NEAT1 inhibits the angiogenic activity of cerebral arterial endothelial cells by inducing the M1 polarization of microglia through the AMPK signaling pathway.

BACKGROUND: Enhancing angiogenesis may be an effective strategy to promote functional recovery after ischemic stroke. Inflammation regulates angiogenesis. Microglia are crucial cells that initiate inflammatory responses after various brain injuries. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays a role in regulating brain injury. This study aimed to explore the effects of NEAT1-regulated microglial polarization on the neovascularization capacity of cerebrovascular endothelial cells and the underlying molecular regulatory mechanisms. METHODS: Mouse cerebral arterial endothelial cells (mCAECs) were co-cultured with BV-2 cells in different groups using a Transwell system. NEAT1 expression levels were measured by fluorescence quantitative reverse transcription PCR. Levels of IL-1ß, IL-6, TNF-α, Arg-1, IL-4, and IL-10 were determined using ELISA. Expression levels of CD86 and CD163 were detected by immunofluorescence. The neovascularization capacity of mCAECs was assessed using CCK-8, Transwell, Transwell-matrigel, and tube formation assays. Label-free quantification proteomics was carried out to identify differentially expressed proteins. Protein levels were measured by Western blotting. RESULTS: NEAT1 overexpression induced M1 polarization in BV-2 cells, whereas NEAT1 knockdown blocked lipopolysaccharide-induced M1 polarization in microglia. NEAT1-overexpressing BV-2 cells suppressed the angiogenic ability of mCAECs, and NEAT1-knocking BV-2 cells promoted the angiogenic ability of mCAECs under lipopolysaccharide treatment. Label-free quantitative proteomic analysis identified 144 upregulated and 131 downregulated proteins that were induced by NEAT1 overexpression. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the Kyoto Encyclopedia of Genes and Genomes analysis of the differentially expressed proteins. Further verification showed that NEAT1 inactivated the AMPK signaling pathway. Moreover, the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide reversed the effect of NEAT1 on BV-2 polarization and the regulatory effect of NEAT1-overexpressing BV-2 cells on the angiogenic ability of mCAECs. CONCLUSIONS: NEAT1 inhibits the angiogenic activity of mCAECs by inducing M1 polarization of BV-2 cells through the AMPK signaling pathway. This study further clarified the impact and mechanism of NEAT1 on microglia and the angiogenic ability of cerebrovascular endothelial cells.

An Injecting Molding Method for Forming the HFRP/PA6 Composite Parts.

Carbon/glass fiber-reinforced polymer hybrid composite (HFRP) has the advantages of a light weight and high strength. For the lightweight design of automobile parts, composite parts made of HFRP and polymer materials are increasingly in demand. The method of the injection molding is usually adopted to fabricate composite part with HFRP and polymer materials. The connecting strength between the two materials has an important influence on the service life of the composite part. In this paper, HFRP and polyamide-6 (PA6) were used to fabricate a composite part by the injection molding method. In order to improve the connecting strength between HFRP and PA6, a kind of micro-grooves was fabricated on the HFRP surface. The micro-grooves on the surface of the HFRP provided sufficient adhesion and infiltrating space of molten PA6 material into the mold. In addition, the glass fiber in HFRP can also be used as nucleating agent to facilitate the rapid crystallization of PA6. The micro-grooves on the surface of HFRP were embedded into PA6 like nails, which could improve the connecting strength at the interface effectively. The paper investigated the effects of mold temperature, injection pressure, holding pressure and holding time on the injection quality and connecting strength of composite parts in detail. With a mold temperature of 240 °C, an injection pressure of 8 MPa, a holding pressure of 8 MPa and a holding time of 3 s, the maximum tensile strength of 10.68 MPa was obtained for the composite part. At the effect of micro-grooves, the tensile strength of the composite part could be increased by 126.27%.

The Association of Blood Urea Nitrogen to Creatinine Ratio and the Prognosis of Critically Ill Patients with Cerebral Infarction: A Cohort Study.

Background: To evaluate the association between blood urea nitrogen (BUN) to creatinine (Cr) (BUN/Cr) ratio and the in-hospital mortality of critically ill patients with cerebral infarction in intensive care unit (ICU). Methods: In this cohort study, the data of 3059 participants with cerebral infarction were collected from the Medical Information Mart for Intensive Care (MIMIC)-III and the MIMIC-IV database. After propensity score matching (PSM) on age and gender, 2085 people were involved in and divided into the alive group (n = 1390) and the dead group (n = 695) based on the results of follow-up. Multivariate logistic analyses were applied to identify the confounders and the association between BUN/Cr and mortality of cerebral infarction. Results: The median follow-up time was 10.5 days. Among 2778 participants, 695 were dead at the end of follow-up. Univariate analysis revealed that BUN/Cr [risk ratio (RR) = 1.01, 95% confidence interval (CI): 1.01-1.02] might be associated with the in-hospital mortality of cerebral infarction patients. After adjusting for respiratory failure, malignant cancer, anticoagulation, liver disease, white blood cell (WBC), red cell distribution width (RDW), glucose, bicarbonate, and temperature, BUN/Cr had week correlation with the increased risk of in-hospital mortality of cerebral infarction patients (RR = 1.01, 95% CI: 1.01-1.02). Conclusion: This study evaluated the association between BUN/Cr and the in-hospital mortality of cerebral infarction patients in ICU and found that BUN/Cr had weak correlation with the increased risk of in-hospital mortality of patients with cerebral infarction in ICU especially in males and those with respiratory failure, malignant cancer, and without liver disease, as well as those receiving anticoagulation.

[Surgical management of sacral neurogenic tumors].

OBJECTIVE: To observe the efficacy and complications of one-stage tumor resection to treat primary sacral neurogenic tumors and to discuss some details in the clinically relevant anatomy. METHODS: A retrospective analysis of 26 patients with neurogenic turors of the sacral spine who were surgically treated from January 2001 to January 2018, including 16 males and 10 females, aged from 21 to 69 years old with an average age of (39.3±10.9) years old. The courses of diseases ranged from 3 to 56 months with an average of (17.9±10.1) months. The diameters of presacral components ranged from 3.3 to 19.6 cm with an average of (8.7±4.1) cm. The proximal margin of presacral lesions was above the L5S1 level in 6 cases, and lower than L5S1 in 20 cases. A posterior incision approach for one-stage complete resection of the tumor was used firstly, and an anterior approach was combined when necessary. Spinal-pelvic reconstruction with the modified Galveston technique was also carried out in relevant cases. Whether to preserve the tumor-involved nerve roots depended on the situation during the operation. The operation time, intraoperative blood loss, pain relief, and complications were recorded. The lumbosacral spine stability and sacral plexus neurological function were evaluated during postoperative follow-up, and local recurrence and distant metastasis were examined as well. RESULTS: Total excision was achieved in all 26 patients, with an operation time of (160.4±35.3) mins and an intraoperative blood loss of (1 092.3±568.8) ml. Tumors have been removed via a posterior-only approach in 21 cases and via combined anterior/posterior approaches in 5 cases. The diameter of presacral masses components ranged from 11.3 to 19.6 cm with an average of (15.1±3.2) cm in patients with combined anterior/posterior approaches, and ranged from 3.3 to 10.9 cm with an average of (7.2±2.4) cm in patients with a posterior-only approach. Five of the six patients whose proximal margin of presacral masses was above the L5S1 level adopted combined anterior/posterior approaches, and 20 patients lower than the L5S1 level adopted the posterior-only approach. All the patients were followed up for 6 to 82 months with an average of(45.4±18.2)months. Postoperative lumbosacral pain and lower extremity radicular pain were significantly relieved, and sensation, muscle strength and bowel and bladder function were also improved to varying degrees. The postoperative early complications included superficial wound infection in 1 case and cerebrospinal fluid leakage in 2 cases. Pathology confirmed 17 cases of schwannoma, 7 cases of neurofibroma and 2 cases of malignant schwannoma. Local recurrence was observed in two cases of benign neurogenic tumors. One patient with a malignant nerve sheath tumor had lung metastasis, who died 20 months after the operation. In 17 cases of upper sacral neurogenic tumors, 4 cases did not undergo spinal-pelvic reconstruction with internal fixation, of which 2 cases suffered from postoperative segmental instability. Tumor-involved nerve roots were resected during surgery in 7 cases. One of these patients who had S2 and S3 nerve roots sacrificed simultaneously had an impaired bladder and bowel function postoperatively, and did not recover completely. In the other 6 cases, the neurological function was not damaged obviously or recovered well. CONCLUSION: The posterior approach can directly expose the lesions, and it is also convenient to deal with nerve roots and blood vessels. The operation time, intraoperative blood loss, degree of symptom relief, complication rate, and recurrence and metastasis rate can be controlled at an appropriate level. It is a safe and effective surgical approach. When the upper edge of the presacral mass is higher than the L5S1 level or the diameter of the presacral mass exceeds 10 cm, an additional anterior approach should be considered. The stress between the spine and pelvis is high, and internal fixation should be used to restore the mechanical continuity of the spine and pelvis during resection of neurogenic tumors of the high sacral spine. Most of the parent nerve roots have lost their function. Resection of a single parent nerve root is unlikely to cause severe neurological dysfunction, while the adjacent nerve roots have compensatory functions and should be preserved as much as possible during surgery.

LncRNA NEAT1 alleviates ischemic stroke via transcriptional inhibition of NLRP3 mediated by the miR­10b­5p/BCL6 axis.

Cerebral ischemic stroke (CIS) is a significant cause of disability and death. Inflammation usually occurs after CIS and accelerates cellular damage. NLRP3 plays a key role in the formation of CIS­associated inflammasome. Understanding how NLRP3 is regulated bears great importance. We hypothesized that lncRNA NEAT1 can downregulate NLRP3 expression by regulating the miR­10b­5p/BCL6 axis, and thus regulate microglia­driven inflammation. The expression of NEAT1 was analyzed in CIS patients and an in vitro model of oxygen and glucose deprivation/re­oxygenation (OGD/R). We assessed the levels of pro­inflammatory cytokines IL­18 and IL­1ß with ELISA. Interactions between NEAT1/miR­10b­5p and miR­10b­5p/BCL6 were determined by luciferase assay. The interaction of BCL6 and NLRP3 was identified by ChIP; RNA, and protein levels were evaluated by qRT­PCR and western blot, respectively. We found that NEAT1 level was decreased in CIS patients and OGD/R treated cells. OGD/R exerted pro­inflammasome effects by increasing the expression of inflammasome­associated proteins and ROS and malondialdehyde (MDA) while inhibiting SOD production. This effect was partially antagonized by NEAT1. We bioinformatically identified interactions between NEAT1/miR­10b­5p, BCL6/miR­10b­5p, and NLRP3­promoter/BCL6, and validated them by luciferase assay, qRT­PCR, and ChIP. NEAT1 inhibited miR­10b­5p and upregulated BCL6 by ceRNA mechanism and alleviated OGD/R induced cell damage. We also proved that BCL6 was a repressive transcription factor in the regulation of NLRP3 expression. Thus, lncRNA NEAT1 inhibited inflammasome activation by NLRP3 in microglia via the NEAT1/ miR­10b­5p/BCL6/NLRP3 regulatory axis, which alleviated deleterious outcomes of ischemic stroke.

LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3.

BACKGROUND: Recent studies revealed that long non-coding RNAs (lncRNAs) have significant roles in regulating the pathogenesis of ischemia stroke, and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell apoptosis. Aberrant expression of NEAT1 was found after the injury of ischemia-reperfusion, but the mechanism was not fully understood. METHODS: The expression of NEAT1 and Mfn2 were detected in BV-2 and N2a cell with or without OGD/R-induced by qRT-PCR. Inflammatory cytokines secretion was detected by enzyme-linked immunosorbent assay (ELISA). The oxidative stress was evaluated by the examination of ROS, MDA and SOD levels. Flow cytometry and apoptosis marker detection by western blot were performed to examined apoptosis. RESULTS: The expression of NEAT1 and Mfn2 were decreased in OGD/R-induced cell model. Overexpression of NEAT1 or Mfn2 reduced oxidative stress and apoptosis by OGD/R-induced in neuronal cells, while knockdown of Sirt3 reversed the protective effect of NEAT1 and Mfn2. NEAT1 stabilized Mfn2 mRNA via recruiting Nova. NEAT1 alleviates the oxidative stress and apoptosis by OGD/R-induced via activating Sirt3. CONCLUSION: LncRNA NEAT1 stabilizes Mfn2 mRNA via recruiting Nova, therefore increase the expression of Mfn2 and alleviates ischemia-reperfusion induced oxidative stress and apoptosis via Mfn2/Sirt3 pathway.

Knockdown of circRNA-Memo1 Reduces Hypoxia/Reoxygenation Injury in Human Brain Endothelial Cells Through miRNA-17-5p/SOS1 Axis.

Circ-Memo1 has been proved to be upregulated in ischemia-reperfusion induced acute injury of kidney tissues. However, the potential role of circ-Memo1 in cerebral hypoxia/reoxygenation (H/R) injury is still unclear.Blood samples were collected from 25 ischemic stroke patients and 25 healthy controls. To construct the H/R model, human brain microvascular endothelial cells (HBMVECs) were cultured under the hypoxic condition, followed by reoxygenation. Cell viability was analyzed by MTT assay. Flow cytometry was carried out to examine cell apoptosis. The level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured by MDA and SOD assay kits, respectively. The levels of TNF-α, IL-1ß, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter gene detection was employed to verify the binding relationships between circ-Memo1, miR-17-5p, and SOS1.Circ-Memo1 and SOS1 expressions were increased, and miR-17-5p expression was reduced in ischemic stroke patients. Circ-Memo1 silencing promoted cell viability, inhibited the activation of ERK/NF-κB signaling pathway, reduced oxidative stress and inflammatory response, and inhibited cell apoptosis. Moreover, miR-17-5p functioned as the sponge of circ-Memo1, and SOS1 was identified as the target of miR-17-5p. The protective effect of circ-Memo1 knockdown on cell injury after H/R treatment was weakened by miR-17-5p inhibition.Knockdown of circ-Memo1 alleviated H/R injury of HBMVEC cells by regulating the miR-17-5p/SOS1 axis, indicating that circ-Memo1 might be a potential treatment target for cerebral H/R injury.

MiR-17-5p inhibits cerebral hypoxia/reoxygenationinjury by targeting PTEN through regulation of PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: To investigate the role and mechanism of miR-17-5p in cerebral hypoxia/reoxygenation (H/R)-induced apoptosis. METHODS: The present study used human brain microvascular endothelial cells (HBMVECs) to establish cerebral H/R model. MTT was used to measure the cell viability. Flow cytometry was used to detect the cell apoptosis. The interaction between miR-17-5p and PTEN was determined using dual luciferase reporter assay. RT-qPCR and Western blotting were used for determination of the expression of miR-17-5p, PTEN, apoptosis- and PI3K/AKT/mTOR signalling-related proteins. RESULTS: The cell viability and the expression of miR-17-5p were obviously down-regulated while the expression of PTEN was obviously up-regulated in H/R cells. The cell viability was remarkably enhanced, and the cell apoptosis induced by H/R injury was dramatically reduced when miR-17-5p was overexpressed in HBMVECs under H/R condition, which was reversed by overexpression of PTEN. Dual luciferase reporter assay showed PTEN was a direct target of miR-17-5p. Treatment of PI3K inhibitor LY294002 significantly increased the apoptosis rate of HBMVECs, and this effect was significantly reversed by transfection of miR-17-5p mimics, while further dramatically enhanced by overexpression of PTEN. CONCLUSION: MiR-17-5p could ameliorate cerebral I/R injury-induced cell apoptosis by directly targeting PTEN and regulation of PI3K/AKT/mTOR signalling.

LncRNA NEAT1 facilitates survival and angiogenesis in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs) via targeting miR-377 and upregulating SIRT1, VEGFA, and BCL-XL.

OBJECTIVE: The present study was designed to investigate the mechanism by which lncRNA NEAT1 regulates survival and angiogenesis in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs). METHODS: OGD-treated BMECs were used to mimic cerebral ischaemia in vitro. The expression of lncRNA NEAT1 and miR-377 and proteins including VEGFA, SIRT1, and BCL-XL were measured by real-time quantitative PCR (qRT-PCR) and western blot, respectively. Cell viability and caspase 3 activity of BMECs under different conditions were determined using MTT and caspase activity assays, respectively. Matrigel-based angiogenesis assays were employed to evaluate the effect of lncRNA NEAT1 on angiogenesis. A dual-luciferase reporter assay was used to validate direct binding of miR-377 to putative targets. RESULTS: OGD exposure reduced the cell viability of BMECs. Upregulation of lncRNA NEAT1 and downregulation of miR-377 were also observed under OGD conditions. Knockdown of lncRNA NEAT1 inhibited angiogenesis and aggravated apoptosis in OGD-induced BMECs. Meanwhile, the expression level of miR-377 was upregulated while its downstream targets (VEGFA, SIRT1, and BCL-XL) were downregulated after lncRNA NEAT1 knockdown. Furthermore, miR-377 inhibited the angiogenesis and survival of OGD-induced BMECs. The expression of VEGFA, SIRT1, and BCL-XL were all attenuated by miR-377 overexpression. The dual-luciferase reporter assay proved miR-377 targeted the 3' UTR sequences of lncRNA NEAT1, VEGFA, SIRT1, and BCL-XL. CONCLUSION: lncRNA NEAT1 facilitated the survival and angiogenesis of OGD-induced BMECs via targeting miR-377 and promoting the expression of VEGFA, SIRT1, and BCL-XL, suggesting that lncRNA NEAT1 could be a promising target for cerebral ischaemia treatment.

Design, Synthesis and Antibacterial Evaluation of 3-Substituted Ocotillol-Type Derivatives.

Antibiotic resistance has become a serious global problem that threatens public health. In our previous work, we found that ocotillol-type triterpenoid saponin showed good antibacterial activity. Based on preliminary structure-activity relationship, novel serious C-3 substituted ocotillol-type derivatives 7⁻26 were designed and synthesized. The in vitro antibacterial activity was tested on five bacterial strains (B. subtilis 168, S. aureus RN4220, E. coli DH5α, A. baum ATCC19606 and MRSA USA300) and compared with the tests on contrast. Among these derivatives, C-3 position free hydroxyl substituted compounds 7⁻14, showed good antibacterial activity against Gram-positive bacteria. Furthermore, compound 22 exhibited excellent antibacterial activity with minimum inhibitory concentrations (MIC) values of 2 µg/mL against MRSA USA300 and 4 µg/mL against B. subtilis. The structure-activity relationships of all current ocotillol-type derivatives our team synthesised were summarized. In addition, the prediction of absorption, distribution, metabolism, and excretion (ADME) properties and the study of pharmacophores were also conducted. These results can provide a guide to further design and synthesis works.

Tannic Acid/Fe3+ Nanoscaffold for Interfacial Polymerization: Toward Enhanced Nanofiltration Performance.

Conventional thin-film composite (TFC) membranes suffer from the trade-off relationship between permeability and selectivity, known as the "upper bound". In this work, we report a high performance thin-film composite membrane prepared on a tannic acid (TA)-Fe nanoscaffold (TFCn) to overcome such upper bound. Specifically, a TA-Fe nanoscaffold was first coated onto a polysulfone substrate, followed by performing an interfacial polymerization reaction between trimesoyl chloride (TMC) and piperazine (PIP). The TA-Fe nanoscaffold enhanced the uptake of amine monomers and provided a platform for their controlled release. The smaller surface pore size of the TA-Fe coated substrate further eliminated the intrusion of polyamide into the substrate pores. The resulting membrane TFCn showed a water permeability of 19.6 ± 0.5 L m2- h-1 bar-1, which was an order of magnitude higher than that of control TFC membrane (2.2 ± 0.3 L m-2 h-1 bar-1). The formation of a more order polyamide rejection layer also significantly enhanced salt rejection (e.g., NaCl, MgCl2, Na2SO4, and MgSO4) and divalent to monovalent ion selectivity (e.g., NaCl/MgSO4). Compared to conventional TFC nanofiltration membranes, the novel TFCn membrane successfully overcame the longstanding permeability and selectivity trade-off. The current work paves a new avenue for fabricating high performance TFC membranes.

Switchable Access to 3-Carboxylate-4-quinolones and 1-Vinyl-3-carboxylate-4-quinolones via Oxidative Cyclization of Isatins and Alkynes.

An efficient transition-metal-free oxidative cyclization reaction using isatins and alkynes for the facile synthesis of structurally diverse 4-quinolones has been developed. Intriguingly, switchable access to substituted 3-carboxylate-4-quinolones and 1-vinyl-3-carboxylate-4-quinolones could be achieved by choosing a different base in the reaction. The obtained products could undergo further transformations, increasing the application potential of the method in organic synthesis.

Effect of willed movement training on neurorehabilitation after focal cerebral ischemia and on the neural plasticity-associated signaling pathway.

Neurorehabilitation training is a therapeutic intervention for the loss of neural function induced by focal cerebral ischemia, however, the effect varies depending on the neurorehabilitation exercises. Willed movement (WM) training is defined as task­oriented training, which increases enthusiasm of patients to accomplish a specific task. The current study was performed to the evaluate effect of WM training on neurorehabilitation following focal cerebral ischemia, and further investigate the influence on neural plasticity­associated signaling pathway. Sprague­Dawley rats following temporary middle cerebral artery occlusion (tMCAO) were randomly divided into four groups: tMCAO (no rehabilitation training), CR (control rehabilitation), EM (environmental modification) and WM groups. Rats in the CR group were forced to exercise (running) in a rotating wheel. In the WM group, food was used to entice rats to climb on a herringbone ladder. Herringbone ladders were also put into the cages of the rats in the CR and EM groups, however without the food attraction. WM group exhibited an improvement in neurobehavioral performance compared with other groups. TTC staining indicated an evident reduction in brain damage in the WM group. There were increased synaptic junctions following WM training, based on the observations of transmission election microscopy. Investigation of the molecular mechanism suggested that WM training conferred the greatest effect on stimulating the extracellular signal­related kinase (ERK)/cyclic adenosine monophosphate response element­binding protein 1 (CREB) pathway and glutamate receptor 2 (GluR2)/glutamate receptor interacting protein 1­associated protein 1 (GRASP­1)/protein interacting with C­kinase 1 (PICK1) cascades among groups. Collectively, the improvement of neurobehavioral performance by WM training following tMCAO is suggested to involve the ERK/CREB pathway and GluR2/GRASP­1/PICK1 cascades. The present study provided a preliminary foundation for future research on the therapeutic effect of WM training against stroke­induced neuron damage.

miR-142-3p Contributes to Early Cardiac Fate Decision of Embryonic Stem Cells.

MicroRNAs (miRNAs) play important roles in cell fate decisions. However, the miRNAs and their targets involved in the regulation of cardiac lineage specification are largely unexplored. Here, we report novel functions of miR-142-3p in the regulation of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). With a miRNA array screen, we identified a number of miRNAs significantly changed during mESC differentiation into the mesodermal and cardiac progenitor cells, and miR-142-3p was one among the markedly downregulated miRNAs. Ectopic expression and inhibition of miR-142-3p did not alter the characteristics of undifferentiated ESCs, whereas ectopic expression of miR-142-3p impaired cardiomyocyte formation. In addition, ectopic expression of miR-142-3p inhibited the expression of a cardiac mesodermal marker gene Mesp1 and downstream cardiac transcription factors Nkx2.5, Tbx5, and Mef2c but not the expression of three germ layer-specific genes. We further demonstrated that miR-142-3p targeted the 3'-untranslated region of Mef2c. These results reveal miR-142-3p as an important regulator of early cardiomyocyte differentiation. Our findings provide new knowledge for further understanding of roles and mechanisms of miRNAs as critical regulators of cardiomyocyte differentiation.

A concise construction of 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones via an unusual TBHP/Na2CO3 promoted cascade oxidative cyclization and interrupted Dimroth rearrangement.

An efficient transition-metal-free cascade reaction has been developed for the facile synthesis of 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-one derivatives from commercially available isatins and 2-haloaryl isothiocyanates. A preliminary mechanistic study suggested an interrupted Dimroth rearrangement was the key step for the successful transformation.

Larger rate dependence of late sodium current in cardiac Purkinje cells: A potential link to arrhythmogenesis.

BACKGROUND: Purkinje cells (PCs) have a steeper rate dependence of repolarization and are more susceptible to arrhythmic activity than do ventricular myocytes (VMs). Late sodium current (INaL) is rate dependent and contributes to rate dependence of repolarization. OBJECTIVE: This study sought to test our hypothesis that PCs have a larger rate dependence of INaL, contributing to their steeper rate dependence of repolarization and higher susceptibility to arrhythmic activity, than do VMs. METHODS: INaL was recorded in isolated rabbit PCs and VMs with the whole-cell patch clamp technique. Action potential was examined using the microelectrode technique. RESULTS: Compared with VMs, PCs exhibited a significantly larger rate dependence of INaL with a larger INaL to basic cycle length (BCL) slope. Moreover, PCs had a larger rate dependence of INaL decay and slower recovery kinetics. Interestingly, the larger rate dependence of INaL matched to a steeper rate dependence of action potential duration (APD) in PCs. The INaL blocker tetrodotoxin significantly blunted, while the INaL enhancer anemone toxin (ATX-II) significantly increased, the rate dependence of INaL and APD in PCs and VMs. In the presence of ATX-II, the rate dependence of INaL in PCs was markedly larger than that in VMs, causing a much steeper rate dependence of APD in PCs. Accordingly, PCs exhibited greater rate-dependent electrical instability and were more prone to ATX-II-induced early afterdepolarizations, which were completely inhibited by the INaL inhibitor ranolazine. CONCLUSION: PCs have a significantly larger rate dependence of INaL than do VMs because of distinctive INaL decay and recovery kinetics, which contributes to their larger rate adaptation, and simultaneously predisposes them to a higher risk of arrhythmogenesis.

Substrates as Electron-Donor Precursors: Synthesis of Naphtho-Fused Oxindoles via Benzannulation of 2-Halobenzaldehydes and Indolin-2-ones.

An unusual benzannulation reaction has been realized by integrating intermolecular adol condensation with subsequent intramolercular base-promoted homolytic aromatic substitution. This novel cascade reaction provides a straightforward approach toward various naphtho-fused oxindoles from 2-halobenzaldehydes and indolin-2-ones in the presence of Cs2CO3 in DMSO. The enolates of indolin-2-ones as new and internal electron donors have been demonstrated to initiate intramolecular radical dehalogenative coupling.

Divergent Synthesis of Quinazolin-4(3H)-ones and Tryptanthrins Enabled by a tert-Butyl Hydroperoxide/K3PO4-Promoted Oxidative Cyclization of Isatins at Room Temperature.

A synergetic tert-butyl hydroperoxide/K3PO4-promoted oxidative cyclization has been developed for the facile synthesis of various functionalized quinazolin-4(3H)-ones from commercially available isatins and amidine hydrochlorides at room temperature. The synthetic utility of this strategy was illustrated by the convenient synthesis of tryptanthrin derivatives via a self-dimerization of isatins under the same conditions.

Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromoaldehydes, Benzylamines, and Sodium Azide for the Assembly of Quinazoline Derivatives.

An efficient three-component domino reaction of 2-bromoaldehydes, benzylamines, and sodium azide has been developed for the synthesis of quinazoline derivatives. This domino process involves copper-catalyzed SNAr, oxidation/cyclization, and denitrogenation sequences. The mild catalytic system enabled the effective construction of three C-N bonds in one operation.

Coronary Plaque Characteristics Affect No-Reflow During Primary Percutaneous Coronary Intervention: A Pooled Analysis of 14 Observational Studies Using Intravascular Ultrasound.

The association between coronary plaque composition and no-reflow during percutaneous coronary intervention (PCI) is still debated. We performed a systematic literature search using MEDLINE, Embase, Cochrane, and Ovid databases for intravascular ultrasound (IVUS) studies evaluating the relationship between coronary plaque characteristics and no-reflow after PCI. Fourteen observational trials were included in the meta-analysis, including 1457 patients (237 in the no-reflow group, 1220 in the normal reflow group). Pooled analysis indicated that the no-reflow group had a significantly higher absolute volume of fibrofatty plaque (weighted mean differences [WMD], 4.94 mm(3); 95% confidence interval [CI], 1.83-l8.06; P = .002), external elastic membrane cross-sectional area (EEM-CSA) (WMD, 3.40 mm2; 95% CI, 2.22-4.58; P = .00001), plaque area (WMD, 4.06 mm(2); 95% CI, 2.24-5.89; P = .0001), and artery remodeling index (WMD, 0.09; 95% CI, 0.06-0.13; P = .00001), and a smaller percentage of fibrous plaque (WMD, -5.89 %; 95% CI, -0.66 to -11.12; P = .03) than in the normal reflow group. There were no significant differences in the other plaque components between the two groups. This meta-analysis confirmed that high absolute volume of fibrofatty plaque, EEM-CSA, plaque area, and coronary artery remodeling index, and a decreased percentage of fibrous plaque as detected by IVUS in culprit lesions, are linked with the development of the no-reflow phenomenon after PCI.