of the Pd-catalyzed asymmetric allylic cycloaddition as a key step. Six stereoisomers of the lignan acetals have been synthesized via a 7-8 step sequence in up to 14% overall yield. The in vitro cytotoxicity against several cancer cells has preliminarily been examined for the obtained six stereoisomers of lignan acetals.

Pd-Catalyzed Regio- and Enantioselective Aminoarylation of Allenols with Aryl Iodides and 2-Pyridones.

A new asymmetric catalytic protocol for the synthesis of enantioenriched N-allyl 2-pyrodones has been developed via the first Pd-catalyzed regio- and enantioselective aminoarylation of allenols with aryl iodides and 2-pyridones. By using a palladium complex generated in situ from Pd2(dba)3·CHCl3 and (S,S,S)-SKP as a catalyst, the three-component aminoarylation proceeded smoothly to afford a variety of functionalized N-allylic 2-pyridones in high yields with good regioselectivities and excellent enantioselectivities.

anti-Diastereo- and enantioselective carbonyl (hydroxymethyl)allylation from the alcohol or aldehyde oxidation level: allyl carbonates as allylmetal surrogates.

Enantioselective transfer hydrogenation of carbonate 1a in the presence of aromatic, allylic, or aliphatic alcohols 2a-2i employing a cyclometalated iridium C,O-benzoate derived from allyl acetate, 4-cyano-3-nitrobenzoic acid and (S)-SEGPHOS delivers products of (hydroxymethyl)allylation 4a-4i in good isolated yields (60-74%), good anti-diastereoselectivities (5:1-10:1 dr) and exceptional levels of enantiocontrol (93-99% ee). Under identical reaction conditions, but in the presence of isopropanol, aldehydes 3a-3i are converted to an equivalent set of adducts 4a-4i in good isolated yields (58-74%), good anti-diastereoselectivities (4:1-14:1 dr), and exceptional levels of enantiocontrol (95-99% ee). Thus, identical sets of adducts 4a-4i are produced with equal facility from the alcohol or aldehyde oxidation level. These studies represent the first general method for enantioselective carbonyl (hydroxymethyl)allylation, a process that has no highly stereoselective counterpart in conventional allylmetal chemistry.