Single-Cell RNA-Seq Reveals Coronary Heterogeneity and Identifies CD133+TRPV4high Endothelial Subpopulation in Regulating Flow-Induced Vascular Tone in Mice.

BACKGROUND: Single-cell RNA-Seq analysis can determine the heterogeneity of cells between different tissues at a single-cell level. Coronary artery endothelial cells (ECs) are important to coronary blood flow. However, little is known about the heterogeneity of coronary artery ECs, and cellular identity responses to flow. Identifying endothelial subpopulations will contribute to the precise localization of vascular endothelial subpopulations, thus enabling the precision of vascular injury treatment. METHODS: Here, we performed a single-cell RNA sequencing of 31 962 cells and functional assays of 3 branches of the coronary arteries (right coronary artery/circumflex left coronary artery/anterior descending left coronary artery) in wild-type mice. RESULTS: We found a compendium of 7 distinct cell types in mouse coronary arteries, mainly ECs, granulocytes, cardiac myocytes, smooth muscle cells, lymphocytes, myeloid cells, and fibroblast cells, and showed spatial heterogeneity between arterial branches. Furthermore, we revealed a subpopulation of coronary artery ECs, CD133+TRPV4high ECs. TRPV4 (transient receptor potential vanilloid 4) in CD133+TRPV4high ECs is important for regulating vasodilation and coronary blood flow. CONCLUSIONS: Our study elucidates the nature and range of coronary arterial cell diversity and highlights the importance of coronary CD133+TRPV4high ECs in regulating coronary vascular tone.

Accelerated Redox Reactions Enable Stable Tin-Lead Mixed Perovskite Solar Cells.

The facile oxidation of Sn2+ to Sn4+ poses an inherent challenge that limits the efficiency and stability of tin-lead mixed (Sn-Pb) perovskite solar cells (PSCs) and all-perovskite tandem devices. In this work, we discover the sustainable redox reactions enabling self-healing Sn-Pb perovskites, where their intractable oxidation degradation can be recovered to their original state under light soaking. Quantitative and operando spectroscopies are used to investigate the redox chemistry, revealing that metallic Pb0 from the photolysis of perovskite reacts with Sn4+ to regenerate Pb2+ and Sn2+ spontaneously. Given the sluggish redox reaction kinetics, V3+ /V2+ ionic pair is designed as an effective redox shuttle to accelerate the recovery of Sn-Pb perovskites from oxidation. The target Sn-Pb PSCs enabled by V3+ /V2+ ionic pair deliver an improved power conversion efficiency (PCE) of 21.22 % and excellent device lifespan, retaining nearly 90 % of its initial PCE after maximum power point tracking under light for 1,000 hours.

Synthesis of Enantioenriched (Z)-Disubstituted Allylic Alcohols via Ru-Catalyzed Selective Dehydrogenation.

A highly efficient kinetic resolution of allylic alcohols with Z/E mixtures was achieved via Ru-catalyzed selective dehydrogenation. Not only allylic alcohols were obtained with pure Z-geometry, but the corresponding selectivity factors rank among the few highest for kinetic resolution reported in the literature.

Menthol relieves acid reflux inflammation by regulating TRPV1 in esophageal epithelial cells.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays an important role in pain and inflammatory responses. Previous studies have shown that the expression of TRPV1 increases in the sensory neurons of the esophagus during the development of gastroesophageal reflux disease and esophagitis, but the response of TRPV1 in esophageal epithelial cells (EECs), which directly confront the refluxed acid, is still unknown. Here, we found that acid reflux triggered esophageal damage, which was accompanied by increased expression of TRPV1 in EECs and TRPV1 channel activity in these cells. Furthermore, menthol inhibited the Ca2+ influx induced by acid stimulation in EECs. After menthol treatment, the expression of TRPV1 in EECs was significantly reduced, and their hyperplasia was significantly reduced; finally, the inflammation pathway elicited in EECs was diminished in mice with acid reflux. These results suggest that menthol improves the clinical symptoms caused by gastroesophageal acid reflux by interfering with TRPV1 in EECs.

Hospital mortality in acute coronary syndrome: adjustment of GRACE score by D-dimer enables a more accurate prediction in a prospective cohort study.

BACKGROUD: To assess the value of D-dimer and its combination with The Global Registry of Acute Coronary Events (GRACE) score in predicting in-hospital mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: In 5923 ACS patients undergoing PCI, the role of D-dimer and the added value of D-dimer to GRACE score for predicting in-hospital mortality were tested. RESULTS: After multivariable adjustment, D-dimer could significantly predict in-hospital mortality. Also, it could significantly improve the prognostic performance of GRACE score (C-statistic: z = 2.269, p = 0.023; IDI: 0.016, p = 0.032; NRI: 0.291, p = 0.035). CONCLUSION: In patients with ACS undergoing PCI, D-dimer was an independent predictor of in-hospital death. It could also improve the prognostic performance of GRACE score.

Value of the fT3/fT4 ratio and its combination with the GRACE risk score in predicting the prognosis in euthyroid patients with acute myocardial infarction undergoing percutaneous coronary intervention: a prospective cohort study.

BACKGROUND: Thyroid hormones deeply influence the cardiovascular system; however, the association between the fT3/fT4 ratio and the clinical outcome in euthyroid patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) is not well defined. Therefore, the present study aimed to assess the prognostic performance of the fT3/fT4 ratio in predicting the long-term prognosis in euthyroid patients with AMI undergoing PCI. METHODS: In a prospective cohort study with a 1-year follow-up, according to the clinical end point, 953 euthyroid individuals (61.0 ± 11.6; female, 25.8%) were divided into two groups: (1) the survival group (n = 915) and (2) the death group (n = 38). RESULTS: According to Cox regression multivariate analysis, fT4 (HR: 1.249, 95% CI: 1.053-1.480, p = 0.010) and the fT3/fT4 ratio (HR: 3.546, 95% CI: 1.705-7.377, p = 0.001) were associated with an increased risk of 1-year all-cause mortality. The prognostic performance of the fT3/fT4 ratio was similar to the Global Registry of Acute Coronary Events (GRACE) score in predicting 1-year all-cause mortality (C-statistic: z = 0.261, p = 0.794; IDI: -0.017, p = 0.452; NRI: -0.049, p = 0.766), but better than fT4 (C-statistic: z = 2.438, p = 0.015; IDI: 0.053, p = 0.002; NRI: 0.656, p < 0.001). The fT3/fT4 ratio also significantly improved the prognostic performance of the GRACE score (GRACE score vs GRACE score + fT3/fT4 ratio: C-statistic: z = 2.116, p = 0.034; IDI: 0.0415, p = 0.007; NRI: 0.614, p < 0.001). CONCLUSIONS: In euthyroid patients with AMI undergoing PCI, the fT3/fT4 ratio was an independent predictor of 1-year all-cause mortality. Its prognostic performance was similar to the GRACE score, and also improved its prognostic performance (GRACE score vs GRACE score + fT3/fT4 ratio).

Predictive Value of Mean Platelet Volume/Platelet Count for Prognosis in Acute Myocardial Infarction.

Increased mean platelet volume (MPV) has been associated with adverse clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). We aim to assess whether MPV/platelet count (MPV/PC) ratio is a useful marker to predict long-term prognosis in patients with STEMI undergoing PCI. Moreover, the prognostic accuracy of MPV/PC ratio is compared with MPV. 962 consecutive patients with STEMI treated with P-PCI were considered. According to the admission MPV/PC values, the population was divided into two groups: high MPV/PC group (n = 320, MPV/PC ≥ 0.055) and low MPV/PC group (n = 642, MPV/PC < 0.055). Multivariate analysis showed that high MPV/PC was an independent predictor of major adverse cardiovascular event (MACE; hazard ratio [HR]: 1.121, 95% confidence interval [CI]: 1.056-1.190, P < 0.01), all-cause mortality (HR: 1.109, 95% CI: 1.016-1.209, P = 0.020), cardiac mortality (HR: 1.141, 95% CI: 1.038-1.253, P = 0.006), nonfatal myocardial reinfarction (HR: 1.148, 95% CI: 1.044-1.262, P = 0.004), and unplanned repeat revascularization (HR: 1.073, 95% CI: 1.007-1.144, P = 0.030), respectively. MPV/PC ratio has good accuracy for predicting MACE (the area under the receiver-operating characteristic curve: 0.764), and the cut-off value was 0.054 with a sensitivity of 0.813 and a specificity of 0.662. The discriminatory performance of MPV/PC ratio was better than MPV for predicting MACE (MPV/PC ratio versus MPV: z = 2.285, P = 0.022), in patients with STEMI undergoing P-PCI. MPV/PC ratio is able to but better than MPV to predict long-term adverse outcomes in patients with STEMI undergoing P-PCI.

TrpC5 regulates differentiation through the Ca2+/Wnt5a signalling pathway in colorectal cancer.

Transient receptor potential channel 5 (TrpC5) is a member of the TrpC subgroup, and it forms a receptor-activated, non-selective Ca2+ channel. The architecture of the TrpC5 channel is poorly understood. In the present study, we report that TrpC5 is a key factor in regulating differentiation in colorectal cancer (CRC). Through a study of specimens from a large cohort of patients with CRC, we found that TrpC5 was highly expressed and its cellular level correlated with tumour grade. We showed further that up-regulated TrpC5 caused a robust rise in intracellular calcium concentration [Ca2+]i, increased Wnt5a expression and the nuclear translocation of ß-catenin, leading to a reduction in cancer differentiation and an increase in cancer cell stemness. Notably, patients with tumours that expressed high levels of TrpC5 showed significantly poorer disease-free and overall survival. Therefore, our findings suggest that TrpC5 is an independent adverse prognostic factor for death in CRC, reducing differentiation through the Ca2+/Wnt5a signalling pathway.

Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance.

A critical challenge for chemotherapy is the development of chemoresistance in breast cancer. However, the underlying mechanisms and validated predictors remain unclear. Extracellular vesicles (EVs) have gained attention as potential means for cancer cells to share intracellular contents. In adriamycin-resistant human breast cancer cells (MCF-7/ADM), we analyzed the role of transient receptor potential channel 5 (TrpC5) in EV formation and transfer as well as the diagnostic implications. Up-regulated TrpC5, accumulated in EVs, is responsible for EV formation and trapping of adriamycin (ADM) in EVs. EV-mediated intercellular transfer of TrpC5 allowed recipient cells to acquire TrpC5, consequently stimulating multidrug efflux transporter P-glycoprotein production through a Ca(2+)- and activated T-cells isoform c3-mediated mechanism and thus, conferring chemoresistance on nonresistant cells. TrpC5-containing circulating EVs were detected in nude mice bearing MCF-7/ADM tumor xenografts, and the level was lower after TrpC5-siRNA treatment. In breast cancer patients who underwent chemotherapy, TrpC5 expression in the tumor was significantly higher in patients with progressive or stable disease than in patients with a partial or complete response. TrpC5-containing circulating EVs were found in peripheral blood from patients who underwent chemotherapy but not patients without chemotherapy. Taken together, we found that TrpC5-containing circulating EVs may transfer chemoresistance property to nonchemoresistant recipient cells. It may be worthwhile to further explore the potential of using TrpC5-containing EVs as a diagnostic biomarker for chemoresistant breast cancer.

Notch3 negatively regulates chemoresistance in breast cancers.

To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells. Increased Fra1 activated the EMT process. Finally, Notch3 expression was confirmed in clinically chemoresistant samples of breast cancers from patients receiving anthracycline-based chemotherapy. Low expression of Notch3 was an unfavorable predictor of distant relapse-free survival in ER positive breast cancers. Taken together, our findings demonstrate that the Notch3-Fra1 signaling pathway mediates chemoresistance via the EMT.

Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol.

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Transient receptor potential channel C5 in cancer chemoresistance.

The transient receptor potential (TRP) superfamily contains at least 28 homologs in mammalian. These proteins form TRP channels are permeable to monovalent and divalent cations and participate in a variety of physiological functions. Dysregulation of TRP channels is responsible for numerous diseases. This review provides a brief short overview of mammalian TRP channels with a focus on TRPC5 and its role in cancers. Dysregulation of TRPC5 interrupts Ca(2+) homeostasis in cancer cells, which activates signaling pathways that are highly associated with cancer progression, especially cancer chemoresistance. Based on the important role of TRPC5, we also discuss the potential of TRPC5 as a target for therapeutic intervention. Either direct targeting of TRPC5 or indirect interruption of TRPC5-related signaling pathways may effectively overcome cancer chemoresistance.

Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells.

An attractive strategy to overcome multidrug resistance in cancer chemotherapy is to suppress P-glycoprotein (P-gp), which is a pump overproduced in cancer cells to remove cytotoxic drugs from cells. In the present study, a Ca(2+)-permeable channel TRPC5 was found to be overproduced together with P-gp in adriamycin-resistant breast cancer cell line MCF-7/ADM. Suppressing TRPC5 activity/expression reduced the P-gp induction and caused a remarkable reversal of adriamycin resistance in MCF-7/ADM. In an athymic nude mouse model of adriamycin-resistant human breast tumor, suppressing TRPC5 decreased the growth of tumor xenografts. Nuclear factor of activated T cells isoform c3 (NFATc3) was the transcriptional factor that links the TRPC5 activity to P-gp production. Together, we demonstrated an essential role of TRPC5-NFATc3-P-gp signaling cascade in P-gp induction in drug-resistant cancer cells.

A methylation-based regulatory network for microRNA 320a in chemoresistant breast cancer.

We previously demonstrated that the overexpression of transient receptor potential channel C5 (TRPC5) and nuclear factor of activated T-cells isoform c3 (NFATC3) are essential for cancer chemoresistance, but how TRPC5 and NFATC3 are regulated was still unclear. In this study, microRNA 320a (miR-320a) was found to be down-regulated in chemoresistant cancer cells. MiR-320a directly targeted TRPC5 and NFATC3, and down-regulation of miR-320a triggered TRPC5 and NFATC3 overexpression. In chemoresistant cells, down-regulation of miR-320a was associated with regulation by methylation, which implicated promoter methylation of the miR-320a coding sequence. Furthermore, the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1), which inhibited miR-320a expression, was activated in chemoresistant cancer cells; such activation was associated with hypomethylation of the ETS-1 promoter. Lastly, the down-regulation of miR-320a and high expression of TRPC5, NFATC3, and ETS-1 were verified in clinically chemoresistant samples. Low expression of MiR-320a was also found to be a significant unfavorable predictor for clinic outcome. In conclusion, miR-320a is a mediator of chemoresistance by targeting TRPC5 and NFATC3. Expression of miR-320a is regulated by methylation of its promoter and that of ETS-1.

Bilayer 2D-3D Perovskite Heterostructures for Efficient and Stable Solar Cells.

With a stacking-layered architecture, the bilayer two-dimensional-three-dimensional (2D-3D) perovskite heterostructure (PHS) not only eliminates surface defects but also protects the 3D perovskite matrix from external stimuli. However, these bilayer 2D-3D PHSs suffer from impaired interfacial charge carrier transport due to the relatively insulating 2D perovskite fragments with a random phase distribution. Over the past decade, substantial efforts have been devoted to pioneering molecular and structural designs of the 2D perovskite interlayers for improving their charge carrier mobility, which enables state-of-the-art perovskite solar cells with high power conversion efficiency and exceptional operational stability. Herein, this review offers a comprehensive and up-to-date overview on the recent progress of bilayer 2D-3D PHSs, encompassing advancements on spacer cation engineering, interfacial charge carrier modification, advanced deposition protocols, and characterization techniques. Then, the evolutionary trajectory of bilayer 2D-3D PHSs is outlined by summarizing its mainstream development trends, followed by a perspective discussion about its future research opportunities toward efficient and durable perovskite solar cells.

Complement factor C1q mediates vascular endothelial dysfunction in STZ-induced diabetic mice.

Diabetes is a significant global public health issue with implications for vascular endothelial cells (ECs) dysfunction and the subsequent development and advancement of diabetic complications. This study aims to compare the cellular and molecular properties of the aorta in normal and streptozotocin (STZ)-induced diabetic mice, with a focus on elucidating potential mechanism underlying EC dysfunction. Here, we performed a single-cell RNA sequencing survey of 32,573 cells from the aorta of normal and STZ-induced diabetic mice. We found a compendium of 10 distinct cell types, mainly ECs, smooth muscle cells (SMCs), fibroblast, pericyte, immune cells and stromal cells. As the diabetes condition progressed, we observed a subpopulation of aortic ECs that exhibited significantly elevated expression of complement (C) molecule C1qa compared to their healthy counterparts. This increased expression of C1qa was found to induce reactive oxygen species (ROS) production, facilitate EC migration and increased permeability, and impair the vasodilation within the aortic segment of mice. Furthermore, AAV-Tie2-shRNA-C1qa was administered into diabetic mice by tail vein injection, showing that inhibition of C1qa in the endothelium led to a reduction in ROS production, decreased vascular permeability, and improved vasodilation. Collectively, these findings highlight the crucial involvement of C1qa in endothelial dysfunction associated with diabetes.

Polarizability matters in enantio-selection.

The prevalence of chirality, or, handedness in biological world is a fundamental phenomenon and a characteristic hallmark of life. Thus, understanding the origin of enantio-selection, i.e., the sense and magnitude of asymmetric induction, has been a long-pursued goal in asymmetric catalysis. Herein, we demonstrated a polarizability-derived electronic effect that was shown to be capable of rationalizing a broad range of stereochemical observations made in the field of asymmetric catalysis. This effect provided a consistent enantio-control model for the prediction of major enantiomers formed in a ruthenium-catalyzed asymmetric transfer hydrogenations of ketones. Direct and quantitative linear free energy relationships between substrates' local polarizabilities and observed enantio-selectivity were also revealed in three widely known asymmetric catalytic systems covering both reductions and oxidations. This broadly applicable polarizability-based electronic effect, in conjunction with conventional wisdom mainly leveraging on steric effect considerations, should aid rational design of enantio-selective processes for better production of chiral substances.

Anti-angiogenesis effect of trichosanthin and the underlying mechanism.

The growth and metastasis of tumors depend on angiogenesis. Tumor angiogenesis is initiated by the secretion of growth factors from tumor cells; downstream signals are then triggered in pre-existing blood vessels to sprout a new vascular network. Trichosanthin (TCS) is a type I ribosome-inactivating protein that has anti-tumor activity, but the underlying mechanism remains unclear. In this study, we found that a non-toxic dose of TCS decreased the wound-healing and the migration of H5V mouse heart capillary endothelial cells (ECs) induced by human choriocarcinoma (JAR) cells, as well as the JAR-induced angiogenesis of rat third-order mesenteric arteries. TCS was effective on both tumor cells and ECs/arteries. First, TCS decreased vascular endothelial growth factor transcription and secretion by JAR cells. Second, TCS consequently inhibited the tumor cell-induced, extracellular signal-regulated kinase-mediated angiogenic signal in ECs and blood vessels. In conclusion, the ability of TCS to inhibit tumor angiogenesis contributes to its anti-tumor activity.

Functional role of coupling the endothelial TRPV4 and KCa 3.1 channels in regulating coronary vascular tone.

BACKGROUND AND PURPOSE: High-fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+ -activated K+ (KCa ) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with KCa channels in regulating coronary vascular tone in HFD mice requires further exploration. EXPERIMENTAL APPROACH: TRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and KCa 3.1 channels were verified by co-immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4EC -/- ) mice were used to study the effect of the interactions between TRPV4-KCa 3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. KEY RESULTS: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+ -sensitive K+ channel (KCa 3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1-heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4-KCa 3.1 channels and to improve coronary arterial function. CONCLUSION AND IMPLICATIONS: Our data highlight the importance of coupling between TRPV4 and KCa 3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events.

Erratum: A Long Non-coding RNA Lnc712 Regulates Breast Cancer Cell Proliferation: Erratum.

[This corrects the article DOI: 10.7150/ijbs.36429.].