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1.
Chemosphere ; 244: 125498, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31812049

RESUMO

BACKGROUND: Heavy metal exposure induces oxidative stress, which is critical for adverse male reproductive health. OBJECTIVE: To explore the mediating effect of oxidative stress on the relationship of heavy metal exposure with semen quality. METHODS: Urinary levels of three oxidative stress markers, semen quality, and urinary arsenic, cadmium and lead were examined among 1020 men. Multivariate linear regression was applied to explore cross-sectional associations, and the role of oxidative stress as mediators was investigated. RESULTS: Quartiles of metals showed significant dose-dependent relationships with increasing levels of 8-hydroxy-2deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA). Significant or suggestive associations were also found between urinary 8-OHdG levels and the percentage of normal sperm morphology (ptrend < 0.001), between urinary 8-isoPGF2α levels and total motility (ptrend = 0.052), progressive motility (ptrend = 0.050) respectively. The mediation analysis showed that about 14.59%, 18.06%, 15.35% or 16.49% of the association between arsenic/cadmium exposure and the decreased total motility/progressive motility was mediated by 8-isoPGF2α, respectively. In addition, about 16.47% of the relationship between lead exposure and the decreased percentage of normal sperm morphology was mediated by 8-OHdG. CONCLUSIONS: Our findings suggest that higher urinary arsenic, cadmium and lead levels were associated with increased oxidative stress markers, which also related with altered semen quality. 8-isoPGF2α and 8-OHdG might be the possible mediators of the associations between urinary heavy metals and total motility, progressive motility or the proportion of normal sperm morphology.

2.
ACS Infect Dis ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815418

RESUMO

As more than two billion people possibly have a latent tuberculosis (LTB) infection, early LTB diagnosis is crucial for the efficient control and elimination of tuberculosis (TB). The aim of this study is to detect the serum antibody responses to dormancy-related DosR regulon antigens of Mycobacterium tuberculosis for the diagnosis of active and latent TB infections. A membrane array with 25 latency antigens detected by silver-enhanced gold nanoparticles was used to determine the corresponding cognate antibody levels in clinical serum samples from healthy controls, TB patients and individuals with LTB. The array is sized to fit into a 24-well ELISA plate and follows an ELISA-like experimental procedure without expensive instrumentation. Linear discriminant analysis (LDA) of the resulting antibody profiling dataset identified a panel of nine DosR antigens with significant discriminatory capability among different subjects with ≥ 90% sensitivity, specificity, and overall accuracy. Furthermore, the high predictive performance validated by an independent test sample set reflects the robustness and reliability of the LDA classification model. Our current data demonstrate that the nine DosR antigen combination associated with the proposed membrane array platform is a clinically feasible approach for distinguishing different TB infection statuses. The proposed methodology in this study could be further developed for multiple disease serodiagnoses with high sensitivity and specificity.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31848206

RESUMO

BACKGROUND: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSFs) who may benefit from low-dose computed tomography (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated six-year risk >0.0151. According to two US reports, only 36.6% female lung cancer patients met the USPSTF criteria, while 38% of the ever-smokers aged 55-74 met the USPSTF criteria. METHODS: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case-control study, consisting of 1748 lung cancer patients and 6535 controls. Using these and an estimated age-specific lung cancer six-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). RESULTS: The AUC based on the NSFs aged 55-70 in LCPG and TWB2 was 0.714 (95% CI 0.660, 0.768). For women in TWB2 aged 55-70, 3.94% (95% CI 2.95, 5.13) had risk higher than 0.0151. For women in LCPG aged 55-74, 27.03% (95% CI 19.04, 36.28) had risk higher than 0.0151. CONCLUSIONS: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high risk Asian NSFs aged 55-74 deserves attention. IMPACT: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

4.
J Nat Prod ; 82(11): 3065-3073, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31718182

RESUMO

Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 µM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 µM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 µM) than hederagenin (IC50 > 20 µM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 µM) and osimertinib-resistant H1975-LTC (IC50 7.6 µM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.

6.
Biosci Biotechnol Biochem ; : 1-10, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694485

RESUMO

This study aimed to explore the influence of Tryptophanyl-tRNA synthetase (WARS) expression on the proliferation and migration of uveal melanoma (UM) cells, and the potential mechanisms. Bioinformatics analysis based on Gene Expression Omnibus (GEO) database showed that WARS expression in metastatic cancer was significantly higher than that in no-metastatic group. Kaplan-Meier analysis based on The Cancer Genome Atlas (TCGA) database showed that high WARS expression was associated with lower survival. Biological function experiments showed that overexpression of WARS in OCM-1A cells can promote cell proliferation, migration, and invasion, whereas knockdown of WARS in C918 cells showed the opposite effect. Finally, we observed that the up-regulation of WARS induced the activation of phosphatidylinositol 3-kinase/AKT (PI3K/AKT) signaling, whilst depletion of WARS resulted in opponent outcomes. Taken together, our results illustrated that WARS was overexpressed in UM cells and contributed to the viability and motility of UM cells via modulating PI3K/AKT signaling pathway.

7.
BMC Plant Biol ; 19(1): 473, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694537

RESUMO

BACKGROUND: Soil salinization and alkalization are among the major agricultural threats that affect crop productivity worldwide, which are increasing day by day with an alarming rate. In recent years, several halophytes have been investigated for their utilization in soil remediation and to decipher the mechanism of salt-tolerance in these high salt tolerant genetic repositories. Suaeda salsa is an annual halophytic herb in the family Amaranthaceae, displaying high salt and alkali-resistance and having nutritive value. However, the fundamental biological characteristics of this valuable plant remain to be elucidated until today. RESULTS: In this study, we observed the morphology and development of Suaeda salsa, including seed morphology, seed germination, plant morphology, and flower development. Using microscopy, we observed the male and female gametophyte developments of Suaeda salsa. Also, chromosome behaviour during the meiosis of male gametophyte was studied. Eventually, the genome size of Suaeda salsa was estimated through flow cytometry using Arabidopsis as reference. CONCLUSIONS: Our findings suggest that the male and female gametophyte developments of Suaeda salsa are similar to those of the model plant Arabidopsis, and the diploid Suaeda salsa contains nine pairs of chromosomes. The findings also indicate that the haploid genome of Suaeda salsa is approximately 437.5 MB. The observations and results discussed in this study will provide an insight into future research on Suaeda salsa.

8.
Gut Pathog ; 11: 53, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695752

RESUMO

Background: Enterohemorrhagic Escherichia coli O157:H7 (EHEC O157) causes bloody diarrhea and hemolytic-uremic syndrome. EHEC O157 encounters varied microenvironments during infection, and can efficiently adapt to these using the two-component system (TCS). Recently, a functional TCS, RstAB, has been implicated in the regulation of virulence of several bacterial pathogens. However, the regulatory function of RstAB in EHEC O157 is poorly understood. This study aimed at providing insights into the global effects of RstA on gene expression in EHEC O157. Results: In the present study, we analyzed gene expression differences between the EHEC O157 wild-type strain and a ΔrstA mutant using RNA-seq technology. Genes with differential expression in the ΔrstA mutant compared to that in the wild-type strain were identified and grouped into clusters of orthologous categories. RstA promoted EHEC O157 LEE gene expression, adhesion in vitro, and colonization in vivo by indirect regulation. We also found that RstA could bind directly to the promoter region of hdeA and yeaI to enhance acid tolerance and decrease biofilm formation by modulating the concentration of c-di-GMP. Conclusions: In summary, the RstAB TCS in EHEC O157 plays a major role in the regulation of virulence, acid tolerance, and biofilm formation. We clarified the regulatory function of RstA, providing an insight into mechanisms that may be potential drug targets for treatment of EHEC O157-related infections.

9.
mSystems ; 4(6)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771974

RESUMO

The 7th cholera pandemic began in 1961 in Sulawesi, Indonesia, and then spread around the world in at least three waves. However, the lack of genome sequences for Vibrio cholerae strains under long-term surveillance in East Asia, especially in China, has restricted our understanding of the dynamics of the intracountry and intercountry evolution and transmission of the 7th-pandemic clones. In this study, we obtained the genome sequences of 60 V. cholerae strains isolated in Shanghai, the largest port in the world and the largest city in China, from 1961 to 2011. Our whole-genome-based phylogeny of 7th-pandemic strains revealed that all but one fell into five "stages," most of which are single clades and share independent ancestors. Each stage dominated in succession for a period, with little overlap between them. In addition, two near-identical Shanghai strains belonging to a pre-7th-pandemic precursor and 4 nontoxigenic O1/O139 strains attributed to independent recombination events at the O-antigen loci were present. The major lineages of the 7th pandemic in Shanghai appeared to be closely related to V. cholerae strains isolated from South or Southeast Asia. Stage succession was consistently related to changes in society and human activity, implying that human-caused niche change may play a vital role in the cholera dynamics in Shanghai.IMPORTANCE V. cholerae is the causative agent of cholera, a life-threatening disease characterized by severe, watery diarrhea. The 7th pandemic started in Indonesia in 1961 and spread globally, currently infecting 1.3 million to 4 million people annually. Here, we applied whole-genome sequencing to analyze a long-term collection of V. cholerae clinical strains to reveal the phylogenetic background and evolutionary dynamics of the 7th pandemic in Shanghai, which had undergone breathtakingly rapid development in the last half-century. All but one of the Shanghai 7th-pandemic strains fell into five "stages" that were dominant in Shanghai and appeared to be closely related to 7th-pandemic strains of South or Southeast Asia. Our findings extended the understanding of the dynamics of the evolution and transmission of the 7th-pandemic clones in East Asia and the relationship between social changes and cholera epidemiology.

10.
J Hazard Mater ; : 121431, 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31672436

RESUMO

Spermatogenesis-related microRNAs (miRNAs) are vulnerable to polycyclic aromatic hydrocarbons (PAHs). Changes in spermatogenesis-related miRNAs may be biological intermedia in mechanisms linking PAHs and semen quality. This study aimed to investigate whether spermatogenesis-related microRNAs mediate the associations between PAHs and semen quality. We measured 10 monohydroxylated PAHs (OH-PAHs) in repeated urine samples and three candidate spermatogenesis-related miRNAs (miRNA106a, miRNA21, and miRNA34c) in seminal plasma from men attending an infertility clinic (n = 111). Mediation analysis was applied to determine the mediating role of spermatogenesis-related miRNAs in the association of PAH exposure with semen quality. Urinary 2-OHFlu and 2-OHPh were related to reduced seminal plasma miRNA34c (p for trend = 0.05 and 0.03, respectively). Urinary 9-OHPh was related to reduced seminal plasma miR106a (p for trend = 0.02), which in turn, was positively associated with sperm concentration, sperm count, sperm total motility, and progressive motility (all p for trends<0.05). Up to 43.8% of the eff ;ect of urinary 9-OHPh on decreased sperm concentration was mediated by seminal plasma miR106a. Our results suggested that certain PAH exposure was associated with reduced spermatogenesis-related miRNAs and such alterations might be an intermediate mechanism by which PAHs exert its adverse effects on semen quality.

12.
J Infect Dis ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31630185

RESUMO

The human intestinal pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes bloody diarrhea, hemorrhagic colitis, and fatal hemolytic uremic syndrome. Its genome contains 177 unique O islands (OIs), which contribute largely to the high virulence and pathogenicity although most OI genes remain uncharacterized. In the current study, we demonstrated that OI-19 is required for EHEC O157:H7 adherence to host cells. Z0442 (OI-encoded virulence regulator A [OvrA]) encoded in OI-19 positively regulated bacterial adherence by activating locus of enterocyte effacement (LEE) gene expression through direct OvrA binding to the gene promoter region of the LEE gene master regulator Ler. Mouse colonization experiments revealed that OvrA promotes EHEC O157:H7 adherence in mouse intestine, preferentially the colon. Finally, OvrA also regulated virulence in other non-O157 pathogenic E. coli, including EHEC strains O145:H28 and O157:H16 and enteropathogenic E. coli strain O55:H7. Our work markedly enriches the understanding of bacterial adherence control and provides another example of laterally acquired regulators that mediate LEE gene expression.

13.
BMC Genomics ; 20(1): 768, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646960

RESUMO

BACKGROUND: The Hafnia genus is an opportunistic pathogen that has been implicated in both nosocomial and community-acquired infections. Although Hafnia is fairly often isolated from clinical material, its taxonomy has remained an unsolved riddle, and the involvement and importance of Hafnia in human disease is also uncertain. Here, we used comparative genomic analysis to define the taxonomy of Hafnia, identify species-specific genes that may be the result of ecological and pathogenic specialization, and reveal virulence-related genetic profiles that may contribute to pathogenesis. RESULTS: One complete genome sequence and 19 draft genome sequences for Hafnia strains were generated and combined with 27 publicly available genomes. We provided high-resolution typing methods by constructing phylogeny and population structure based on single-copy core genes in combination with whole genome average nucleotide identity to identify two distant Hafnia species (alvei and paralvei) and one mislabeled strain. The open pan-genome and the presence of numerous mobile genetic elements reveal that Hafnia has undergone massive gene rearrangements. Presence of species-specific core genomes associated with metabolism and transport suggests the putative niche differentiation between alvei and paralvei. We also identified possession of diverse virulence-related profiles in both Hafnia species., including the macromolecular secretion system, virulence, and antimicrobial resistance. In the macromolecular system, T1SS, Flagellum 1, Tad pilus and T6SS-1 were conserved in Hafnia, whereas T4SS, T5SS, and other T6SSs exhibited the evolution of diversity. The virulence factors in Hafnia are related to adherence, toxin, iron uptake, stress adaptation, and efflux pump. The identified resistance genes are associated with aminoglycoside, beta-lactam, bacitracin, cationic antimicrobial peptide, fluoroquinolone, and rifampin. These virulence-related profiles identified at the genomic level provide insights into Hafnia pathogenesis and the differentiation between alvei and paralvei. CONCLUSIONS: Our research using core genome phylogeny and comparative genomics analysis of a larger collection of strains provides a comprehensive view of the taxonomy and species-specific traits between Hafnia species. Deciphering the genome of Hafnia strains possessing a reservoir of macromolecular secretion systems, virulence factors, and resistance genes related to pathogenicity may provide insights into addressing its numerous infections and devising strategies to combat the pathogen.


Assuntos
Genoma Bacteriano , Hafnia/classificação , Hafnia/patogenicidade , Virulência , Sistemas de Secreção Bacterianos/genética , Hibridização Genômica Comparativa , Farmacorresistência Bacteriana/genética , Genótipo , Filogenia , Especificidade da Espécie , Fatores de Virulência/genética
14.
J Comput Biol ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31638412

RESUMO

RHOJ is a small G protein characterized by its abundant expression in endothelial cells. Existing research has documented a link between abnormal RHOJ expression and carcinogenesis. This research aims to investigate the protective role of RHOJ in nonsmall cell lung cancer (NSCLC). In this study, Cancer Genome Atlas database and Gene Expression Omnibus were collected to analyze RHOJ expression and gene regulation networks in NSCLC. Oncomine™ and Gene Expression Profiling Interactive Analysis tools were first utilized to analyze RHOJ expression, and then cBioPortal was employed for identification of RHOJ alterations and associated functional networks. To identify differential RHOJ expression, LinkedOmics was used, which also served to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Besides, the target networks of kinases factors were explored using gene enrichment analysis. Our results suggested that lower expression of RHOJ was observed in patients with NSCLC compared with normal people. Low expression of this gene is linked to functional networks involving cytoskeleton, adhesion, infection, and Ras signaling pathways. Functional network analysis suggested that RHOJ regulates the Staphylococcus aureus infection, AGE-RAGE signaling pathway, and DNA and RNA damage. In conclusion, the results in this study demonstrated that data mining is an effective approach that can uncover information about RHOJ expression and potential regulatory networks in NSCLC, thus laying the groundwork for future studies of a similar kind.

15.
Virulence ; 10(1): 783-792, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31502495

RESUMO

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) is a major foodborne pathogen that causes severe illness in humans worldwide. The genome of O157 contains 177 genomic islands known as O islands (OIs), including Shiga toxin-converting phages (OI-45 and OI-93) and the locus for enterocyte effacement (LEE) pathogenicity island (OI-148). However, most genes in OIs are uncharacterized and code for unknown functions. In this study, we demonstrated, for the first time, that OI-9 encodes a novel transcriptional activator, Z0346 (named OvrB), which is required for bacterial adherence to host cells and LEE gene expression in O157. OvrB directly binds to the promoter region of LEE1 and activates the transcription of ler (encoding a master regulator of LEE genes), which in turn activates LEE1-5 genes to promote O157 adherence. Furthermore, mouse oral infection assays showed that OvrB promotes O157 colonization in the mouse intestine. Finally, OvrB is shown to be a widespread transcriptional activator of virulence genes in other enterohemorrhagic and enteropathogenic Escherichia coli serotypes. Our work significantly expands the understanding of bacterial virulence control and provides new evidence suggesting that horizontally transferred regulator genes mediate LEE gene expression.

16.
Environ Sci Technol ; 53(20): 12026-12034, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525872

RESUMO

The effects of disinfection byproducts (DBPs) on adverse birth outcomes remain unsettled. Maternal genetic variants in relation to DBP metabolism may modify this effect. Pregnant women during late pregnancy (n = 1306) were included from a Chinese cohort. Maternal urinary trichloroacetic acid (TCAA) was measured as a biomarker of DBP exposure. Maternal genotyping was conducted in cytochrome P450 2E1 (CYP2E1; rs2031920, rs3813867, and rs915906) and glutathione S-transferase zeta-1 (GSTZ1; rs7975). The associations between maternal urinary TCAA and birth outcomes and statistical interactions between maternal exposure and genetic polymorphisms were estimated. We found that maternal urinary TCAA levels were associated with decreased birth weight (P for trend = 0.003) and ponderal index (P for trend = 0.004). Interaction analyses showed that maternal urinary TCAA in association with decreased birth weight was observed only among subjects with CYP2E1 rs3813867 GC/CC versus GG (Pint = 0.07) and associations with decreased birth length, ponderal index, and gestational age were observed only among subjects with GSTZ1 rs7975 GA/AA versus GG (Pint = 0.07, 0.02, and 0.02, respectively). Our results suggested that prenatal DBP exposure was negatively associated with birth weight and ponderal index, and maternal genetic polymorphisms in CYP2E1 and GSTZ1 might modify these associations.


Assuntos
Citocromo P-450 CYP2E1 , Efeitos Tardios da Exposição Pré-Natal , Biomarcadores , Peso ao Nascer , Desinfecção , Feminino , Glutationa Transferase , Humanos , Exposição Materna , Polimorfismo Genético , Gravidez , Trialometanos
17.
Biochem Biophys Res Commun ; 517(3): 427-432, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31376937

RESUMO

Citrobacter species are opportunistic bacterial pathogens that are implicated in both nosocomial and community-acquired infections. Among the Citrobacter species, Citrobacter koseri is often isolated from clinical material, and it can cause meningitis and brain abscesses in neonates and immunocompromised individuals, thus posing a great threat to human health. However, the virulence determinants of C. koseri remain largely unknown. Myo-inositol is an abundant carbohydrate in the environment and in certain organs of the human body, especially the brain. The C. koseri genome harbors a cluster of genes, QCQ70420.1 to QCQ70429.1 (named the Ino-cluster in this study), which encode IolBCDE, MmsA, and an ATP-binding cassette transporter. The gene cluster may be involved in the utilization of myo-inositol. To investigate the functions of the Ino-cluster in C. koseri, we constructed a mutant strain by deleting the Ino-cluster and found that the mutant could not use myo-inositol as the sole carbon source, confirming that this cluster is responsible for myo-inositol utilization. Moreover, we investigated the function of the Ino-cluster and myo-inositol utilization in C. koseri pathogenicity. Deletion of the Ino-cluster significantly impaired C. koseri colonization of the brain of infected Sprague-Dawley (SD) rats and BALB/c mice, and this increased the survival rate of the infected animals, indicating that the Ino-cluster and the ability to use myo-inositol are essential for C. koseri pathogenicity. Taken together, our findings suggest that using the Ino-cluster products, C. koseri can exploit the abundant myo-inositol in the brain as a carbon source for growth, thus promoting colonization and virulence.

18.
Eur J Med Chem ; 181: 111584, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419740

RESUMO

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of ß-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and ß-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.


Assuntos
Quinolonas/química , Quinolonas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/química
19.
Mol Med Rep ; 20(4): 3224-3232, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432115

RESUMO

Alcohol consumption causes liver steatosis in humans. Metabolic disorders of lipids are one of the factors that cause liver steatosis in hepatocytes. Hepatic Niemann­Pick C1­like 1 (NPC1L1) regulates lipid homeostasis in mammals. The relationship between NPC1L1 and autophagy in those with a history of alcohol abuse is unclear. The present study aimed to investigate the function of NPC1L1 in the activation of hepatic autophagy in a mouse model with a human (h)NPC1L1 transgene under alcohol feeding conditions. The mice expressing hNPC1L1 (Ad­L1) or controls (Ad­null) were created by retro­orbital adenovirus injection. The Ad­L1 and Ad­null mice were fed with alcohol or a non­alcoholic diet to mimic chronic alcohol consumption in humans. Hepatic autophagy was demonstrated in isolated primary hepatocytes by monitoring autophagic vacuoles under fluorescence microscopy, and by western blotting for autophagic makers. Isolated hepatocytes from the livers of Ad­L1 mice were treated with different doses of ezetimibe to study the restoration of autophagy. Chronic alcohol feeding caused liver injury and steatosis, shown by significantly higher levels of plasma alanine transaminase and aspartate transaminase activity, and by hematoxylin and eosin staining in Ad­L1 and Ad­null mice. Compared to Ad­null control mice, the microtubule­associated proteins 1A/1B light chain 3 (LC3) particles in the isolated hepatocytes of Ad­L1 mice were decreased, both under alcohol and non­alcoholic feeding. The ratio of LC3II/LC3I was significantly decreased, and the level of p62/sequestosome­1 protein was significantly increased in Ad­L1 mice compared with Ad­null mice after alcohol feeding. Levels of LC3II protein were statistically increased in hepatocytes isolated from Ad­L1 mice with ezetimibe treatment. The increase in LC3II expression was dose dependent. Within the tested range, it reached its highest level at 40 µM. The livers of Ad­L1 mice represent a more human­like state for the study of hepatic autophagy. Hepatic expression of human NPC1L1 resulted in an inhibition of autophagy; it may contribute to alcoholic fatty liver disease in humans.

20.
Chem Commun (Camb) ; 55(61): 9011-9014, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290869

RESUMO

For effective hydrogen generation with remarkable durability, carbon nanotubes (CNTs) grown on Ni nanofibers and their post hydroxylation treatment engendered active Ni nanofiber catalysts an efficient decomposition of hydrous hydrazine with a turnover frequency (TOF) of 19.4 h-1 and an activation energy down to 51.05 KJ mol-1.

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