Minimum residual root dentin thickness of mandibular premolars restored with a post: A finite element analysis study.

STATEMENT OF PROBLEM: Thin root dentin after post space preparation will increase the risk of root fracture. However, the minimum residual root dentin thickness to be preserved after post space preparation is unclear. PURPOSE: The purpose of this finite element analysis (FEA) study was to measure the residual root dentin thicknesses and analyze the stress distributions of post-restored mandibular premolars. MATERIAL AND METHODS: The cone beam computed tomography (CBCT) data of 90 first and second mandibular premolars from Chinese participants (44 men, 46 women; aged between 20 and 79 years) were analyzed. Cross-sections 5 to 9 mm from the radiologic apex were used to measure the buccolingual and mesiodistal root diameters. The probability that the residual thickness of the buccolingual and mesiodistal root walls would be no less than 0.5, 0.6, 0.7, 0.8, 0.9, and 1 mm after post space preparation with a #2 Peeso reamer was calculated. Six 3-dimensional finite element models of cast post-restored mandibular premolars with 0.5, 0.6, 0.7, 0.8, 0.9, and 1 mm mesial and distal root dentin thicknesses were established. A static force of 100 N was applied to the buccal cusp tip at 45, 60, 75, and 90 degrees to the long axis of the tooth, and the maximum tensile stress and von Mises stress were analyzed. The Bonferroni post hoc test (αcorrected=.003) was used for multiple comparisons. RESULTS: The buccolingual root diameter of mandibular premolars was wider than the mesiodistal root diameter. The probabilities that the mesiodistal residual root dentin thickness of mandibular first and second premolars at 5 mm from the apex would be no less than 1 mm after post space preparation with a #2 Peeso reamer were only 10% and 28%, respectively. The maximum tensile stress was at a minimum when the mesial and distal residual root dentin thickness was 0.6 mm in the external cervical dentin adjacent to the crestal bone and 1 mm in the apical dentin corresponding to the apex of the post. The maximum tensile stress of the mandibular premolar model with 0.6-mm mesial and distal residual root dentin thicknesses was lower than that with 0.9 mm and 1.0 mm thicknesses (Pcorrected<.001). CONCLUSIONS: Short posts or smaller instruments for post space preparation are recommended to obtain a 1-mm residual root dentin thickness in the mesiodistal direction of mandibular premolars. If a 1-mm thickness cannot be preserved, a minimum residual root dentin thickness of 0.6 to 0.9 mm in the mesiodistal direction should be retained.

[Differential Expression of Long Non-coding RNA Cancer Susceptibility Candidate 2 and Imprinted Gene H19 in Extrahepatic Cholangiocarcinoma].

Objective To investigate the expression and the potential roles of long non-coding RNA(lncRNA)cancer susceptibility candidate 2(CASC2)and imprinted gene H19 in extrahepatic cholangiocarcinoma(ECC). Methods Four samples from patients with ECC were collected for high-throughput sequencing which was conducted to reveal the transcriptomic profiles of lncRNA CASC2 and H19.Bioinformatics tools were employed to predict the potential roles of the two genes.Another 22 ECC tissue samples and the cholangiocarcinoma cell lines(RBE,QBC939,HuH-28,and HuCCT1)with different degrees of differentiation were selected for validation.The para-carcinoma tissue and normal human intrahepatic biliary epithelial cell(HIBEC)were used as the control groups.The expression levels of lncRNA CASC2 and H19 in carcinoma tissue,para-carcinoma tissue,and cell lines were determined by real-time quantitative polymerase chain reaction(qRT-PCR).The correlation analysis was carried out for the clinical indicators of patients with the expression levels of the target genes. Results The two target genes showed significantly different expression between carcinoma tissue and para-carcinoma tissue(all P<0.05).Specifically,CASC2 had higher expression level in the carcinoma tissue than in the para-carcinoma tissue(t=1.262,P=0.025),whereas the expression of H19 showed an opposite trend(t=1.285,P=0.005).The expression levels of CASC2 in QBC939(t=8.114,P=0.015)and HuH-28(t=9.202,P=0.012)cells were significantly higher than that in the control group.The expression levels of H19 were significantly lower in RBE(t=-10.244,P<0.001),QBC939(t=-10.476,P<0.001),HuH-28(t=-19.798,P<0.001),and HuCCT1(t=-16.193,P=0.004)cells than in the control group.Bioinformatics analysis showed that CASC2 was mainly involved in the metabolic process and H19 in the development of multicellular organisms.Both CASC2 and H19 were related to catalytic activity.The expression level of lncRNA CASC2 was correlated with pathological differentiation(χ 2=6.222,P=0.022)and lymph node metastasis(χ2=5.455,P=0.020),and that of lncRNA H19 with pathological differentiation(χ2=1.174,P=0.029)and tumor size(χ2=-0.507,P=0.037). Conclusions In the case of ECC,lncRNA CASC2 and H19 have transcription disorders.lncRNA CASC2 is generally up-regulated in the carcinoma tissue,while H19 is down-regulated.Both genes have the potential to become new molecular markers for ECC.

Strength deterioration mechanism of bentonite modified loess after wetting-drying cycles.

The employment of bentonite modified loess (BML) is a common method of constructing the anti-seepage lining of landfills in the loess region of China, and its long-term secure performance is threatened by wetting-drying (W-D) cycles. Taking the remolded loess (RL) and BML with 15% in mass of bentonite as research objects, the W-D cycles test, scanning electron microscope test and direct shear test were carried out to analyze the effects of W-D cycles on the microstructure and shear strength of samples. The regression equations between strength and micro-pore structure parameters were established by the multivariate linear stepwise regression method. The damage mechanism of BML after W-D cycles was studied by establishing damage degree models based on pore area ratio and cohesion. Results indicate that the water absorption and expansion of bentonite effectively block the intergranular pores, resulting in more medium and small pores and more pronounced surface contact of particles. After W-D cycles, the particle arrangement of samples before and after bentonite modification tends to be loose. Both the pore area ratio and fractal dimension increase and tend to stabilize after five cycles. The BML exhibits lower pore area ratio and greater fractal dimension while its cohesion and internal friction angle show more significant decrease after W-D cycles than those of RL. The damage variables based on pore area ratio and cohesion well describe the W-D induced damage of loess before and after modification from macro- and micro-scale perspectives. The damage degree of samples increases with W-D cycles, but the increment decreases.

Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy.

ABSTRACT: Desmoplakin (DSP), encoded by the DSP gene, is the main desmosome component and is abundant in the myocardial tissue. There are three DSP isoforms that assume the role of supporting structural stability through intercellular adhesion. It has been found that DSP regulates the transcription of adipogenic and fibrogenic genes, and maintains appropriate electrical conductivity by regulating gap junctions and ion channels. DSP is essential for normal myocardial development and the maintenance of its structural functions. Studies have suggested that DSP gene mutations are associated with a variety of hereditary cardiomyopathy, such as arrhythmia cardiomyopathy, dilated cardiomyopathy (DCM), left ventricular noncompaction, and is also closely associated with the Carvajal syndrome, Naxos disease, and erythro-keratodermia-cardiomyopathy syndrome with skin and heart damage. The structure and function of DSP, as well as the clinical manifestations of DSP-related cardiomyopathy were reviewed in this article.

Establishment of a Canine Training Model for Digestive Tract Reconstruction after Pancreaticoduodenectomy.

PURPOSE: Practical training models can be a viable and effective educational tool that allows surgeons to acquire specific surgical techniques or skills. However, a suitable animal training model for reconstruction after a pancreaticoduodenectomy (PD) has not yet been reported. Therefore, we explored the feasibility and safety of establishing an animal training model for digestive tract reconstruction after a simulated PD using mongrel dogs. METHODS: We used the anatomical similarity between the canine and human digestive tract to simulate the digestive tract reconstruction after pancreatoduodenectomy. A hepatobiliary surgeon performed simulated PD digestive reconstructions on 6 mongrel canines. Pancreaticojejunostomy (PJ), biliary-enteric anastomosis (BEA), and jejuno-jejunal anastomosis (JJ) were performed sequentially. The survival rate, surgical operation time, complications, body weight changes, gross specimen, and pathological examination of the anastomotic region were observed 30 days after surgery. RESULTS: The survival rate 30 days after surgery was 100%. Total mean operative time was 230.5 ± 39.7 min. The operative time for PJ, BEA, and JJ was calculated as 21.5 ± 7 min, 21.7 ± 8.7 min, and 13.2 ± 1.8 min, respectively. An incision infection occurred in 1 case (16.7%); there was 1 case of ascites (16.7%), and 1 case of vomiting (16.7%). The total protein and total bilirubin indicators of the 6 dogs and the serum amylase index of 5 dogs 30 days postoperatively were within the normal range. The 6th dog's serum amylase was approximately double the normal value, possibly due to pancreatitis. Observing the gross specimen, the mucosa of the anastomosis was intact and smooth. Masson staining showed that the bile duct and jejunum anastomosis, the pancreas, and jejunum of the 6 canines were all integrated with rich collagen. CONCLUSION: Establishing an animal model for digestive tract reconstruction after a simulated PD in canines is feasible and safe.

Mechanism of Shuang-Huang-Lian Oral Liquid for Treatment of Mycoplasmal Pneumonia in Children on Network Pharmacology.

BACKGROUND AND OBJECTIVE: Mycoplasmal pneumonia (MP) can lead to inflammation, multiple system immune damage, and mixed infection in children. The pathogenesis is still unclear. Shuang-Huang-Lian (SHL) oral liquid can treat acute upper respiratory tract infection, acute bronchitis and light pneumonia. However, our current understanding of the molecular mechanisms supporting its clinical application still lags behind due to the lack of researches. It is difficult to understand the overall sensitization mechanism of SHL oral liquid. The purpose is to explain the mechanism of action of drugs in this study, which is useful to ensure the safety of medication for children. METHODS: The therapeutic mechanism of SHL oral liquid was investigated by a system pharmacology approach integrating drug-likeness evaluation, oral bioavailability prediction, ADMET, protein-protein interaction worknet, Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes database pathway performance, C-T-P network construction and molecular docking. RESULTS: A total of 18 active ingredients contained in SHL oral liquid and 53 major proteins were screened out as effective players in the treatment of M. pneumoniae disease through some related pathways and molecular docking. The majority of targets, hubs and pathways were highly related to anti-mycoplasma therapy, immunity and inflammation process. CONCLUSION: This study shows that the anti-bacterial effect of SHL oral liquid has multicomponent, multi-target and multi-pathway phenomena. The proposed approach may provide a feasible tool to clarify the mechanism of traditional Chinese medicines and further develop their therapeutic potentials.

A Review: The Anti-inflammatory, Anticancer and Antibacterial Properties of Four Kinds of Licorice Flavonoids Isolated from Licorice.

Plants have always been an important source of medicines for humans, and licorice is a very significant herb in the development of humans. As a traditional herb, it is widely cultivated in China, Japan, Russia, Spain and India. With the development of organic chemistry and biochemistry, various chemical ingredients extracted from licorice have been studied and identified. Among them, many chemical components were considered to have strong pharmacological activities, such as anti-inflammatory, anti-ulcer, antibacterial, anticancer and so on. Based on those reports, licorice has attracted the attention of many researchers in recent years, and they are devoted to discovering the active ingredients and mechanism of action of active compounds. Licorice flavonoids are one of the main extracts of licorice root and stem and have many potential biological properties. This paper aims to summarize the four kinds of licorice flavonoids, including liquiritigenin, isoliquiritigenin, licochalcone (including licochalcone A and licochalcone B) and glabridin, about their biological activities of anti-inflammatory, anticancer, antibacterial.

Virtual Screening of Potential Anti-fatigue Mechanism of Polygonati Rhizoma Based on Network Pharmacology.

BACKGROUND AND OBJECTIVE: A large number of people are facing the danger of fatigue due to the fast-paced lifestyle. Fatigue is common in some diseases, such as cancer. The mechanism of fatigue is not definite. Traditional Chinese medicine is often used for fatigue, but the potential mechanism of Polygonati Rhizoma (PR) is still not clear. This study attempts to explore the potential anti-fatigue mechanism of Polygonati Rhizoma through virtual screening based on network pharmacology. METHODS: The candidate compounds of PR and the known targets of fatigue are obtained from multiple professional databases. PharmMapper Server is designed to identify potential targets for the candidate compounds. We developed a Herbal medicine-Compound-Disease-Target network and analyzed the interactions. Protein-protein interaction network is developed through the Cytoscape software and analyzed by topological methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment are carried out by DAVID Database. Finally, we develop Compound-Target-Pathway network to illustrate the anti-fatigue mechanism of PR. RESULTS: This approach identified 12 active compounds and 156 candidate targets of PR. The top 10 annotation terms for GO and KEGG were obtained by enrichment analysis with 35 key targets. The interaction between E2F1 and PI3K-AKT plays a vital role in the anti-fatigue effect of PR due to this study. CONCLUSION: This study demonstrates that PR has multi-component, multi-target and multipathway effects.

Design, synthesis, biological evaluation of benzoyl amide derivatives containing nitrogen heterocyclic ring as potential VEGFR-2 inhibitors.

For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 8h showed the best inhibitory activity (IC50 = 0.34 ±â€¯0.02 µM against VEGFR-2, IC50 = 1.08 ±â€¯0.06 µM and 2.44 ±â€¯0.15 µM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 8h induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.

Recent approaches to His-Purkinje system pacing.

OBJECTIVE: Physiologic cardiac pacing is a novel technique which has been largely popularized in recent decades. His bundle pacing (HBP) has been long considered the most physiologic pacing method; however, with the widespread implementation of this method, its disadvantages have become apparent. In this context, left bundle branch pacing (LBBP)-directly engaged in the His-Purkinje system-has been foreseen as the best pacing method to mimic physiologic activation patterns. This review aimed to summarize recent approaches to physiologic cardiac pacing. DATA SOURCES: This review included fully peer reviewed publications up to July 2018, found in the PubMed database using the keywords "His bundle branch pacing," "right ventricular pacing," and "physiologic pacing." STUDY SELECTION: All selected articles were in English, with no restriction on study design. RESULTS: The HBP has been studied worldwide, and is currently considered the most physiologic pacing method. However, it has disadvantages, such as high pacing threshold, unsatisfactory sensing and long procedure times, among others. Although LBBP is theoretically superior to HBP, the clinical relevance of this difference remains under debate, as few large randomized clinical trials with LBBP have been published. CONCLUSIONS: Although HBP indeed appears to be the most physiologic pacing method, it has certain shortcomings, such as high pacing threshold, difficult implantation due to specific anatomic features, and others. Further studies are required to clarify the clinical significance of LBBP.

Expression and potential molecular mechanisms of miR­204­5p in breast cancer, based on bioinformatics and a meta­analysis of 2,306 cases.

Breast cancer (BC) is the most common cancer among women worldwide. However, there is insufficient research that focuses on the expression and molecular mechanisms of microRNA (miR)­204­5p in BC. In the current study, data were downloaded from the Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO) and the University of California Santa Cruz (UCSC) Xena databases. They were then used to undertake a meta­analysis that leveraged the standard mean difference (SMD) and summarized receiver operating characteristic (sROC) to evaluate the expression of the precursor miR­204 and mature miR­204­5p in BC. Additionally, an intersection of predicted genes, differentially expressed genes (DEGs) from the TCGA database and the GEO database were plotted to acquire desirable putative genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein­protein interaction (PPI) network analyses were performed to assess the potential pathways and hub genes of miR­204­5p in BC. A decreased trend in precursor miR­204 expression was detected in 1,077 BC tissue samples in comparison to 104 para­carcinoma tissue samples in the TCGA database. Further, the expression of mature miR­204­5p was markedly downregulated in 756 BC tissue samples in comparison to 76 para­carcinoma tissue samples in the UCSC Xena database. The outcome of the SMD from meta­analysis also indicated that the expression of miR­204­5p was markedly reduced in 2,306 BC tissue samples in comparison to 367 para­carcinoma tissue samples. Additionally, the ROC and sROC values indicated that miR­204­5p had a great discriminatory capacity for BC. In GO analysis, 'cell development', 'cell surface activity', and 'receptor agonist activity' were the most enriched terms; in KEGG analysis, 'endocytosis' was significantly enriched. Rac GTPase activating protein 1 (RACGAP1) was considered the hub gene in the PPI network. In conclusion, miR­204­5p may serve a suppressor role in the oncogenesis and advancement of BC, and miR­204­5p may have crucial functions in BC by targeting RACGAP1.

Identification and Biological Evaluation of Novel Type†II B-RafV600E Inhibitors.

The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-RafV600E . New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B-RafV600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-N-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzamide was the most potent agent with IC50 values of 0.035±0.004 µm (B-RafV600E kinase) and 0.39±0.04 µm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B-Raf inhibitor candidates.

Design, synthesis, and biological evaluation of pyrazole derivatives containing acetamide bond as potential BRAFV600E inhibitors.

With the increasingly acquired resistance, relapse and side effects of known marketed BRAFV600E inhibitors, it's significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamide bond had been designed and synthesized on the basis of analysis of the endogenous ligands extracted from the known B-Raf co-crystals in the PDB database. Then, the compounds were evaluated for biological activities as potential BRAFV600E inhibitors. The bioassay results in vitro against three human tumor cell lines revealed that some of the compounds showed very impressed antiproliferative property. Among them, the compound 5r with IC50 values of 0.10 ±â€¯0.01 µM against BRAFV600E and 0.96 ±â€¯0.10 µM against A375 cell line, showed the most potent inhibitory effect, compared with the positive-controlled agents vemurafenib (IC50 = 0.04 ±â€¯0.004 µM for BRAFV600E, IC50 = 1.05 ±â€¯0.10 µM against A375). Further investigation confirmed that the compound 5r could induce A375 cell apoptosis, induce A375 cell death through changing mitochondrial membrane potential, and result in A375 cell arrest at the G1 phase of the cell cycle. Docking simulations results indicated that the compound 5r could bind tightly at the BRAFV600E active site. Meanwhile, 3D-QSAR model suggested that these compounds may be potential anticancer inhibitors. Overall, the article provided some new molecular scaffolds for the further BRAFV600E inhibitors.

Endoscopic linear stapler-assisted resection of a giant solid pseudopapillary pancreatic tumor with concurrent regional portal hypertension: a case report.

Solid pseudopapillary tumor of the pancreas (SPTP) is a rare neoplasm with a low incidence and low rate of malignancy. We herein report a rare case of SPTP concurrent with regional portal hypertension (RPH) that was successfully treated by distal pancreatectomy and splenectomy. A 22-year-old woman presented with a left upper abdominal apophysis and normal liver function. She was diagnosed with an SPTP and RPH by abdominal ultrasound and computed tomography, and she subsequently underwent distal pancreatectomy and splenectomy. Noticeably, varicose vein plexus with wide range appeared on the upper edge of the pancreatic body and posterior gastric wall of the patient. Therefore, we created a path to avoid touching the varicose veins and took advantage of the endoscopic linear stapler to staple the veins. We herein report our surgical experience on SPTP assisted with the endoscopic linear stapler, which will be very realistic for the management of this rare clinical entity.

Design of potent B-RafV600E inhibitors by multiple copy simulation search strategy.

B-Raf kinase is a vital intermedium in the mitogen-activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases such as somatic tumors. So far, the development of B-Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task. In this study, we designed and evaluated a series of novel B-RafV600E inhibitors. A fragment library has been established before the docking simulation carried out using the MCSS strategy (multicopy simulation search). The appropriate fragments were reassembled to provide new candidate compounds, which were further screened by iterative docking simulations and molecular dynamics. Bioassays were carried out to evaluate the pharmacological profile of the compounds identified and synthesized. The result showed that compound 5n had an impressive enzyme inhibitory and antiproliferation activity, suggesting a promising potential in the future study.

Clinical Significance and Effect of lncRNA HOXA11-AS in NSCLC: A Study Based on Bioinformatics, In Vitro and in Vivo Verification.

HOXA11 antisense RNA (HOXA11-AS) has been shown to be involved in tumorigenesis and development of different cancers. However, the role of HOXA11-AS in non-small cell lung cancer (NSCLC) remains unclear. In this study, we firstly explored and confirmed the expression of HOXA11-AS in NSCLC tissues and cells. Cytometry, CCK-8, cell scratch, migration, Matrigel invasion and flow cytometry assays were performed to determine the biological impact of HOXA11-AS in vitro. Furthermore, a chick embryo chorioallantoic membrane (CAM) model of NSCLC was constructed to explore the effect of HOXA11-AS on tumorigenicity and angiogenesis in vivo. Additionally, bioinformatics analyses were performed to investigate the prospective pathways of HOXA11-AS co-expressed genes. As results, HOXA11-AS was markedly highly expressed in NSCLC tissues and cells. Furthermore, the proliferation, migration, invasion, tumorigenic and angiogenic ability of NSCLC cells were all inhibited and apoptosis was induced after HOXA11-AS knock-down. HOXA11-AS RNAi also led to cell cycle arrest on G0/G1 or G2/M phase. In addition, the non-small cell lung cancer pathway might be involved in regulating the co-expressed genes of HOXA11-AS in NSCLC. These results indicate that HOXA11-AS plays pivotal roles in NSCLC and it can become a novel therapeutic direction for treating NSCLC.

Identification of novel B-RafV600E inhibitors employing FBDD strategy.

B-Raf kinase is the key point in a main branch of mitogen-activated protein kinase pathways and some of its mutations, such as the V600E mutation, lead to the persistent activation of ERK signaling and the trigger of severe diseases, including melanoma and other somatic cancers. Several potent drugs have been approved to treat B-Raf-related tumors, however, cases of resistance and relapse have been reported universally. Hence, differential scaffolds are in need to alleviate the scarcity of drugs and benefit the therapy of B-Raf-mutant cancers. Herein we report our recent work on the construction of novel B-RafV600E inhibitors employing fragment-based drug design strategy. In this research, we decomposed known inhibitors to fragments and rebuilt new candidates using these blocks according to the evaluation of their potential. Lead compounds were synthesized after selection by means of virtual screening and molecular dynamics validation. Afterwards, we tested the pharmacological efficiency of these entities both in vitro and in vivo utilizing A375 xenograft model. The results favored our rational design intention and hinted this new kind of inhibitors might be helpful in the further explorations of potent agents.

Design, synthesis and biological evaluation of novel benzo-α-pyrone containing piperazine derivatives as potential BRAFV600E inhibitors.

The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAFV600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAFV600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAFV600E inhibitor and exerted an anticancer effect through BRAFV600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAFV600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent.

Toll-like receptor 4 knockout protects against isoproterenol-induced cardiac fibrosis: the role of autophagy.

BACKGROUND: Toll-like receptor 4 participates in the process of acute heart injury. The underlying mechanisms of its protection are multifactorial, but we hypothesized that toll-like receptor-mediated autophagy control plays a vital role. The purpose of this study was to clarify the effect of autophagy on cardiac fibrosis. METHODS: Cardiac fibrosis was induced by subcutaneous isoproterenol (ISO) injection, and rapamycin was simultaneously administered orally for 14 days. Animal echocardiography was then used to evaluate the success of the cardiac fibrosis model, and the mice were killed after the echocardiography examination. RESULTS: Toll-like receptor 4 knockout (TLR4 KO) mice had better heart function than did wild-type (WT) mice (P < .05). Rapamycin treatment reduced the left ventricular ejection fraction to 23.5% (P < .05), and the collagen volume fraction of the ISO and ISO plus rapamycin groups was 5.9% and 25.9%, respectively, in TLR4 KO mice. Compared with the WT mice, Beclin 1 and autophagy were downregulated in TLR4 KO mice (P < .05); however, the ISO plus rapamycin group had higher autophagy activity than did the ISO group in TLR4 KO mice (P < .05). CONCLUSIONS: Our results suggest that TLR4 KO-induced cardioprotection against ISO-induced cardiac fibrosis is associated with reduced autophagy induction. Cardiac fibroblast autophagy participates in its own activation. The moderate inhibition of autophagic activity may be a new strategy for treating cardiac fibrosis.