A growing global health concern is metabolic syndrome, which is defined by low HDL, diabetes, hypertension, and abdominal obesity. Nuclear receptors are attractive targets for treatment of diseases ...associated with metabolic syndrome. Liver X receptors (LXRs) have become one of the most significant pharmacological targets among nuclear receptors. Multiple research studies emphasize the essential function of the liver X receptor (LXR) in the pathophysiology of metabolic syndrome. Puniceloid D, among natural products, demonstrated promising effects on LXRα. However, attempts at the total synthesis of natural products were faced with challenges, including long synthetic steps and low yields, requiring a more efficient approach. In this study, for the first time, we successfully synthesized puniceloid D through a seven-step process and conducted docking studies to gain a comprehensive understanding of the interactions involved in the binding of puniceloid D to LXR within different heterodimeric contexts. Our understanding of the pathophysiology of metabolic syndrome could be improved by these findings, which might assist with the development of novel treatment strategies.
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by ...massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF
and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell ...migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only
-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.
A catalyst-free, additive-free, and eco-friendly method for synthesizing 1,2,4-triazolo1,5-
pyridines under microwave conditions has been established. This tandem reaction involves the use of ...enaminonitriles and benzohydrazides, a transamidation mechanism followed by nucleophilic addition with nitrile, and subsequent condensation to yield the target compound in a short reaction time. The methodology demonstrates a broad substrate scope and good functional group tolerance, resulting in the formation of products in good-to-excellent yields. Furthermore, the scale-up reaction and late-stage functionalization of triazolo pyridine further demonstrate its synthetic utility. A plausible reaction pathway, based on our findings, has been proposed.
Abstract
In this study, we have developed solvent‐controlled regioselective Mannich reaction of cyclicimines (benzoxazinones) with various ketones by using ʟ‐proline as catalyst to afford Mannich ...products in high yields with excellent enantio‐ and diastereoselectivity. The unsymmetrical ketones produced the linear isomer as the major product in chloroform solvent. On contrary, using the DMSO solvent favoured the formation of branch isomer product with excellent enantio‐ and diastereoselectivity. The aromatic auxiliary was successfully removed and afforded
N
‐protected chiral amino acid derivative.
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The purpose of this article is to compare the diagnostic performances of shearwave and strain elastography for the differentiation of benign and malignant breast lesions.
B-mode ultrasound and ...shear-wave and strain elastography were performed in 150 breast lesions; 71 were malignant. BI-RADS final assessment, elasticity values in kilopascals, and elasticity scores on a 5-point scale were assessed before biopsy. The results were compared using the area under the receiver operating characteristic curve (AUC).
The AUC for shear-wave elastography was similar to that of strain elastography (0.928 vs 0.943). The combined use of B-mode ultrasound and either elastography technique improved diagnostic performance in the differentiation of benign and malignant breast lesions compared with the use of B-mode ultrasound alone (B-mode alone, AUC = 0.851; B-mode plus shear-wave elastography, AUC = 0.964; B-mode plus strain elastography, AUC = 0.965; p < 0.001). With the best cutoff points of 80 kPa on shear-wave elastography and a score between 3 and 4 on strain elastography, the sensitivity was higher in shear-wave elastography, and specificity was higher in strain elastography (95.8% vs 81.7%, p = 0.002; 93.7% vs 84.8%, p = 0.016). In cases of infiltrating ductal carcinoma, mean elasticity scores were lower in grade 3 than in grade 1 and 2 cancers (p = 0.017) with strain elastography causing false-negative findings.
The diagnostic performance of shear-wave and strain elastography was similar. Either elastography technique can improve overall diagnostic performance in the differentiation of benign and malignant lesions when combined with B-mode ultrasound. However, the sensitivity and specificity of shear-wave and strain elastography were different according to lesion histologic profile, tumor grade, and breast thickness.
Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a ...previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-2-(1-cyclohexen-1-yl)ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ
-infused mice, and microglial BV-2 cells and astrocytes.
We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ
-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ
for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ
-induced memory loss.
A memory recovery effect was found to be associated with the reduction of Aβ
-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ
-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro.
These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic ...conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low‐PDI‐expression group. Conclusion: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855–868).
This report describes the synthesis of 4‐aryl‐2‐halopyridines via γ‐functionalization of α,β‐unsaturated nitriles, which were obtained by the HWE reaction with the corresponding ketones. The key ...features of our methods involve a conjugated γ‐enamine formation of α,β‐unsaturated nitrile (enamino nitrile), followed by consecutive intramolecular cyclization, resulting in heteroaromatic compounds like 2‐halopyridines, α‐pyrone, etc.
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