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1.
BMC Psychiatry ; 20(1): 158, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32272912

RESUMO

BACKGROUND: Previous studies of brain structure in methamphetamine users have yielded inconsistent findings, possibly reflecting small sample size and inconsistencies in duration of methamphetamine abstinence as well as sampling and analyses methods. Here we report on a relatively large sample of abstinent methamphetamine users at various stages of long-term abstinence. METHODS: Chronic methamphetamine users (n = 99), abstinent from the drug ranging from 12 to 621 days, and healthy controls (n = 86) received T1-weighted structural magnetic resonance imaging brain scans. Subcortical and cortical gray-matter volumes and cortical thickness were measured and the effects of group, duration of abstinence, duration of methamphetamine use and onset age of methamphetamine use were investigated using the Freesurfer software package. RESULTS: Methamphetamine users did not differ from controls in gray-matter volumes, except for a cluster in the right lateral occipital cortex where gray-matter volume was smaller, and for regions mainly in the bilateral superior frontal gyrui where thickness was greater. Duration of abstinence correlated positively with gray-matter volumes in whole brain, bilateral accumbens nuclei and insulae clusters, and right hippocampus; and with thickness in a right insula cluster. Duration of methamphetamine use correlated negatively with gray-matter volume and cortical thickness of a cluster in the right lingual and pericalcarine cortex. CONCLUSIONS: Chronic methamphetamine use induces hard-to-recover cortical thickening in bilateral superior frontal gyri and recoverable volumetric reduction in right hippocampus, bilateral accumbens nuclei and bilateral cortical regions around insulae. These alternations might contribute to methamphetamine-induced neurocognitive disfunctions and reflect a regional specific response of the brain to methamphetamine.

2.
New Phytol ; 226(6): 1873-1885, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32162345

RESUMO

●Inflorescence architecture in plants is often complex and challenging to quantify, particularly for inflorescences of cereal grasses. Methods for capturing inflorescence architecture and for analyzing the resulting data are limited to a few easily captured parameters that may miss the rich underlying diversity. ●Here, we apply X-ray computed tomography combined with detailed morphometrics, offering new imaging and computational tools to analyze three-dimensional inflorescence architecture. To show the power of this approach, we focus on the panicles of Sorghum bicolor, which vary extensively in numbers, lengths, and angles of primary branches, as well as the three-dimensional shape, size, and distribution of the seed. ●We imaged and comprehensively evaluated the panicle morphology of 55 sorghum accessions that represent the five botanical races in the most common classification system of the species, defined by genetic data. We used our data to determine the reliability of the morphological characters for assigning specimens to race and found that seed features were particularly informative. ●However, the extensive overlap between botanical races in multivariate trait space indicates that the phenotypic range of each group extends well beyond its overall genetic background, indicating unexpectedly weak correlation between morphology, genetic identity, and domestication history.

3.
Hepatology ; 71(2): 463-476, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31278760

RESUMO

Nucleos(t)ide analogues (NAs) have been widely used for the treatment of chronic hepatitis B (CHB). Because viral DNA polymerase lacks proofreading function (3' exonuclease activity), theoretically, the incorporated NAs would irreversibly terminate viral DNA synthesis. This study explored the natures of nascent hepatitis B virus (HBV) DNA and infectivity of progeny virions produced under NA treatment. HBV infectivity was determined by infection of HepG2-NTCP cells and primary human hepatocytes (PHHs). Biochemical properties of HBV DNA in the progeny virions were investigated by qPCR, northern blotting, or Southern blotting hybridization, sucrose gradient centrifugation, and in vitro endogenous DNA polymerase assay. Progeny HBV virions produced under NA treatment were mainly not infectious to HepG2-NTCP cells or PHHs. Biochemical analysis revealed that under NA treatment, HBV DNA in nucleaocapsids or virions were predominantly short minus-strand DNA with irreversible termination. This finding was supported by the observation of first disappearance of relaxed circular DNA and then the proportional decline of HBV-DNA levels corresponding to the regions of PreC/C, S, and X genes in serial sera of patients receiving NA treatment. Conclusion: HBV virions produced under NA treatment are predominantly replication deficient because the viral genomes are truncated and elongation of DNA chains is irreversibly terminated. Clinically, our results suggest that the viral loads of CHB patients under NA therapy vary with the different regions of genome being detected by qPCR assays. Our findings also imply that NA prevention of perinatal and sexual HBV transmission as well as infection of transplanted livers works not only by reducing viral loads, but also by producing noninfectious virions.

4.
Sci Total Environ ; 711: 134661, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812402

RESUMO

Invasive species have imposed huge negative impacts on worldwide aquatic ecosystems and are generally difficult or impossible to be eradicated once established. Consequently, it becomes particularly important to ascertain their invasion risk and its determinants since such information can help us formulate more effective preventive or management actions and direct these measures to those areas where they are truly needed so as to ease regulatory burdens. Here, we examined the global invasion risk and its determinants of sharpbelly (Hemiculter leucisculus), one freshwater fish which has a high invasive potential, by using species distribution models (SDMs) and a layer overlay method. Specifically, first an ensemble species distribution model and its basal models (developed from seven machine learning algorithms) were explored to forecast the global habitat-suitability and variables importance for this species, and then a global invasion risk map was created by combining habitat-suitability with a proxy for introduction likelihood (entailing propagule pressure and dispersal constraints) of exotic sharpbelly. The results revealed that (1) the ensemble model had the highest predictive power in forecasting sharpbelly's global habitat-suitability; (2) areas with high invasion risk by sharpbelly patchily spread over the world except Antarctica; and (3) the Human Influence Index (HII), rather than any of the bioclimatic variables, was the most important factor influencing sharpbelly' future invasion. Based on these results, the present study also attempted to propose a series of prevention and management strategies to eliminate or alleviate the adverse effects caused by this species' further expansion.

6.
Emerg Microbes Infect ; 8(1): 1511-1523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631785

RESUMO

Interferons (IFNs) control viral infections by inducing expression of IFN-stimulated genes (ISGs) that restrict distinct steps of viral replication. We report herein that gamma-interferon-inducible lysosomal thiol reductase (GILT), a lysosome-associated ISG, restricts the infectious entry of selected enveloped RNA viruses. Specifically, we demonstrated that GILT was constitutively expressed in lung epithelial cells and fibroblasts and its expression could be further induced by type II interferon. While overexpression of GILT inhibited the entry mediated by envelope glycoproteins of SARS coronavirus (SARS-CoV), Ebola virus (EBOV) and Lassa fever virus (LASV), depletion of GILT enhanced the entry mediated by these viral envelope glycoproteins. Furthermore, mutations that impaired the thiol reductase activity or disrupted the N-linked glycosylation, a posttranslational modification essential for its lysosomal localization, largely compromised GILT restriction of viral entry. We also found that the induction of GILT expression reduced the level and activity of cathepsin L, which is required for the entry of these RNA viruses in lysosomes. Our data indicate that GILT is a novel antiviral ISG that specifically inhibits the entry of selected enveloped RNA viruses in lysosomes via disruption of cathepsin L metabolism and function and may play a role in immune control and pathogenesis of these viruses.


Assuntos
Ebolavirus/fisiologia , Doença pelo Vírus Ebola/imunologia , Febre Lassa/imunologia , Vírus Lassa/fisiologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/imunologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Catepsina L/genética , Catepsina L/imunologia , Linhagem Celular , Ebolavirus/genética , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Humanos , Febre Lassa/genética , Febre Lassa/virologia , Vírus Lassa/genética , Lisossomos/genética , Lisossomos/imunologia , Lisossomos/virologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Proteínas do Envelope Viral/genética , Replicação Viral
7.
Nat Commun ; 10(1): 3592, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399588

RESUMO

Catalytic difunctionalization of alkenes has been an ideal strategy to generate structurally complex molecules with diverse substitution patterns. Although both phosphonyl and carboxyl groups are valuable functional groups, the simultaneous incorporation of them via catalytic difunctionalization of alkenes, ideally from abundant, inexpensive and easy-to-handle raw materials, has not been realized. Herein, we report the phosphonocarboxylation of alkenes with CO2 via visible-light photoredox catalysis. This strategy is sustainable, general and practical, providing facile access to important ß-phosphono carboxylic acids, including structurally complex unnatural α-amino acids. Diverse alkenes, including enamides, styrenes, enolsilanes and acrylates, undergo such reactions efficiently under mild reaction conditions. Moreover, this method represents a rare example of redox-neutral difunctionalization of alkenes with H-P(O) compounds, including diaryl- and dialkyl- phosphine oxides and phosphites. Importantly, these transition-metal-free reactions also feature low catalyst loading, high regio- and chemo-selectivities, good functional group tolerance, easy scalability and potential for product derivatization.

8.
Clin Sci (Lond) ; 133(14): 1609-1627, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31315969

RESUMO

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.

9.
Nat Prod Res ; : 1-8, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31305141

RESUMO

Five new natural compounds (1-5) along with four known ones, involving dibenzo-α-pyrone derivatives, a benzo-γ-pyrone derivative and an amide-type compound were obtained from Alternaria alternata, an endophyte isolated from Paeonia lactiflora. The structures of these isolates were elucidated by intensive analysis of spectroscopic data including NMR, HRMS (ESI and EI), UV and IR spectra. Compounds (1-4) were evaluated for their cytotoxicities against five selected human tumourtumour cell lines (A-549, MDA-MB-231, MCF-7, KB and KB-VIN), and compound 3 exhibited activities against MDA-MB-231and MCF-7 with IC50 values of 20.1 µM and 32.2 µM.

10.
ACS Infect Dis ; 5(7): 1139-1149, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31060350

RESUMO

Stimulator of interferon genes (STING) is an integral ER-membrane protein that can be activated by 2'3'-cGAMP synthesized by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) upon binding of double-stranded DNA. It activates interferon (IFN) and inflammatory cytokine responses to defend against infection by microorganisms. Pharmacologic activation of STING has been demonstrated to induce an antiviral state and boost antitumor immunity. We previously reported a cell-based high-throughput-screening assay that allowed for identification of small-molecule cGAS-STING-pathway agonists. We report herein a compound, 6-bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide (BNBC), that induces a proinflammatory cytokine response in a human-STING-dependent manner. Specifically, we showed that BNBC induced type I and III IFN dominant cytokine responses in primary human fibroblasts and peripheral-blood mononuclear cells (PBMCs). BNBC also induced cytokine response in PBMC-derived myeloid dendritic cells and promoted their maturation, suggesting that STING-agonist treatment could potentially regulate the activation of CD4+ and CD8+ T lymphocytes. As anticipated, treatment of primary human fibroblast cells with BNBC induced an antiviral state that inhibited the infection of several kinds of flaviviruses. Taken together, our results indicate that BNBC is a human-STING agonist that not only induces innate antiviral immunity against a broad spectrum of viruses but may also stimulate the activation of adaptive immune responses, which is important for the treatment of chronic viral infections and tumors.

11.
Ann Plast Surg ; 82(6): 679-685, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31082848

RESUMO

INTRODUCTION: Craniosynostosis is typically corrected surgically within the first year of life through cranial vault reconstruction. These procedures often leave open calvarial defects at the time of surgery, which are anticipated to close over time in a large proportion of cases. However, residual calvarial defects may result as long-term sequelae from cranial vault remodeling. When larger defects are present, they may necessitate further reconstruction for closure.Better understanding of the calvarial osseous healing process may help to identify which defects will resolve or shrink to acceptable size and which will require further surgery. Our study aims to assess the long-term changes in defect size after cranial vault reconstruction for craniosynostosis. METHODS: One-year postoperative and long-term computed tomography scans were retrieved from the craniofacial anomalies archive. Analysis used custom software. All defects above the size of 1 cm were analyzed and tracked for calvarial location, surface area, and circularity. Monte Carlo simulation was performed to model the effect of initial defect size on the rate of defect closure. RESULTS: We analyzed a total of 74 defects. The mean ± SD initial defect surface area was 3.27 ± 3.40 cm. The mean ± SD final defect surface area was 1.71 ± 2.54 cm. The mean ± SD percent decrease was 55.06% ± 28.99%. There was a significant difference in the percentage decrease of defects in the parietal and frontoparietal locations: 68.4% and 43.7%, respectively (P = 0.001). Monte Carlo simulation results suggest that less than 10% of defects above the size of 9 cm will close to the size of 2.5 cm or less. CONCLUSIONS: We describe and make available a novel validated method of measuring cranial defects. We find that the large majority of initial defects greater than 9 cm remain at least 1 in in size (2.5 cm) 1 year postoperatively. In addition, there appear to be regional differences in closure rates across the cranium, with frontoparietal defects closing more slowly than those in the parietal region. This information will aid surgeons in the decision-making process regarding cranioplasty after craniosynostosis correction.

12.
PLoS Pathog ; 15(4): e1007742, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31026293

RESUMO

Persistent hepatitis B virus (HBV) infection relies on the establishment and maintenance of covalently closed circular (ccc) DNA, a 3.2 kb episome that serves as a viral transcription template, in the nucleus of an infected hepatocyte. Although evidence suggests that cccDNA is the repair product of nucleocapsid associated relaxed circular (rc) DNA, the cellular DNA polymerases involving in repairing the discontinuity in both strands of rcDNA as well as the underlying mechanism remain to be fully understood. Taking a chemical genetics approach, we found that DNA polymerase alpha (Pol α) is essential for cccDNA intracellular amplification, a genome recycling pathway that maintains a stable cccDNA pool in infected hepatocytes. Specifically, inhibition of Pol α by small molecule inhibitors aphidicolin or CD437 as well as silencing of Pol α expression by siRNA led to suppression of cccDNA amplification in human hepatoma cells. CRISPR-Cas9 knock-in of a CD437-resistant mutation into Pol α genes completely abolished the effect of CD437 on cccDNA formation, indicating that CD437 directly targets Pol α to disrupt cccDNA biosynthesis. Mechanistically, Pol α is recruited to HBV rcDNA and required for the generation of minus strand covalently closed circular rcDNA, suggesting that Pol α is involved in the repair of the minus strand DNA nick in cccDNA synthesis. Our study thus reveals that the distinct host DNA polymerases are hijacked by HBV to support the biosynthesis of cccDNA from intracellular amplification pathway compared to that from de novo viral infection, which requires Pol κ and Pol λ.


Assuntos
DNA Polimerase I/metabolismo , DNA Circular/genética , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Replicação Viral/genética , DNA Circular/metabolismo , DNA Viral/metabolismo , Células Hep G2 , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Vírion
13.
PeerJ ; 7: e6772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011492

RESUMO

Despite being the most dominant and widespread small fish species in the lakes along the middle and lower reaches of the Yangtze River basin, Toxabramis swinhonis has been paid little attention by fisheries scientists and little is known about its population characteristics. For this reason, we estimated age, growth, mortality and recruitment of this species based on three shallow lakes, Biandantang Lake, Shengjin Lake and Kuilei Lake (BDT, SJH and KLH, respectively) in this region. A total of 13,585 (8,818 in BDT, 2,207 in SJH and 2,560 in KLH) individuals were collected during monthly sampling from July 2016 to September 2017. The results revealed that the age structures of T. swinhonis consisted of four age groups (0+-3+), with 0+-1+ year old fish comprising more than 98% of the samples. Allometric growth patterns were displayed by fish from all sampling sites and the von Bertalanffy growth functions estimated were L t = 173.25 (1 - e-1.20 (t + 1.09)): BDT; L t = 162.75 (1 - e-1.20 (t + 1.08)): SJH and L t = 215.25 (1 - e-1.20 (t + 1.12)): KLH, respectively. The rates of total mortality (Z), natural mortality (M) and fishing mortality (F) at BDT, SJH and KLH were computed as 5.82, 5.50 and 4.55 year-1; 1.89, 1.87 and 1.75 year-1; 3.93, 3.63 and 2.80 year-1, respectively. Meanwhile, growth performance indices (φ') were 0.68 (in BDT), 0.66 (in SJH) and 0.62 (in KLH), which indicated that T. swinhonis were overfished slightly in all study areas. Area-specific recruitment patterns were similar to each other, displaying evidence of batch spawning, with major peaks in April and August, accounting for 92.21% (BDT), 88.21% (SJH) and 88.73% (KLH) of total recruitment, respectively. These results showed that brief generation-time, fast growth rate, relatively high natural mortality rate and strong reproductive capacity (r-strategies) are reasons why this species became the most dominant species in many lakes of China.

14.
J Virol ; 93(11)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867306

RESUMO

In order to identify host cellular DNA metabolic enzymes that are involved in the biosynthesis of hepatitis B virus (HBV) covalently closed circular (ccc) DNA, we developed a cell-based assay supporting synchronized and rapid cccDNA synthesis from intracellular progeny nucleocapsid DNA. This was achieved by arresting HBV DNA replication in HepAD38 cells with phosphonoformic acid (PFA), a reversible HBV DNA polymerase inhibitor, at the stage of single-stranded DNA and was followed by removal of PFA to allow the synchronized synthesis of relaxed circular DNA (rcDNA) and subsequent conversion into cccDNA within 12 to 24 h. This cccDNA formation assay allows systematic screening of the effects of small molecular inhibitors of DNA metabolic enzymes on cccDNA synthesis but avoids cytotoxic effects upon long-term treatment. Using this assay, we found that all the tested topoisomerase I and II (TOP1 and TOP2, respectively) poisons as well as topoisomerase II DNA binding and ATPase inhibitors significantly reduced the levels of cccDNA. It was further demonstrated that these inhibitors also disrupted cccDNA synthesis during de novo HBV infection of HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). Mechanistic analyses indicate that whereas TOP1 inhibitor treatment prevented the production of covalently closed negative-strand rcDNA, TOP2 inhibitors reduced the production of this cccDNA synthesis intermediate to a lesser extent. Moreover, small interfering RNA (siRNA) knockdown of topoisomerase II significantly reduced cccDNA amplification. Taking these observations together, our study demonstrates that topoisomerase I and II may catalyze distinct steps of HBV cccDNA synthesis and that pharmacologic targeting of these cellular enzymes may facilitate the cure of chronic hepatitis B.IMPORTANCE Persistent HBV infection relies on stable maintenance and proper functioning of a nuclear episomal form of the viral genome called cccDNA, the most stable HBV replication intermediate. One of the major reasons for the failure of currently available antiviral therapeutics to cure chronic HBV infection is their inability to eradicate or inactivate cccDNA. We report here a chemical genetics approach to identify host cellular factors essential for the biosynthesis and maintenance of cccDNA and reveal that cellular DNA topoisomerases are required for both de novo synthesis and intracellular amplification of cccDNA. This approach is suitable for systematic screening of compounds targeting cellular DNA metabolic enzymes and chromatin remodelers for their ability to disrupt cccDNA biosynthesis and function. Identification of key host factors required for cccDNA metabolism and function will reveal molecular targets for developing curative therapeutics of chronic HBV infection.

15.
Front Pharmacol ; 10: 92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814950

RESUMO

Objective: To evaluate therapeutic efficacy of different combined antimicrobial treatments against Acinetobacter baumannii ventilator-associated pneumonia (VAP). Methods: Clinical outcomes were retrospectively analyzed to elucidate the efficacy of four combined antimicrobial regimens. The chessboard and micro broth dilution methods determined the minimum inhibitory concentrations (MICs) of four antiseptic drugs singly used and combined two drugs against 36 isolates of multidrug-resistant (MDR) A. baumannii. Results: The incidence of VAP was approximately 6.9% (237/3424) between January 1, 2015 and December 31, and 35.9% (85/237) of the cases were caused by A. baumannii. Among these cases, 60 belonged to AB-VAP, for whom antimicrobial treatment plan was centralized and clinical data was complete. Moreover, all 60 strains of A. baumannii were MDR bacteria from reports microbiological laboratory. Resistance rate was lowest for amikacin (68.3%) and ampicillin sulbactam (71.7%). Resistance rate for imipenem increased from 63.2 to 90.9% during the 3 years. However, in these 60 cases of AB-VAP, the combination between 4 antibiotics was effective in most cases: the effective rate was 75% (18/24) for sulbactam combined with etilmicin, 71.4% (10/14) for sulbactam combined with levofloxacin, 72.7% (8/11) for meropenem combined with etilmicin, and 63.6% (7/11) for meropenem combined with levofloxacin. There was no statistical difference between four regimens (P > 0.05). Sulbactam combined with etilmicin decreased 1/2 of MIC50 and MIC90 of sulbactam while the decreases in etilmicin were more obviously than single drug. When adopting meropenem combined with levofloxacin or etilmicin, the MIC of meropenem reduced to 1/2 of that in applying single drug. As for sulbactam or meropenem combined with levofloxacin, it also lessened the MIC50 of levofloxacin to 1/2 of that for single drug. FIC results suggested that the effects of four combined antimicrobial regimens were additive or unrelated. When sulbactam was combined with etimicin, the additive effect was 63.89%. Conclusion: Drug combination sensitivity test in vitro may be helpful for choosing antimicrobial treatment plans. Sulbactam or meropenem as the basis of treatment regimens can function as the alternatives against AB-VAP. Sulbactam combined with etimicin has been regarded as a recommended regimen in Suizhou, Hubei, China.

16.
Nat Prod Res ; 33(15): 2133-2138, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30822136

RESUMO

A new steroid lactone aspergilolide (1), and nine known compounds helvolic acid (2), verruculogen (3), tryprostatin B (4), 13-oxofumitremorgin B (5), fumitremorgin C (6), demethoxy fumitremorgin C (7), terezine D (8), aszonalenin (9), 12, 13-dihydroxy-fumitremorgin C (10) from cultures of the endophytic fungus Aspergillus sp. MBL1612. Their chemical structures were determined by a series of extensive spectroscopic methods. All of the compounds were isolated from this genus for the first time. The cytotoxicity against five human cancer cell lines of new compound were detected.


Assuntos
Aspergillus/metabolismo , Lactonas/metabolismo , Paeonia/microbiologia , Esteroides/biossíntese , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Lactonas/farmacologia , Análise Espectral/métodos , Esteroides/química , Esteroides/farmacologia
17.
Surg Infect (Larchmt) ; 20(4): 292-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785859

RESUMO

Background: Intra-cranial infection with Acinetobacter baumannii is a tough problem because of the presence of multi-resistance and poor drug penetration through the blood-brain barrier. Such intra-cranial infections can lead to serious complications and death. We retrospectively analyzed the culture results and clinical characteristics of patients with intra-cranial infections in our hospital and suggested intravenous (IV) meropenem and intra-thecal (IT) amikacin therapy may be effective in the management of A. baumannii infection. Case presentation: We reported four cases of post-neuro-surgical A. baumannii intra-cranial infection whose clinical futures were high fever and consciousness disturbance. Our patients were treated successfully with IV meropenem and IT amikacin. Conclusion: We presented our cases of pandrug-resistant A. baumannii intra-cranial infection that was managed successfully with a systemic provision of IV meropenem and IT amikacin. Therefore, these cases exemplify that systemic administration of IV meropenem and IT amikacin can be a good therapeutic option against A. baumannii intra-cranial infection when colistin is not available.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Infecções do Sistema Nervoso Central/tratamento farmacológico , Meropeném/administração & dosagem , Procedimentos Neurocirúrgicos/efeitos adversos , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecções por Acinetobacter/patologia , Acinetobacter baumannii/isolamento & purificação , Administração Intravenosa , Adulto , Idoso , Infecções do Sistema Nervoso Central/patologia , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/patologia , Resultado do Tratamento
18.
ACS Infect Dis ; 5(5): 759-768, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30525438

RESUMO

Hepatitis B virus (HBV) core protein is a small protein with 183 amino acid residues and assembles the pregenomic (pg) RNA and viral DNA polymerase to form nucleocapsids. During the last decades, several groups have reported HBV core protein allosteric modulators (CpAMs) with distinct chemical structures. CpAMs bind to the hydrophobic HAP pocket located at the dimer-dimer interface and induce allosteric conformational changes in the core protein subunits. While Type I CpAMs, heteroaryldihydropyrimidine (HAP) derivatives, misdirect core protein dimers to assemble noncapsid polymers, Type II CpAMs, represented by sulfamoylbenzamides, phenylpropenamides, and several other chemotypes, induce the assembly of empty capsids with global structural alterations and faster mobility in native agarose gel electrophoresis. Through high throughput screening of an Asinex small molecule library containing 19 920 compounds, we identified 8 structurally distinct CpAMs. While 7 of those compounds are typical Type II CpAMs, a novel benzamide derivative, designated as BA-53038B, induced the formation of morphologically "normal" empty capsids with slow electrophoresis mobility. Drug resistant profile analyses indicated that BA-53038B most likely bound to the HAP pocket but obviously modulated HBV capsid assembly in a distinct manner. BA-53038B and other CpAMs reported herein provide novel structure scaffolds for the development of core protein-targeted antiviral agents for the treatment of chronic hepatitis B.

19.
Nat Prod Res ; 33(24): 3493-3499, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29914271

RESUMO

Two new sesquiterpenoids, curkwangsien A-B (1-2), and seven known compounds (3-9) were isolated from rhizomes of Curcuma kwangsiensis. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of compounds 1-2 were determined by the quantum chemical ECD calculations. Compounds 3-9 are firstly reported from this plant. In the in vitro assays, compound 3 was found to inhibit human colon cancer RKO cell migration in time-dependent manner.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Curcuma/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Rizoma/química
20.
ACS Infect Dis ; 5(5): 659-674, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29893548

RESUMO

Hepatitis B virus (HBV) has infected one-third of world population, and 240 million people are chronic carriers, to whom a curative therapy is still not available. Similar to other viruses, persistent HBV infection relies on the virus to exploit host cell functions to support its replication and efficiently evade host innate and adaptive antiviral immunity. Understanding HBV replication and concomitant host cell interactions is thus instrumental for development of therapeutics to disrupt the virus-host interactions critical for its persistence and cure chronic hepatitis B. Although the currently available cell culture systems of HBV infection are refractory to genome-wide high throughput screening of key host cellular factors essential for and/or regulating HBV replication, classic one-gene (or pathway)-at-a-time studies in the last several decades have already revealed many aspects of HBV-host interactions. An overview of the landscape of HBV-hepatocyte interaction indicates that, in addition to more tightly suppressing viral replication by directly targeting viral proteins, disruption of key viral-host cell interactions to eliminate or inactivate the covalently closed circular (ccc) DNA, the most stable HBV replication intermediate that exists as an episomal minichromosome in the nucleus of infected hepatocyte, is essential to achieve a functional cure of chronic hepatitis B. Moreover, therapeutic targeting of integrated HBV DNA and their transcripts may also be required to induce hepatitis B virus surface antigen (HBsAg) seroclearance and prevent liver carcinogenesis.

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