COF-based membranes for liquid phase separation: Preparation, mechanism and perspective.

Covalent organic frameworks (COFs) are a new kind of crystalline porous materials composed of organic molecules connected by covalent bonds, processes the characteristics of low density, large specific surface area, adjustable pore size and structure, and easy to functionalize, which have been widely used in the field of membrane separation technology. Recently, there are more and more researches focusing on the preparation methods, separation application, and mechanism of COF membranes, which need to be further summarized and compared. In this review, we primarily summarized several conventional preparation methods, such as two-phase interfacial polymerization, in-situ growth on substrate, unidirectional diffusion method, layer-by-layer assembly method, mixed matrix membranes, and so on. The advantages and disadvantages of each method are briefly summarized. The application potential of COF membrane in liquid separation are introduced from four aspects: dyeing wastewater treatment, heavy metal removal, seawater desalination and oil-water separation. Then, the mechanisms including pore structure, hydrophilic/hydrophobic, electrostatic repulsion/attraction and Donnan effect are introduced. For the efficient removal of different kind of pollutions, researchers can select different ligands to construct membranes with specific pore size, hydrophily, salt or organic rejection ability and functional group. The ideas for the design and preparation of COF membranes are introduced. Finally, the future direction and challenges of the next generation of COF membranes in the field of separation are prospected.

Advances in antitumor research of bifunctional small molecule inhibitors targeting heat shock protein 90 / 药学学报

The heat shock protein 90 (Hsp90) protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis. Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions, such as cell growth, cell cycle control and apoptosis. Hsp90 is closely associated with the occurrence and development of tumors and other diseases, making it an attractive target for cancer therapeutics. Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously. Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy, toxicity or drug resistance, but they have obvious synergistic anti-tumor effect when used with histone deacetylase (HDAC) inhibitors, tubulin inhibitors or topoisomerase II (Topo II) inhibitors. To address this issue, the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance, making it an effective tumor treatment strategy. In this paper, the domain and biological function of Hsp90 are briefly introduced, and the design, discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed, in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.

Diagnosis and treatment of post-cholecystectomy diarrhoea.

The incidence of cholecystitis is relatively high in developed countries and may usually be attributed to gallstones, the treatment for which involves complete surgical removal of the gallbladder (cholecystectomy). Bile acids produced following cholecystectomy continue to flow into the duodenum but are poorly absorbed by the colon. Excessive bile acids in the colon stimulate mucosal secretion of water and electrolytes leading, in severe cases, to diarrhoea. Bile acid diarrhoea (BAD) is difficult to diagnose, requiring a comprehensive medical history and physical examination in combination with laboratory evaluation. The current work reviews the diagnosis and treatment of BAD following cholecystectomy.

Effects of hypertension on subcortical nucleus morphological alternations in patients with type 2 diabetes.

Objectives: Type 2 diabetes mellitus(T2DM) and hypertension(HTN) are common comorbidities, and known to affect the brain. However, little is known about the effects of the coexisting HTN on brain in T2DM patients. So we aim to investigate the impact of HTN on the subcortical nucleus morphological alternations in T2DM patients. Materials & methods: This work was registered by the clinicaltrials.gov (grant number NCT03564431). We recruited a total of 92 participants, comprising 36 only T2DM patients, 28 T2DM patients with HTN(T2DMH) and 28 healthy controls(HCs) in our study. All clinical indicators were assessed and brain image data was collected for each participant. Voxel-based morphometry(VBM), automatic volume and vertex-based shape analyses were used to determine the subcortical nucleus alternations from each participant's 3D-T1 brain images and evaluate the relationship between the alternations and clinical indicators. Results: T2DMH patients exhibited volumetric reduction and morphological alterations in thalamus compared to T2DM patients, whereas T2DM patients did not demonstrate any significant subcortical alterations compared to HCs. Furthermore, negative correlations have been found between thalamic alternations and the duration of HTN in T2DMH patients. Conclusion: Our results revealed that HTN may exacerbate subcortical nucleus alternations in T2DM patients, which highlighted the importance of HTN management in T2DM patients to prevent further damage to the brain health.

Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome.

Background: Numerous studies have suggested that ferroptosis plays a significant role in the development of polycystic ovary syndrome (PCOS), but the mechanism remains unclear. Methods: In this study, we explored the role of ferroptosis-related genes in the pathogenesis of PCOS using a comprehensive bioinformatics method. First, we downloaded several Gene Expression Omnibus (GEO) datasets and combined them into a meta-GEO dataset. Differential expression analysis was performed to screen for significant ferroptosis-related genes between the normal and PCOS samples. The least absolute shrinkage selection operator regression and support vector machine-recursive feature elimination were used to select the best signs to construct a PCOS diagnostic model. Receiver operating characteristic curve analysis and decision curve analysis were applied to test the performance of the model. Finally, a ceRNA network-related ferroptosis gene was constructed. Results: Five genes, namely, NOX1, ACVR1B, PHF21A, FTL, and GALNT14, were identified from 10 differentially expressed ferroptosis-related genes to construct a PCOS diagnostic model. Finally, a ceRNA network including 117 lncRNAs, 67 miRNAs, and five ferroptosis-related genes was constructed. Conclusion: Our study identified five ferroptosis-related genes that may be involved in the pathogenesis of PCOS, which may provide a novel perspective for the clinical diagnosis and treatment of PCOS.

Contrast enhanced magnetic resonance imaging-based radiomics nomogram for preoperatively predicting expression status of Ki-67 in meningioma: a two-center study.

Background: The aim of this study was to develop and validate a radiomics nomogram for preoperative prediction of Ki-67 proliferative index (Ki-67 PI) expression in patients with meningioma. Methods: A total of 280 patients from 2 independent hospital centers were enrolled. Patients from center I were randomly divided into a training cohort of 168 patients and a test cohort of 72 patients, and 40 patients from center II served as an external validation cohort. Interoperator reproducibility test, Z-score standardization, analysis of variance (ANOVA), and least absolute shrinkage and selection operator (LASSO) binary logistic regression were used to select radiomics features, which were extracted from contrast-enhanced T1-weighted imaging (CE-T1WI) imaging. The radiomics signature for predicting Ki-67 PI expression was developed and validated using 4 classifiers including logistic regression (LR), decision tree (DT), support vector machine (SVM), and adaptive boost (AdaBoost). Finally, combined radiological characteristics with radiomics signature were used to establish the nomogram to predict the risk of high Ki-67 PI expression in patients with meningioma. Results: Fourteen radiomics features were used to construct the radiomics signature. The radiomics nomogram that incorporated the radiomics signature and radiological characteristics showed excellent discrimination in the training, test, and validation cohorts with areas under the curve of 0.817 (95% CI: 0.753-0.881), 0.822 (95% CI: 0.727-0.916), and 0.845 (95% CI: 0.708-0.982), respectively. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. Conclusions: The proposed contrast enhanced magnetic resonance imaging (MRI)-based radiomics nomogram could be an effective tool to predict the risk of Ki-67 high expression in patients with meningioma.

Investigate the multipath erasure of nitrobenzene over nanoscale zero-valent-iron/N-doped biochar hybrid with extraordinary reduction performance.

In this study, the facile carbothermal reduction method was enforced using urea as dopant to modify the structure and chemical composition of nanoscale zero-valent-iron/biochar hybrid thereby boosting its reduction performance. Through fine-tuning the N-doped amount, the optimal nZVI/N-doped BC was obtained, which exhibited more active sites (nZVI, persistent free radicals (PFRs), pyrrolic-N) and superior electrochemical conductivity. With these blessings, the electrons originating from galvanic cell reaction could zip along the highway within the hybrid. Taking nitrobenzene (NB) as the target pollutant, the quantitative analysis revealed that the NB reduction and adsorption removal efficiency were dramatically improved by 2.42 and 2.78 times, respectively. What's more, combining the in-situ experimental detection and theoretical calculations, unexpected NB reductive multipath with respect to PFRs and pyrrolic-N accelerating the Fe3+/Fe2+ cycle within the nZVI/N-doped BC system was decoded. The enhancement of Fe3+/Fe2+ cycle improved the electron utilization efficiency and maintained the reduction reactivity of the hybrid. This work raised awareness of the mechanisms regarding the reduction performance of nZVI/N-doped BC elevated by N-doped and the pollutant reductive pathway within the system, uncovered the dusty roles of PFRs and N-species during the reduction process.

Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Sodium formononetin-3'-sulphonate alleviates cerebral ischemia-reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis.

BACKGROUND: Sodium formononetin-3'-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia-reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis. RESULTS: The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1ß and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke. CONCLUSIONS: Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.

Safety and Efficacy of Drug-Coated Balloons in Patients with Acute Coronary Syndromes and Vulnerable Plaque.

BACKGROUND: Percutaneous coronary intervention (PCI) is the main treatment option for acute coronary syndromes (ACS) often related to the progression and rupture of vulnerable plaques. While drug-eluting stents (DES) are now routinely used in PCI, drug-coated balloons (DCB) are a new strategy to PCI and their practice in the treatment of ACS with vulnerable plaques has not been reported. This study aimed to evaluate the safety and efficacy of DCB in ACS complicated with vulnerable plaque lesions. METHODS: 123 patients were retrospectively analyzed and diagnosed with ACS and given PCI in our Cardiology Department from December 2020 to July 2022. Vulnerable plaques were confirmed by intravenous ultrasound (IVUS) in all patients. According to individual treatment plan, patients were entered into either DCB (n = 55) or DES (n = 68) groups. The results of coronary angiography and IVUS before and immediately after percutaneous coronary intervention were analyzed. The occurrence of major adverse cardiovascular events (MACE) and the results of coronary angiography were also evaluated during follow-up. RESULTS: There were no significant differences in baseline clinical characteristics, preoperative minimal luminal diameter (MLD), and preoperative diameter stenosis (DS) between the two groups. Also, there were no differences in IVUS plaque burden (PB), vessel area, and lumen area in the two groups before and immediately after PCI. The efficacy analysis showed that immediately after PCI, the DCB group had smaller MLD and higher degrees of lumen stenosis than the DES group (P < 0.05). However, during follow-up, no significant differences in MLD and DS were seen in two groups; relatively, late loss in luminal diameter（LLL）in the DCB group was smaller (P＜0.05). Safety analysis showed that during follow-up, 9 patients developed restenosis after DCB implantation while restenosis occurred in 10 patients with DES treatment, no statistical difference in the incidence of restenosis in the two groups. Besides, there was no statistical difference in the incidence of major adverse cardiac events（MACE）during hospitalization and follow-up in the DCB group (7.3% (4/55)) and the DES group (8.8% (6/68)). CONCLUSION: DCB is safe and effective for ACS complicated with vulnerable plaque and has an advantage over DES in LLL.

Analysis of the Correlation Between the Ratio of Monocytes to High-Density Lipoprotein Cholesterol and in-Stent Restenosis in Patients with Premature Coronary Heart Disease.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and monocytes are associated with coronary artery disease, and the ratio of monocytes to high-density lipoprotein (MHR) is associated with long-term adverse outcomes and the recurrence of atrial fibrillation. Currently, the trend of coronary heart disease proned to young people is becoming prominent. However, the relationship between MHR and in-stent restenosis (ISR) in patients with premature coronary heart disease (PCHD) has not been investigated. Therefore, we aimed to assess the relationship between MHR and ISR in patients with PCHD. METHODS: We retrospectively included 257 patients (men ≤ 55 years old, women ≤ 65 years old) with PCHD who underwent drug-eluting stent implantation and follow-up coronary angiography at the First Affiliated Hospital of Zhengzhou University from September 2016 to September 2019. Patients were divided into ISR and non-ISR groups depending on their follow-up coronary angiography results. Relative clinical information was recorded and analyzed. A receiver operating characteristic curve analysis was used to determine the optimum pre-procedural MHR cutoff value to predict ISR. RESULTS: Logistic regression analysis showed that MHR, smoking history, and fibrinogen were independent risk factors for ISR in patients with PCHD. The area under the receiver operating characteristic curve (AUC) of MHR was 0.750 (95% confidence interval, 0.695-0.820; P < .001), the cutoff value was 546.88, and the specificity and sensitivity were 65.2% and 78%, while the AUC of monocytes was 0.631 (95% confidence interval, 0.638-0.794; P < .001), the cutoff value was 590, and the specificity and sensitivity were 77.1% and 60.0%. CONCLUSION: MHR is an independent risk factor for ISR in patients with PCHD and showed a certain predictive value.

New insights into iron/nickel-carbon ternary micro-electrolysis toward 4-nitrochlorobenzene removal: Enhancing reduction and unveiling removal mechanisms.

The ternary micro-electrolysis material iron/nickel-carbon (Fe/Ni-AC) with enhanced reducibility was constructed by introducing the trace transition metal Ni based on the iron/carbon (Fe/AC) system and used for the removal of 4-nitrochlorobenzene (4-NCB) in solution. The composition and structures of the Fe/Ni-AC were analyzed by various characterizations to estimate its feasibility as reductants for pollutants. The removal efficiency of 4-NCB by Fe/Ni-AC was considerably greater than that of Fe/AC and iron/nickel (Fe/Ni) binary systems. This was mainly due to the enhanced reducibility of 4-NCB by the synergism between anode and double-cathode in the ternary micro-electrolysis system (MES). In the Fe/Ni-AC ternary MES, zero-iron (Fe0) served as anode involved in the formation of galvanic couples with activated carbon (AC) and zero-nickel (Ni0), respectively, where AC and Ni0 functioned as double-cathode, thereby promoting the electron transfer and the corrosion of Fe0. The cathodic and catalytic effects of Ni0 that existed simultaneously could not only facilitate the corrosion of Fe0 but also catalyze H2 to form active hydrogen (H*), which was responsible for 4-NCB transformation. Besides, AC acted as a supporter which could offer the reaction interface for in-situ reduction, and at the same time provide interconnection space for electrons and H2 to transfer from Fe0 to the surface of Ni0. The results suggest that a double-cathode of Ni0 and AC could drive much more electrons, Fe2+ and H*, thus serving as effective reductants for 4-NCB reduction.

Utilization of porous carbon synthesized with textile wastes via calcium acetate template for tetracycline removal: The role of template agent and the formation mechanism.

A porous carbon obtained from cotton/polyester textile wastes was synthesized by the calcium acetate template method. This research studied the effect of preparation conditions and evaluated the characterization of porous carbon, and further explored its formation mechanism. The porous carbon possessed a high specific surface area of 1106.63 m2/g under an optimum condition (pyrolysis temperature = 800 °C, mass ratio of CA: CPW = 1.5:1, pyrolysis time = 1.5 h). It was found that calcium acetate played the role of catalyst to promote the degradation of cotton/polyester textile. CaCO3 and CaO fabricated by calcium acetate acted as the template to generate a mesoporous structure. The generated CO2 etched carbon skeleton to create a large number of micropores. Besides, it was supported as the carbon source to fuse with carbon structures, further consolidating the aromatic structures of porous carbon. The optimized porous carbon has a high adsorption capacity of 506.40 mg/g for tetracycline. And the adsorption data fitted better by the first-pseudo-order model and Langmuir isotherms with an endothermic and spontaneous adsorption process. The cotton/polyester-based porous carbon was a promising economical material for tetracycline.

Conversion of cotton textile waste to clean solid fuel via surfactant-assisted hydrothermal carbonization: Mechanisms and combustion behaviors.

The cotton textile was an abundant energy resource while was otherwise treated as waste. In this work, surfactants were used as catalysts in the hydrothermal carbonization (HTC) to transform cotton textile waste (CTW) into clean solid fuel. Furthermore, the conversion mechanisms of hydrothermal products during surfactant-assisted HTC were preliminarily proposed. The results showed that Span 80 and sodium dodecylbenzenesulfonate facilitated the transformation of CTW into bio-oil, while Tween 80 was more conducive to the development of pseudo-lignin, which endowed hydrochars higher energy density and updated the fuel quality and combustion behavior. Therefore, the research presented an effective method to convert CTW to clean solid fuel through the HTC treatment combining with surfactants.

The protective role of SOD1 overexpression in central mediation of bradycardia following chronic intermittent hypoxia in mice.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications. Similar to OSA, chronic intermittent hypoxia (CIH) (a model for OSA) leads to oxidative stress and impairs baroreflex control of the heart rate (HR) in rodents. The baroreflex arc includes the aortic depressor nerve (ADN), vagal efferent, and central neurons. In this study, we used mice as a model to examine the effects of CIH on baroreflex sensitivity, aortic baroreceptor afferents, and central and vagal efferent components of the baroreflex circuitry. Furthermore, we tested whether human Cu/Zn Superoxide Dismutase (SOD1) overexpression in transgenic mice offers protection against CIH-induced deficit of the baroreflex arc. Wild-type C57BL/6J and SOD1 mice were exposed to room air (RA) or CIH and were then anesthetized, ventilated, and catheterized for measurement of mean arterial pressure (MAP) and HR. Compared with wild-type RA control, CIH impaired baroreflex sensitivity but increased maximum baroreceptor gain and bradycardic response to vagal efferent stimulation. Additionally, CIH reduced the bradycardic response to ADN stimulation, indicating a diminished central regulation of bradycardia. Interestingly, SOD1 overexpression prevented CIH-induced attenuation of HR responses to ADN stimulation and preserved HR responses to vagal efferent stimulation in transgenic mice. We suggest that CIH decreased central mediation of the baroreflex and SOD1 overexpression may prevent the CIH-induced central deficit.

Total Synthesis of (-)-Lepadin F based on a Stereoselective Diels-Alder Reaction Controlled by a Ketolactone-type Dienophile.

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels-Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN 2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (-)-lepadin F is synthesized from ethyl l-lactate for the first time.

Hypercholesterolemia Is an Associated Factor for Risk of Differentiated Thyroid Cancer in Chinese Population.

BACKGROUND: Hyperlipidemia has been hypothesized as a risk factor for thyroid cancer. However, the association between hypercholesterolemia and thyroid cancer is unclear, especially in Chinese population without available published data. We conducted this study to investigate the relationship between hypercholesterolemia and differentiated thyroid cancer (DTC) in Chinese population. METHODS: Three thousand seven hundred forty-eight patients were enrolled in the study, including 2,021 DTC patients and 1,727 benign subjects with benign thyroid nodules. Demographic characteristics, medical history, and clinical hematological examination were collected. Stratified analyses of association between hypercholesterolemia and risk of DTC were done. Multivariable logistic regression models were used to estimate the association between hypercholesterolemia and the risk of thyroid nodules being malignant. This study protocol was approved by the ethics committee of Shandong Provincial Qianfoshan Hospital and assigned in ClinicalTrials.gov protocol registration and results system (NCT03006289, https://clinicaltrials.gov/ct2/show/NCT03006289). RESULTS: The level of serum total cholesterol in patients with DTC is higher than that in benign subjects (P < 0.001). After adjusting hypercholesterolemia, age (P < 0.001), triglyceride (P = 0.003), and thyroid stimulating hormone (TSH) (P < 0.001) are found to be confounding factors. The risk of DTC in patients younger than 45 years old is 2.08 times than that of patients older than 45 years old (odds ratio = 0.48, 95% CI (0.38, 0.61), P < 0.001). A high TSH level is highly associated with the increased risk of DTC (P < 0.001). The multivariable logistic regression analysis revealed that the absence of hypercholesterolemia could reduce the risk of thyroid nodules being malignant (odds ratio = -0.75, 95% CI (-1.39, -0.12), P = 0.02). Comparing to the higher level of serum total cholesterol (>5.7 mmol/L), the closer the serum total cholesterol level is to normal (3.17-5.7 mmol/L), the less the risk of thyroid nodules being malignant is, and this difference is statistically significant (odds ratio = -0.67, 95% CI (-1.31, -0.03), P = 0.040). However, this difference is not found in the group of patients with lower level of total cholesterol (<3.17 mmol/L, odds ratio = 0.43, 95% CI (-1.22, 2.09), P = 0.068), suggesting that hypocholesterolemia is not a protective factor in the risk of thyroid nodules being malignant. CONCLUSIONS: Hypercholesterolemia is an associated factor for risk of DTC in Chinese population.

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® assays. Studies in glioblastoma cell lines showed that the most active compound induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

NLRP3 inflammasome mediate palmitate-induced endothelial dysfunction.

AIMS: Free fatty acids (FFA) is a key contributor to insulin resistance and endothelial dysfunction. However, the precise mechanism underlying the role of FFA remains elusive. This study aimed to investigate the role of NLRP3 (NOD-like receptor pyrin domain containing-3) inflammasome in FFA induced endothelial dysfunction. MAIN METHODS: HUVECs were transfected with NLRP3 siRNA and then stimulated with LPS and palmitate. C57 BL/6 J mice transfected with NLRP3 Lenti-Virus were fed with a high-fat diet (HFD). The levels of NLRP3 inflammasome, AMPKα (AMP-activated protein kinase), endothelial nitric oxide synthase (eNOS) and the activity of the insulin signal pathway, in endothelial cells were determined via Western blotting. Endothelial function was determined by measuring the level of endothelium-dependent vasodilatation. KEY FINDINGS: FFA could activate NLRP3 inflammasome and induce IL-1ß release both in vitro. and in vivo. Using siRNA and Lenti-Virus to inhibit NLRP3 abolished palmitate-induced IL-1ß release and restored impaired phosphorylation of IRS-1 (Tyr), Akt (Ser473) and eNOS (Ser1177) and ACh-mediated endothelium-dependent vasorelaxation induced by palmitate. AMPKα activator AICAR(5-aminoimidazole-4-carbox-amide-1-ß-d-ribofuranoside) inhibited NLRP3 inflammasome activation and decreased IL-1ß release and restored impaired insulin signal pathway induced by palmitate. SIGNIFICANCE: NLRP3 inflammasome activation via AMPKα inactivation mediated palmitate-induced endothelial dysfunction through involves IL-1ß-induced insulin signal pathway.

Convergent Formal Synthesis of Ecteinascidin 743.

A concise formal synthesis of ecteinascidin 743 is described. Key features involve the coupling of the multisubstituted tetrahydroisoquinoline and phenylalaninol moieties via a regio- and stereoselective Pictet-Spengler cyclization as well as the subsequent chemoselective MOM protection of the phenol group, which opens a rapid access to the desirable pentacycle. The synthesis successfully delivered the advanced intermediate with the characteristic macrolactone from sesamol in 23 steps.