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1.
Chem Biodivers ; 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33811740

RESUMO

Five new decalins, monalbidins A-E ( 1 , 2 and 7 - 9 ), together with 16 known compounds ( 3 - 6 and 10 - 21 ), were isolated from the EtOAc extract of marine derived fungus Monascus albidus BB3 cultured in GPY medium. Among the known compounds, 1-hydroxymonacolin L ( 11 ), dehydromonacolin J ( 15 ), 8- O -acetylmonacolin J ( 19 ) and O -acetylmonacolin K ( 21 ) were separated from natural sources for the first time.Their structures were determined by comprehensive analysis on the 1D and 2D NMR, HRESIMS, UV and IR data , and their absolute configurations were assigned by experimental and calculated ECD data, and X-ray single-crystal diffraction analysis. Monalbidins C and D ( 7 and 8 ), monacolin K methyl ester ( 13 ), dehydromonacolin L ( 14 ), dehydromonacolin K ( 16 ), monacolin K ( 20 ) and O -acetylmonacolin K ( 21 ) showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, HCT116 and MDA-MB-231.

2.
Nat Struct Mol Biol ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782615

RESUMO

Lipoproteins in the outer membrane of Gram-negative bacteria are involved in various vital physiological activities, including multidrug resistance. Synthesized in the cytoplasm and matured in the inner membrane, lipoproteins must be transported to the outer membrane through the Lol pathway mediated by the ATP-binding cassette transporter LolCDE in the inner membrane via an unknown mechanism. Here, we report cryo-EM structures of Escherichia coli LolCDE in apo, lipoprotein-bound, LolA-bound, ADP-bound and AMP-PNP-bound states at a resolution of 3.2-3.8 Å, covering the complete lipoprotein transport cycle. Mutagenesis and in vivo viability assays verify features of the structures and reveal functional residues and structural characteristics of LolCDE. The results provide insights into the mechanisms of sorting and transport of outer-membrane lipoproteins and may guide the development of novel therapies against multidrug-resistant Gram-negative bacteria.

3.
Oncol Rep ; 45(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33786631

RESUMO

Thyroid carcinoma (THCA) is a common type of endocrine system cancer and its current clinical treatment method is surgical resection. Long non­coding RNAs (lncRNAs) have been revealed to serve important roles in a variety of complex human diseases. Therefore, determining the association between lncRNAs and diseases may provide novel insight into disease­related lncRNAs, with the aim of improving disease treatments and diagnoses. Long intergenic non­protein coding RNA 1816 (LINC01816) was identified to be associated with the survival of patients with colorectal cancer using the IDHI­MIRW method. The present study aimed to investigate the role and molecular mechanism of LINC01816 in THCA. Analysis of datasets from The Cancer Genome Atlas database revealed that the upregulation of LINC01816 expression levels was associated with a variety of cancer types. Reverse transcription­quantitative PCR analysis demonstrated that compared with the normal thyroid tissues, the expression levels of LINC01816 were upregulated in THCA tissues. The results of wound healing and Transwell assays, and western blotting demonstrated that the overexpression of LINC01816 could strengthen the invasive and migratory abilities of THCA cells and enhance epithelial­mesenchymal transition progression. Analysis using the starBase website and dual­luciferase reporter assays identified that microRNA (miR)­34c­5p was a target of LINC01816. The overexpression of miR­34c­5p could inhibit the invasive and migratory abilities of THCA cells, in addition to inhibiting the cellular retinoic acid binding protein 2 (CRABP2) overexpression­induced effects on invasion, migration and EMT processes. In conclusion, the findings of the present study indicated that LINC01816 may be capable of sponging miR­34c­5p to upregulate CRABP2 expression levels, which subsequently promoted the invasion, migration and EMT of THCA cells. Therefore, targeting the LINC01816/miR­34c­5p/CRABP2 pathway may be an effective therapeutic approach for patients with THCA.

4.
IEEE Trans Cybern ; PP2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33729977

RESUMO

Graph-based subspace clustering methods have exhibited promising performance. However, they still suffer some of these drawbacks: they encounter the expensive time overhead, they fail to explore the explicit clusters, and cannot generalize to unseen data points. In this work, we propose a scalable graph learning framework, seeking to address the above three challenges simultaneously. Specifically, it is based on the ideas of anchor points and bipartite graph. Rather than building an n x n graph, where n is the number of samples, we construct a bipartite graph to depict the relationship between samples and anchor points. Meanwhile, a connectivity constraint is employed to ensure that the connected components indicate clusters directly. We further establish the connection between our method and the K-means clustering. Moreover, a model to process multiview data is also proposed, which is linearly scaled with respect to n. Extensive experiments demonstrate the efficiency and effectiveness of our approach with respect to many state-of-the-art clustering methods.

5.
Ecotoxicol Environ Saf ; 214: 112080, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33677380

RESUMO

Resveratrol (RES) is a natural polyphenolic compound with a broad range of physiological and pharmacological properties. Previous studies have shown that RES also plays an important role in protecting and promoting early bone metabolism and differentiation. The accumulation of cadmium (Cd), one of the world's most poisonous substances, can inhibit skeletal growth and bone maturation, thus causing osteoporosis. However, whether RES can prevent the Cd-induced inhibition of osteogenic differentiation remains unknown. In this study, we found that RES promoted the early maturity of osteoblastic MC3T3-E1 cells, as demonstrated by the significantly increased mRNA and protein expression of a range of differentiation markers, including alkaline phosphatase (ALP), collagen 1 (COL1), bone morphogenetic protein-2 (BMP-2), and runt-related transcription factor 2 (RUNX2). In contrast, we found that cadmium chloride (CdCl2) inhibited the viability and osteogenic maturity of MC3T3-E1 cells. We also demonstrated that RES pretreatment for 30 min provided significant protection against Cd-induced apoptosis and attenuated the inhibition of osteogenic differentiation induced by Cd by modulating ERK1/2 and JNK signaling. In conclusion, our results indicate that RES is a potential femoral protectant that not only enhance the viability and early differentiation of osteoblasts, but also protect osteoblasts from cadmium damage.


Assuntos
Cádmio/toxicidade , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2 , Cádmio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Subunidade alfa 1 de Fator de Ligação ao Core , Sistema de Sinalização das MAP Quinases , Proteína Quinase 3 Ativada por Mitógeno , Osteoblastos/citologia , Osteogênese/genética
6.
Oncogene ; 40(13): 2422-2436, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33664452

RESUMO

Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.

7.
J Am Chem Soc ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591738

RESUMO

The copolymerization of carbon dioxide (CO2) and epoxides to produce aliphatic polycarbonates is a burgeoning technology for the large-scale utilization of CO2 and degradable polymeric materials. Even with the wealth of advancements achieved over the past 50 years on this green technology, many challenges remain, including the use of metal-containing catalysts for polymerization, the removal of the chromatic metal residue after polymerization, and the limited practicable epoxides, especially for those containing electron-withdrawing groups. Herein, we provide kinds of pinwheel-shaped tetranuclear organoboron catalysts for epichlorohydrin/CO2 copolymerization with >99% polymer selectivity and quantitative CO2 uptake (>99% carbonate linkages) under mild conditions (25-40 °C, 25 bar of CO2). The produced poly(chloropropylene carbonate) has the highest molecular weight of 36.5 kg/mol and glass transition temperature of 45.4 °C reported to date. The energy difference (ΔEa = 60.7 kJ/mol) between the cyclic carbonate and polycarbonate sheds light on the robust performance of our metal-free catalyst. Control experiments and density functional theory (DFT) calculations revealed a cyclically sequential copolymerization mechanism. The metal-free feature, high catalytic performance under mild conditions, and no trouble with chromaticity for the produced polymers imply that our catalysts are practical candidates to advance the CO2-based polycarbonates.

8.
Plant Dis ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591830

RESUMO

Knowledge about virulent phenotypes of Heterodera glycines Ichinohe, 1952 (soybean cyst nematode, SCN) is essential for breeding resistant cultivars and managing this nematode. Heilongjiang Province is the major soybean producing region in China. SCN has been reported in 63 regions in Heilongjiang Province. To determine the prevalence and virulence of phenotypes of SCN, 112 soil samples were collected from soybean fields throughout the province in 2015. SCN was detected in 62 samples (55.4%) of these samples, with population densities ranging from 150 to 41,750 eggs and juveniles per 100 cm3 of soil. Eleven HG types, namely HG 0, 1.2.3.5.7, 1.2.3.7, 1.3.4.7, 1.3.7, 2, 2.5.7, 2.7, 6, 6.7, and 7, were detected. The percentages of SCN populations with female indices greater than ten ranged from 4.8% for PI 437654 to 64.5% for PI 548316. This is the first report of seven of the HG types from Heilongjiang. These results provide guidance for breeding efforts and control strategies to combat SCN.

9.
J Ethnopharmacol ; 271: 113810, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33508368

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sperm infertility and testicular atrophy are symptoms associated with aging. BaZiBuShen formula (BZBS), a patented Chinese herbal prescription composed of Semen Cuscutae, Fructus Lycii, Epimedii Folium, Fructus Schisandrae Sphenantherae, Fructus Cnidii, Fructus Rosae Laevigatae, Semen Allii Tuberosi., Radix Morindae Officinalis, Herba Cistanches, Fructus Rubi, Radix Rehmanniae Recens, Radix Cyathulae, Radix Ginseng, Cervi Cornu Pantotrichum, Hippocampus, and Fuctus Toosendan, has been used as a kidney-tonifying and anti-aging drug as well as for the treatment of impotence and male infertility in traditional Chinese medicine. AIM OF THE STUDY: We aimed at investigating whether BZBS preserves sperm and testes morphology in aging mice, and to explore the underlying mechanisms. MATERIALS AND METHODS: BZBS was orally administered to aging mice induced by D-galactose (D-gal) and NaNO2 for 65 days. Sperm quality and testes pathophysiological alterations were examined by a Semen Analysis System, hematoxylin-eosin staining, transmission electron microscopy, and mitochondrial complex IV activity. In addition, serum levels of total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-desoxyguanosine (8-OH-dG), reduced glutathione (GSH), oxidized glutathione disulfide (GSSG), testosterone (T), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and tumor necrosis factor-α (TNF-α) were determined by ELISA. The expressions of P450 aromatase (CYP19), sirtuin 6 (Sirt6), P53, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB)-p65, and phospho-NF-κB-p65 (NF-κB-pp65) in the testes were examined by western blot and/or immunohistochemical staining. RESULTS: Sustained exposure to D-gal/NaNO2 caused a deterioration of sperm quality and testes morphology in this rapid aging mouse model. BZBS treatment curtailed these alterations. These beneficial effects were associated with increased serum levels of TAC, GSH/GSSG, T, E2, and FSH, and decreased levels of MDA, TNF-α, and 8-OH-dG. BZBS treatment also downregulated the expressions of P53, iNOS, and NF-κB-pp65, as well as upregulated the expressions of Sirt6 and CYP19 in aging testes. CONCLUSIONS: BZBS preserves testicular morphology and spermatogenesis possibly via inhibition of oxidative stress and the modulation of the Sirt6/P53 and Sirt6/NF-κB signaling pathways. The results shed light on the beneficial effect of BZBS on sperm quality and fertility in aging males.

10.
Ecotoxicol Environ Saf ; 208: 111668, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396178

RESUMO

Cadmium is an environmental metal pollutant that has been a focus of research in recent years, which is reported to cause bone disease; however, its skeletal toxicity and the mechanism involved are not yet fully known. Therefore, this study used MC3T3-E1 subclone 14 cells to determine the mechanism of cadmium toxicity on bone. Cadmium chloride (Cd) significantly reduced cell viability in a concentration-dependent manner. Exposure to Cd inhibited osteoblast-related proteins (Runx2, Col-1, STC2) and decreased alkaline phosphatase (ALP) activity. Cd caused Exportin-1 accumulation and induced DNA damage. Cd significantly down-regulated caspase 9 and induced cleaved-PARP, cleaved-caspase 3 protein level. Treatment with JNK inhibitor, SP600125, suppressed cadmium-induced elevation in the ratio of phosphorylation of JNK to JNK. Inhibition of caspase with pan-caspase inhibitor, Z-VAD-FMK, prevented MC3T3-E1 subclone 14 cells from cadmium-induced reduction of Runx2, STC2, caspase 9, and accumulation of cleaved PARP and cleaved caspase 3. Cd-induced cell survival enhanced by SP600125 but rescued by Z-VAD-FMK or KPT-335. These results suggest that cadmium cytotoxicity on bone involved exportin 1 accumulation, phosphorylation of JNK, induction of DNA damage and pro-apoptosis, which was induced by activation of caspase-dependent pathways.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Dano ao DNA/efeitos dos fármacos , Carioferinas/metabolismo , MAP Quinase Quinase 4/metabolismo , Osteoblastos/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Caspases/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação/efeitos dos fármacos
11.
Med Image Anal ; 67: 101824, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091741

RESUMO

With the rapidly worldwide spread of Coronavirus disease (COVID-19), it is of great importance to conduct early diagnosis of COVID-19 and predict the conversion time that patients possibly convert to the severe stage, for designing effective treatment plans and reducing the clinicians' workloads. In this study, we propose a joint classification and regression method to determine whether the patient would develop severe symptoms in the later time formulated as a classification task, and if yes, the conversion time will be predicted formulated as a classification task. To do this, the proposed method takes into account 1) the weight for each sample to reduce the outliers' influence and explore the problem of imbalance classification, and 2) the weight for each feature via a sparsity regularization term to remove the redundant features of the high-dimensional data and learn the shared information across two tasks, i.e., the classification and the regression. To our knowledge, this study is the first work to jointly predict the disease progression and the conversion time, which could help clinicians to deal with the potential severe cases in time or even save the patients' lives. Experimental analysis was conducted on a real data set from two hospitals with 408 chest computed tomography (CT) scans. Results show that our method achieves the best classification (e.g., 85.91% of accuracy) and regression (e.g., 0.462 of the correlation coefficient) performance, compared to all comparison methods. Moreover, our proposed method yields 76.97% of accuracy for predicting the severe cases, 0.524 of the correlation coefficient, and 0.55 days difference for the conversion time.


Assuntos
/classificação , Pneumonia Viral/classificação , Pneumonia Viral/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Interpretação de Imagem Radiográfica Assistida por Computador , Radiografia Torácica , Índice de Gravidade de Doença , Fatores de Tempo
12.
Pest Manag Sci ; 77(1): 568-576, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32815305

RESUMO

BACKGROUND: The soybean cyst nematode (SCN, Heterodera glycines) is the most devastating and yield-limiting pest in soybean worldwide. With the increasing awareness of environmental protection, biological control becomes more and more urgent. The Bacillus megaterium Sneb207 has previously shown the ability to inhibit the movement of SCN, but little is known about its effect on nematode control in agricultural settings. The aim of this study was to evaluate the efficiency of Sneb207 against SCN and investigate the ability of Sneb207 to induce systemic resistance to H. glycines in soybean. RESULTS: The stability and efficiency of SCN control by Sneb207 was assessed in two field experiments. Compared to non-treated control, Sneb207 significantly reduced the number of cysts, SCN juveniles, and eggs, while it promoted soybean growth. Furthermore, results of two pot experiments showed that the number of initial infections of second-stage juveniles were 231.75 and 131.3 after Sneb207 treatment, respectively, lower than control (274.75 and 215.33). Sneb207 reduced the total number of juveniles and females, and lengthened SCN development time. Moreover, through the split-root system and real-time quantitative PCR experiments, we found that Sneb207 induced systemic resistance and enhanced the gene expression of GmACS9b, GmEDS1, GmPAD4, GmSAMT1, and GmNPR1-1 involved in the salicylic acid, jasmonic acid and ethylene pathways at different levels. CONCLUSION: Our results demonstrate that B. megaterium Sneb207 inhibits the invasion, the development, and reproduction of SCN by inducing systemic resistance. The overall outcomes of the present study support B. megaterium Sneb207 as a potential biocontrol agent for H. glycines.


Assuntos
Bacillus megaterium , Cistos , Tylenchoidea , Animais , Doenças das Plantas , Soja
13.
Mol Neurobiol ; 58(1): 92-105, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32895785

RESUMO

Alcohol use-associated disorders are highly comorbid with anxiety disorders; however, their mechanism remains unknown. The amygdala plays a central role in anxiety. We recently found that 7,8-dihydroxyflavone (7,8-DHF) significantly reduces withdrawal symptoms in a rat model of chronic intermittent alcohol (ethanol) exposure. This study aimed to determine the role of 7,8-DHF in regulating anxiety induced by chronic alcohol exposure and its associated underlying mechanism. Male C57BL/6J mice were exposed to chronic intermittent alcohol for 3 weeks followed by alcohol withdrawal for 12 h with or without 7,8-DHF administered intraperitoneally. All mice were tested using an open field test and elevated plus maze to assess anxiety-like behaviors. Synaptic activity and intrinsic excitability in basal and lateral amygdala (BLA) neurons were assessed using electrophysiological recordings. 7,8-DHF alleviated alcohol-induced anxiety-like behavior and attenuated alcohol-induced enhancement of activities in BLA pyramidal neurons. Furthermore, 7,8-DHF prevented alcohol withdrawal-evoked augmentation of glutamatergic transmission in the amygdala and had no effect on GABAergic transmission in the amygdala, as demonstrated by unaltered frequency and amplitude of spontaneous inhibitory postsynaptic currents. Microinjection of K252a, a tropomyosin-related kinase B (TrkB) antagonist, into the BLA blocked the effects of 7,8-DHF on anxiety-like behavior and neuronal activity in the BLA. Our findings suggest that 7,8-DHF alleviates alcohol-induced anxiety-like behavior induced by chronic alcohol exposure through regulation of glutamate transmission involving TrKB in the BLA.

14.
Med Image Anal ; 67: 101825, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33137699

RESUMO

The enormous social and economic cost of Alzheimer's disease (AD) has driven a number of neuroimaging investigations for early detection and diagnosis. Towards this end, various computational approaches have been applied to longitudinal imaging data in subjects with Mild Cognitive Impairment (MCI), as serial brain imaging could increase sensitivity for detecting changes from baseline, and potentially serve as a diagnostic biomarker for AD. However, current state-of-the-art brain imaging diagnostic methods have limited utility in clinical practice due to the lack of robust predictive power. To address this limitation, we propose a flexible spatial-temporal solution to predict the risk of MCI conversion to AD prior to the onset of clinical symptoms by sequentially recognizing abnormal structural changes from longitudinal magnetic resonance (MR) image sequences. Firstly, our model is trained to sequentially recognize different length partial MR image sequences from different stages of AD. Secondly, our method is leveraged by the inexorably progressive nature of AD. To that end, a Temporally Structured Support Vector Machine (TS-SVM) model is proposed to constrain the partial MR image sequence's detection score to increase monotonically with AD progression. Furthermore, in order to select the best morphological features for enabling classifiers, we propose a joint feature selection and classification framework. We demonstrate that our early diagnosis method using only two follow-up MR scans is able to predict conversion to AD 12 months ahead of an AD clinical diagnosis with 81.75% accuracy.

15.
J Vis Exp ; (166)2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33346199

RESUMO

Currently, ex situ machine perfusion is a burgeoning technique that provides a better preservation method for donor organs than conventional static cold preservation (0-4 °C). A continuous blood supply to organs using machine perfusion from procurement and preservation to implantation facilitates complete prevention of ischemia reperfusion injury and permits ex situ functional assessment of donor livers before transplantation. In this manuscript, we provide a step-by-step ischemia-free liver transplantation protocol in which an ex situ normothermic machine perfusion apparatus is used for pulsatile perfusion through the hepatic artery and continuous perfusion of the portal vein from human donor livers to recipients. In the perfusion period, biochemical analysis of the perfusate is conducted to assess the metabolic activity of the liver, and a liver biopsy is also performed to evaluate the degree of injury. Ischemia-free liver transplantation is a promising method to avoid ischemia-reperfusion injury and may potentially increase the donor pool for transplantation.


Assuntos
Transplante de Fígado/efeitos adversos , Traumatismo por Reperfusão/etiologia , Animais , Criopreservação , Humanos , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos , Perfusão , Traumatismo por Reperfusão/patologia , Soluções , Doadores de Tecidos
16.
Acta Pharmacol Sin ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318625

RESUMO

This study aimed to investigate the inhibitory effect of EM-2, a natural active monomer purified from Elephantopusmollis H.B.K., on the proliferation of human hepatocellular carcinoma cells and the molecular mechanism involved. The results from the MTT assay revealed that EM-2 significantly inhibited the proliferation of human hepatocellular carcinoma (HCC) cells in a dose-dependent manner but exhibited less cytotoxicity to the normal liver epithelial cell line LO2. EdU staining and colony formation assays further confirmed the inhibitory effect of EM-2 on the proliferation of Huh-7 hepatocellular carcinoma cells. According to the RNA sequencing and KEGG enrichment analysis results, EM-2 markedly activated the MAPK pathway in Huh-7 cells, and the results of Western blotting further indicated that EM-2 could activate the ERK and JNK pathways. Meanwhile, EM-2 induced apoptosis in a dose-dependent manner and G2/M phase arrest in Huh-7 cells, which could be partially reversed when treated with SP600125, a JNK inhibitor. Further study indicated that EM-2 induced endoplasmic reticulum stress and blocked autophagic flux in Huh-7 cells by inhibiting autophagy-induced lysosome maturation. Inhibition of autophagy by bafilomycin A1 could reduce cell viability and increase the sensitivity of Huh-7 cells to EM-2. In conclusion, our findings revealed that EM-2 not only promoted G2/M phase arrest and activated ER stress but also induced apoptosis by activating the JNK pathway and blocked autophagic flux by inhibiting autolysosome maturation in Huh-7 hepatocellular carcinoma cells. Therefore, EM-2 is a potential therapeutic drug with promising antitumor effects against hepatocellular carcinoma and fewer side effects.

17.
Technol Cancer Res Treat ; 19: 1533033820971277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33251973

RESUMO

BACKGROUND: Traditional laparoscopic No.12a lymph node dissection in radical gastrectomy for gastric cancer may damage the peripheral blood vessels, and is not conducive to the full exposure of the portal vein and the root ligation of the left gastric vein. We recommend a new surgical procedure, the portal vein approach, to avoid these problems. METHODS: 25 patients with advanced gastric cancer underwent radical laparoscopic gastrectomy and No.12a lymph node were dissected by portal vein approach, including 7 cases with total gastrectomy, 18 cases with distal gastric resection, 14 males and 11 females. Operative time, intraoperative blood loss, time to first flatus, postoperative hospital stay, number of total lymph node dissection and No.12a lymph node dissection, No.12a lymph node metastasis rate and postoperative complications were statistically observed. RESULTS: All the patients were operated successfully and No.12a lymph node were cleaned by portal vein approach. A total of 683 lymph nodes were dissected, with the average number of lymph nodes dissection and positive lymph nodes were (27.3 ± 12.7) and (3.8 ± 5.6) respectively. The average number of No.12a lymph node dissection was (2.4 ± 1.95) and the metastasis rate of No.12a lymph node was 16% (4/25). The average operation time of radical laparoscopic distal and total gastrectomy were (239.2 ± 51.4) min and (295.1 ± 27.7) min respectively. The mean intraoperative blood loss was (134.0 ± 65.7) ml, and postoperative first anal exhaust time was (2.24 ± 0.86) d. The mean time to fluid intake was (4.2 ± 1.7) d, and postoperative hospitalization time was (9.6 ± 5.0) d. Without portal vein injure, anastomotic leakage, gastrointestinal bleeding, intestinal obstruction and other complications were observed in all patient. CONCLUSION: Our results show that the laparoscopic No.12a lymph node dissection by portal vein approach for gastric cancer is safe, feasible and has certain clinical application value.

18.
Bioinformatics ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226062

RESUMO

MOTIVATION: The overall association evidence of a genetic variant with multiple traits can be evaluated by cross phenotype association analysis using summary statistics from genome wide association studies (GWAS). Further dissecting the association pathways from a variant to multiple traits is important to understand the biological causal relationships among complex traits. RESULTS: Here we introduce a flexible and computationally efficient Iterative Mendelian Randomization and Pleiotropy (IMRP) approach to simultaneously search for horizontal pleiotropic variants and estimate causal effect. Extensive simulations and real data applications suggest that IMRP has similar or better performance than existing Mendelian Randomization methods for both causal effect estimation and pleiotropic variant detection. The developed pleiotropy test is further extended to detect colocalization for multiple variants at a locus. IMRP will greatly facilitate our understanding of causal relationships underlying complex traits, in particular, when a large number of genetic instrumental variables are used for evaluating multiple traits. AVAILABILITY: The software IMRP is available at https://github.com/XiaofengZhuCase/IMRP. The simulation codes can be downloaded at http://hal.case.edu/~xxz10/zhu-web/ under the link: MR Simulations software. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
Nat Struct Mol Biol ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199922

RESUMO

The highly asymmetric outer membrane of Gram-negative bacteria functions in the defense against cytotoxic substances, such as antibiotics. The Mla pathway maintains outer membrane lipid asymmetry by transporting phospholipids between the inner and outer membranes. It comprises six Mla proteins, MlaFEDBCA, including the ABC transporter MlaFEDB, which functions via an unknown mechanism. Here we determine cryo-EM structures of Escherichia coli MlaFEDB in an apo state and bound to phospholipid, ADP or AMP-PNP to a resolution of 3.3-4.1 Å and establish a proteoliposome-based transport system that includes MlaFEDB, MlaC and MlaA-OmpF to monitor the transport direction of phospholipids. In vitro transport assays and in vivo membrane permeability assays combined with mutagenesis identify functional residues that not only recognize and transport phospholipids but also regulate the activity and structural stability of the MlaFEDB complex. Our results provide mechanistic insights into the Mla pathway, which could aid antimicrobial drug development.

20.
Autophagy ; : 1-19, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33213267

RESUMO

The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and maturation of osteoclasts, and ultimately results in bone metastasis. Notably, phosphorylation of ULK1 by MAPK1/ERK2-MAPK3/ERK1 kinase triggers its interaction with BTRC and subsequent K48-linked ubiquitination and proteasome degradation. Also, a clearly negative correlation between the expression levels of ULK1 and p-MAPK1/3 was observed in human breast cancer tissues. The MAP2K/MEK inhibitor trametinib is sufficient to restore mitophagy function via upregulation of ULK1, leading to inhibition of NLRP3 inflammasome activation, thereby reduces bone metastasis. These results indicate that ULK1 knockout-mediated mitophagy defect promotes breast cancer bone metastasis and provide evidence to explore MAP2K/MEK- MAPK1/3 pathway inhibitors for therapy, especially in cancers displaying low levels of ULK1. Abbreviations: ATG: autophagy-related; Baf A1: bafilomycin A1; BTRC/ß-TrCP: beta-transducin repeat containing E3 ubiquitin protein ligase; CHX: cycloheximide; CM: conditioned media; FBXW7/FBW7: F-box and WD repeat domain containing 7; MAPK1: mitogen-activated protein kinase 1; MTDR: MitoTracker Deep Red; mtROS: mitochondrial reactive oxygen species; microCT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; SQSTM1: sequestosome 1; ACP5/TRAP: acid phosphatase, tartrate resistant; ULK1: unc-51 like autophagy activating kinase 1.

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