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1.
Clin Immunol ; 265: 110293, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38936523

RESUMO

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Feminino , Adulto Jovem , Mutação , Neutrófilos/imunologia , Células Th17/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Monócitos/imunologia , Citocinas
2.
Cell Tissue Res ; 391(2): 375-391, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36422735

RESUMO

Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na+/K+ movement and regulating the Na+/Ca2+ exchange. In comparison to other Ca2+ inhibitors, bepridil has a long half-life and a complex pharmacology. Additionally, it is widely used in antiviral research and the treatment of various diseases. However, the toxicity of this compound and its other possible effects on embryonic development are unknown. In this study, we investigated the toxicity of bepridil on rat myocardial H9c2 cells. After treatment with bepridil, the cells became overloaded with Ca2+ and entered a state of cytoplasmic vacuolization and nuclear abnormality. Bepridil treatment resulted in several morphological abnormalities in zebrafish embryo models, including pericardium enlargement, yolk sac swelling, and growth stunting. The hemodynamic effects on fetal development resulted in abnormal cardiovascular circulation and myocardial weakness. After inhibiting the Ca2+ transmembrane, the liver of zebrafish larvae also displayed an ectopic and deficient spatial location. Additionally, the results of the RNA-seq analysis revealed the detailed gene expression profiles and metabolic responses to bepridil treatment in zebrafish embryonic development. Taken together, our study provides an important evaluation of antiarrhythmic agents for clinical use in prenatal heart patients.


Assuntos
Bepridil , Peixe-Zebra , Animais , Ratos , Bepridil/metabolismo , Bepridil/farmacologia , Antiarrítmicos/metabolismo , Antiarrítmicos/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo
3.
Curr Microbiol ; 80(4): 132, 2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36894807

RESUMO

An association between type 2 diabetes mellitus (T2DM) and gut microbiota is well established, but the results of related studies are inconsistent. The purpose of this investigation is to elucidate the characteristics of the gut microbiota in T2DM and non-diabetic subjects. Forty-five subjects were recruited for this study, including 29 T2DM patients and 16 non-diabetic subjects. Biochemical parameters, including body mass index (BMI), fasting plasma glucose (FPG), serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and hemoglobin A1c (HbA1c), were analyzed and correlated with the gut microbiota. Bacterial community composition and diversity were detected in fecal samples using direct smear, sequencing, and real-time polymerase chain reaction (PCR). In this study, it was observed that indicators such as BMI, FPG, HbA1c, TC, and TG in T2DM patients were on the rise, concurrent with dysbiosis of the microbiota. We observed an increase in Enterococci and a decrease in Bacteroides, Bifidobacteria, and Lactobacilli in patients with T2DM. Meanwhile, total short-chain fatty acids (SCFAs) and D-lactate concentrations were decreased in the T2DM group. In addition, FPG was positively correlated with Enterococcus and negatively correlated with Bifidobacteria, Bacteroides, and Lactobacilli. This study reveals that microbiota dysbiosis is associated with disease severity in patients with T2DM. The limitation of this study is that only common bacteria were noted in this study, and more in-depth related studies are urgently needed.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Microbiota , Humanos , Hemoglobinas Glicadas , Disbiose/complicações
4.
Mycoses ; 66(1): 59-68, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36111370

RESUMO

BACKGROUND: Cryptococcal meningitis (CM) is increasingly recognised in human immunodeficiency virus (HIV)-uninfected patients with high mortality. The efficacy and safety profiles of induction therapy with high-dose fluconazole plus flucytosine remain unclear. METHODS: HIV-uninfected CM patients who received high-dose fluconazole (800 mg/d) for initial therapy in Huashan Hospital were included in this retrospective study from January 2013 to December 2018. Efficacy and safety of initial therapy, clinical outcomes and risk factors were evaluated. RESULTS: Twenty-seven (71.1%) patients who received high-dose fluconazole with flucytosine combination therapy and 11 (28.9%) having fluconazole alone for induction therapy were included. With a median duration of 42 days (IQR, 28-86), the successful response rate of initial therapy was 76.3% (29/38), while adverse drug reactions occurred in 14 patients (36.8%). The rate of persistently positive cerebrospinal fluid (CSF) culture results was 30.6% at 2 weeks, which was significantly associated with CSF CrAg titre >1:1280 (OR 9.56; 95% CI 1.40-103.65; p = .010) and CSF culture of Cryptococcus >3.9 log10 CFU/ml (OR 19.20; 95% CI 1.60-920.54; p = .011), and decreased to 8.6% at 4 weeks. One-year mortality was 15.8% (6/38), and low serum albumin (35 g/L) was found as an independent risk factor for 1-year mortality (HR 6.31; 95% CI 1.150-34.632; p = .034). CONCLUSIONS: Induction therapy with high-dose fluconazole (800 mg/d), combined with flucytosine, effectively treated HIV-uninfected CM and was well tolerated. Long-term fluconazole treatment with continued monitoring is beneficial for patients with persistent infection.


Assuntos
Infecções por HIV , Meningite Criptocócica , Humanos , Fluconazol/efeitos adversos , Flucitosina/efeitos adversos , Meningite Criptocócica/complicações , Quimioterapia de Indução , Estudos Retrospectivos , Antifúngicos/efeitos adversos , Quimioterapia Combinada , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV
5.
Mycoses ; 66(4): 308-316, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36520582

RESUMO

BACKGROUND: Central nervous system (CNS) aspergillosis is an uncommon but fatal disease, the diagnosis of which is still difficult. OBJECTIVES: We aim to explore the diagnositic performance of noncultural methods for CNS aspergillosis. METHODS: In this retrospective study, all pathologically confirmed rhinosinusitis patients in whom cerebrospinal fluid (CSF) galactomannan (GM) test and metagenomic next-generation sequencing (mNGS) had been performed were included. We evaluated the diagnostic performances of CSF GM optical density indexes (ODI) at different cut-off values and compared performance with mNGS in patients with and without CNS aspergillosis, as well as in patients with different manifestations of CNS aspergillosis. RESULTS: Of the 21 proven and probable cases, one had positive culture result, five had positive mNGS results and 10 had a CSF GM ODI of >0.7. Sample concordance between mNGS and GM test was poor, but best diagnostic performance was achieved by combination of GM test (ODI of >0.7) and mNGS, which generated a sensitivity of 61.9% and specificity of 82.6%. Further investigation of combination diagnostic performances in different kind of CNS aspergillosis was also conducted. Lowest sensitivity (42.9%) was identified in abscess group, while increased sensitivity (60.0%) was achieved in abscess with encephalitis groups. Combination test exhibited the best performance for encephalitis patients who had only CSF abnormalities, in whom the sensitivity and specificity were 77.8% and 82.6%, respectively. CONCLUSIONS: In conclusion, combination of these two tests might be useful for diagnosis of CNS aspergillosis associated with fungal rhinosinusitis, especially in encephalitis patients.


Assuntos
Aspergilose , Encefalite , Humanos , Estudos Retrospectivos , Abscesso , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Aspergilose/diagnóstico , Sensibilidade e Especificidade , Mananas , Sistema Nervoso Central
6.
Altern Ther Health Med ; 29(8): 534-539, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37678850

RESUMO

Purpose: To study the risk factors affecting amputation and survival in patients with diabetic foot (DF) and to construct a predictive model using the machine learning technique for DF foot amputation and survival and evaluate its effectiveness. Materials and Methods: A total of 200 patients with DF hospitalized in the First Affiliated Hospital of Shantou University Medical College in China were selected via cluster analysis screening, Kaplan-Meier survival calculation, amputation rate and Cox proportional hazards model investigation of risk factors associated with amputation and death. In addition, we constructed various models, including Cox proportional hazards regression analysis, the deep learning method convolution neural network (CNN) model, backpropagation (BP) neural network model, and backpropagation neural network prediction model after optimizing the genetic algorithm. The accuracy of the 4 prediction models for survival and amputation was assessed, and we evaluated the reliability of these computational models based on the size of the area under the ROC curve (AUC), sensitivity and specificity. Results: We found that the 1-year survival rate in patients with DF was 88.5%, and the 1-year amputation rate was 12.5%. Wagner's Classification of Diabetic Foot Ulcers grade, ankle-brachial index (ABI), low-density lipoprotein (LDL), and percutaneous oxygen partial pressure (TcPO2) were independent risk factors for amputation in patients with DF, while cerebrovascular disease, Sudoscan sweat gland function score, glycated hemoglobin (HbA1c) and peripheral artery disease (PAD) were independent risk factors for death in patients with DF. In addition, our results showed that in the case of amputation, the COX regression predictive model revealed an AUC of 0.788, sensitivity of 74.1% and specificity of 83.6%. The BP neural network predictive model identified an AUC of 0.874, sensitivity of 87.0% and specificity of 87.7%. An AUC of 0.909, sensitivity of 90.7% and specificity of 91.1% were found after optimizing the BP neural network prediction model via genetic algorithm. In the deep learning CNN model, the AUC, sensitivity and specificity were 0.939, 92.6%, and 95.2%, respectively. In the analysis of risk factors for death, the COX regression predictive model identified the AUC, sensitivity and specificity as 0.800, 74.1% and 85.9%, respectively. The BP neural network predictive model revealed an AUC, sensitivity and specificity of 0.937, 93.1% and 94.4%, respectively. Genetic algorithm-based optimization of the BP neural network predictive model identified an AUC, sensitivity and specificity of 0.932, 91.4% and 95.1%, respectively. The deep learning CNN model found the AUC, sensitivity and specificity to be 0.861, 82.8% and 89.4%, respectively. Conclusion: To identify risk factors for death, the BP neural network predictive model and genetic algorithm-based optimizing BP neural network predictive model have higher sensitivity and specificity than the deep learning method CNN predictive model and COX regression analysis.


Assuntos
Diabetes Mellitus , Pé Diabético , Humanos , Pé Diabético/diagnóstico , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Amputação Cirúrgica
7.
Chin Med Sci J ; 38(2): 159-162, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37198971

RESUMO

Food-dependent, exercise-induced anaphylaxis (FDEIA) is a potentially life-threatening disorder that often occurs with exercise, and patients typically have eaten a specific food within hours before disease onset. This disease is exceedingly rare, with a prevalence of 0.02%. No well-recognized prevention or treatment strategy has been available for FDEIA except avoiding triggers strictly. Here we report an 11-year-old boy with a history of recurrent anaphylaxis of unknown etiology more than 10 times within two years. As the anaphylactic symptoms had not been controlled after traditional treatments, the patient was given subcutaneous injection of dupilumab seven times within 33 weeks. During dupilumab treatments, the patient was exposed to culprit mushrooms plus exercises at least twice a month but without notable anaphylaxis. Thus, Dupilumab may improve the allergic reactions in FDEIA patients.


Assuntos
Anafilaxia , Alergias Induzidas por Exercício , Hipersensibilidade Alimentar , Masculino , Humanos , Criança , Anafilaxia/tratamento farmacológico , Anafilaxia/diagnóstico , Anafilaxia/etiologia , Hipersensibilidade Alimentar/tratamento farmacológico , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico
8.
Eur Radiol ; 32(1): 205-212, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34223954

RESUMO

OBJECTIVES: Early recognition of coronavirus disease 2019 (COVID-19) severity can guide patient management. However, it is challenging to predict when COVID-19 patients will progress to critical illness. This study aimed to develop an artificial intelligence system to predict future deterioration to critical illness in COVID-19 patients. METHODS: An artificial intelligence (AI) system in a time-to-event analysis framework was developed to integrate chest CT and clinical data for risk prediction of future deterioration to critical illness in patients with COVID-19. RESULTS: A multi-institutional international cohort of 1,051 patients with RT-PCR confirmed COVID-19 and chest CT was included in this study. Of them, 282 patients developed critical illness, which was defined as requiring ICU admission and/or mechanical ventilation and/or reaching death during their hospital stay. The AI system achieved a C-index of 0.80 for predicting individual COVID-19 patients' to critical illness. The AI system successfully stratified the patients into high-risk and low-risk groups with distinct progression risks (p < 0.0001). CONCLUSIONS: Using CT imaging and clinical data, the AI system successfully predicted time to critical illness for individual patients and identified patients with high risk. AI has the potential to accurately triage patients and facilitate personalized treatment. KEY POINT: • AI system can predict time to critical illness for patients with COVID-19 by using CT imaging and clinical data.


Assuntos
COVID-19 , Inteligência Artificial , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Tomografia Computadorizada por Raios X
9.
Mycoses ; 64(11): 1402-1411, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34390048

RESUMO

BACKGROUND: Cryptococcal meningitis (CM)-associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non-HIV populations. OBJECTIVES: We aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non-HIV CM IRIS populations. METHODS: In this observational cohort study, 101 previously untreated non-HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared. RESULTS: Immune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non-HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non-HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP-1) became the only cytokine correlated with both IRIS and LTA4H SNPs. CONCLUSIONS: Our study suggested that non-HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP-1.


Assuntos
Epóxido Hidrolases/genética , Síndrome Inflamatória da Reconstituição Imune/complicações , Síndrome Inflamatória da Reconstituição Imune/epidemiologia , Meningite Criptocócica/complicações , Adulto , Estudos de Coortes , Citocinas/líquido cefalorraquidiano , Feminino , Frequência do Gene , Genótipo , Humanos , Síndrome Inflamatória da Reconstituição Imune/imunologia , Imunocompetência , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Fatores de Risco
10.
Emerg Infect Dis ; 26(9): 2137-2147, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818410

RESUMO

We conducted a systematic literature review to obtain risk population-based fungal disease incidence or prevalence data from China. Data were categorized by risk factors and extrapolated by using most recent demographic figures. A total of 71,316,101 cases (5.0% of the population) were attributed to 12 risk factors and 17 fungal diseases. Excluding recurrent Candida vaginitis (4,057/100,000 women) and onychomycosis (2,600/100,000 persons), aspergillosis (317/100,000 persons) was the most common problem; prevalence exceeded that in most other countries. Cryptococcal meningitis, an opportunistic infection, occurs in immunocompetent persons almost twice as often as AIDS. The pattern of fungal infections also varies geographically; Talaromyces marneffei is distributed mainly in the Pearl River Basin, and the Yangtze River bears the greatest histoplasmosis burden. New host populations, new endemic patterns, and high fungal burdens in China, which caused a huge impact on public health, underscore the urgent need for building diagnostic and therapeutic capacity.


Assuntos
Micoses , Talaromyces , China/epidemiologia , Efeitos Psicossociais da Doença , Feminino , Humanos , Micoses/epidemiologia , Prevalência
11.
Mycoses ; 63(6): 579-587, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32222082

RESUMO

BACKGROUND: Causes of voriconazole-related visual adverse events (VVAE) remained controversial. OBJECTIVES: We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. PATIENTS/METHODS: This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. RESULT: Of the 76 patients, a total of 229 steady-state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1-5.5 mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under-presented (OR, 0.11; 95% CI, 0.01-0.84; P = .011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14-69.02; P = .013) in patients with visual hallucination when compared with those without. CONCLUSION: Transient receptor potential melastatin 1 was genetically associated with voriconazole-related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE.


Assuntos
Antifúngicos/efeitos adversos , Alucinações/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Canais de Cátion TRPM/genética , Voriconazol/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Alucinações/genética , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Voriconazol/sangue , Adulto Jovem
12.
Curr Issues Mol Biol ; 33: 225-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166195

RESUMO

Methanol, commercially generated from methane, is a renewable chemical feedstock that is highly soluble, relatively inexpensive, and easy to handle. The concept of native methylotrophic bacteria serving as whole cell catalysts for production of chemicals and materials using methanol as a feedstock is highly attractive. In recent years, the available omics data for methylotrophic bacteria, especially for Methylobacterium extorquens, the most well-characterized model methylotroph, have provided a solid platform for rational engineering of methylotrophic bacteria for industrial production. In addition, there is a strong interest in converting the more traditional heterotrophic production platforms toward the use of single carbon substrates, including methanol, through metabolic engineering. In this chapter, we review the recent progress toward achieving the desired growth and production yields from methanol, by genetically engineered native methylotrophic strains and by the engineered synthetic methylotrophs.


Assuntos
Produtos Biológicos/metabolismo , Biotransformação/fisiologia , Engenharia Metabólica/métodos , Metanol/metabolismo , Methylobacterium extorquens , Organismos Geneticamente Modificados , Redes e Vias Metabólicas/genética , Metano/metabolismo , Methylobacterium extorquens/genética , Methylobacterium extorquens/metabolismo , Biologia Sintética/métodos
13.
Appl Environ Microbiol ; 85(14)2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31053589

RESUMO

Candida albicans and Cryptococcus neoformans, human-pathogenic fungi found worldwide, are receiving increasing attention due to high morbidity and mortality in immunocompromised patients. In the present work, 110 fungus pairs were constructed by coculturing 16 wood-decaying basidiomycetes, among which coculture of Trametes robiniophila Murr and Pleurotus ostreatus was found to strongly inhibit pathogenic fungi through bioactivity-guided assays. A combination of metabolomics and molecular network analysis revealed that 44 features were either newly synthesized or produced at high levels in this coculture system and that 6 of the features that belonged to a family of novel and unusual linear sesterterpenes contributed to high activity with MICs of 1 to 32 µg/ml against pathogenic fungi. Furthermore, dynamic 13C-labeling analysis revealed an association between induced features and the corresponding fungi. Unusual sesterterpenes were 13C labeled only in P. ostreatus in a time course after stimulation by the coculture, suggesting that these sesterterpenes were synthesized by P. ostreatus instead of T. robiniophila Murr. Sesterterpene compounds 1 to 3 were renamed postrediene A to C. Real-time reverse transcription-quantitative PCR (RT-qPCR) analysis revealed that transcriptional levels of three genes encoding terpene synthase, farnesyl-diphosphate farnesyltransferase, and oxidase were found to be 8.2-fold, 88.7-fold, and 21.6-fold higher, respectively, in the coculture than in the monoculture, indicating that biosynthetic gene cluster 10 was most likely responsible for the synthesis of these sesterterpenes. A putative biosynthetic pathway of postrediene A to postrediene C was then proposed based on structures of sesterterpenes and molecular network analysis.IMPORTANCE A number of gene clusters involved in biosynthesis of secondary metabolites are presumably silent or expressed at low levels under conditions of standard laboratory cultivation, resulting in a large gap between the pool of discovered metabolites and genome capability. This work mimicked naturally occurring competition by construction of an artificial coculture of basidiomycete fungi for the identification of secondary metabolites with novel scaffolds and excellent bioactivity. Unusual linear sesterterpenes of postrediene A to C synthesized by P. ostreatus not only were promising lead drugs against human-pathogenic fungi but also highlighted a distinct pathway for sesterterpene biosynthesis in basidiomycetes. The current work provides an important basis for uncovering novel gene functions involved in sesterterpene synthesis and for gaining insights into the mechanism of silent gene activation in fungal defense.


Assuntos
Antifúngicos/farmacologia , Pleurotus/metabolismo , Sesterterpenos/metabolismo , Trametes/metabolismo , Candida albicans/efeitos dos fármacos , Técnicas de Cocultura , Cryptococcus neoformans/efeitos dos fármacos , Sesterterpenos/farmacologia
14.
Nanotechnology ; 30(49): 495407, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31480028

RESUMO

Here, we report a Cu2O-based photocathode applied with pulsed-laser-deposited overlayers with the structure of Ga2O3/AZO/TiO2 and 60 nm dense Pt simultaneously as a hydrogen evolution catalyst and protective layer under backside illumination from ITO substrate. And by depositing thin Au nanoparticles on the bottom of Cu2O, we observe the increase of light harvesting and the production of hot electrons from the surface plasmon resonance effect. The modified photocathode presents a photocurrent density of -4 mA cm-2 at 0 V versus reversible hydrogen electrode and a thermodynamically-based energy conversion efficiency of 0.27% in a weak acidic electrolyte. The stability is tremendously improved compared with other structures without the dense Pt layer. This enhancement is attributed to the formation of a p-n junction at the Cu2O and Ga2O3 interface and surface stabilization by TiO2 and Pt. To demonstrate the impact on the practical application of the photocathode, we fabricate the bias-free solar water-splitting tandem device using a transparent BiVO4 photoanode, which exhibits a stabilized peak photocurrent density of 0.1 mA cm-2 under continuous illumination.

15.
Microb Cell Fact ; 17(1): 194, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572892

RESUMO

BACKGROUND: Butadiene is a platform chemical used as an industrial feedstock for the manufacture of automobile tires, synthetic resins, latex and engineering plastics. Currently, butadiene is predominantly synthesized as a byproduct of ethylene production from non-renewable petroleum resources. Although the idea of biological synthesis of butadiene from sugars has been discussed in the literature, success for that goal has so far not been reported. As a model system for methanol assimilation, Methylobacterium extorquens AM1 can produce several unique metabolic intermediates for the production of value-added chemicals, including crotonyl-CoA as a potential precursor for butadiene synthesis. RESULTS: In this work, we focused on constructing a metabolic pathway to convert crotonyl-CoA into crotyl diphosphate, a direct precursor of butadiene. The engineered pathway consists of three identified enzymes, a hydroxyethylthiazole kinase (THK) from Escherichia coli, an isopentenyl phosphate kinase (IPK) from Methanothermobacter thermautotrophicus and an aldehyde/alcohol dehydrogenase (ADHE2) from Clostridium acetobutylicum. The Km and kcat of THK, IPK and ADHE2 were determined as 8.35 mM and 1.24 s-1, 1.28 mM and 153.14 s-1, and 2.34 mM and 1.15 s-1 towards crotonol, crotyl monophosphate and crotonyl-CoA, respectively. Then, the activity of one of rate-limiting enzymes, THK, was optimized by random mutagenesis coupled with a developed high-throughput screening colorimetric assay. The resulting variant (THKM82V) isolated from over 3000 colonies showed 8.6-fold higher activity than wild-type, which helped increase the titer of crotyl diphosphate to 0.76 mM, corresponding to a 7.6% conversion from crotonol in the one-pot in vitro reaction. Overexpression of native ADHE2, IPK with THKM82V under a strong promoter mxaF in M. extorquens AM1 did not produce crotyl diphosphate from crotonyl-CoA, but the engineered strain did generate 0.60 µg/mL of intracellular crotyl diphosphate from exogenously supplied crotonol at mid-exponential phase. CONCLUSIONS: These results represent the first step in producing a butadiene precursor in recombinant M. extorquens AM1. It not only demonstrates the feasibility of converting crotonol to key intermediates for butadiene biosynthesis, it also suggests future directions for improving catalytic efficiency of aldehyde/alcohol dehydrogenase to produce butadiene precursor from methanol.


Assuntos
Butadienos/síntese química , Ensaios de Triagem em Larga Escala/métodos , Engenharia Metabólica/métodos , Methylobacterium extorquens/patogenicidade , Redes e Vias Metabólicas
16.
BMC Infect Dis ; 18(1): 643, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541454

RESUMO

BACKGROUND: The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse. METHODS: A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated. RESULTS: A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1-667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients. CONCLUSIONS: Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.


Assuntos
Antifúngicos/administração & dosagem , Fluconazol/administração & dosagem , Meningite Criptocócica/tratamento farmacológico , Terapia de Salvação/métodos , Adolescente , Adulto , Idoso , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , China/epidemiologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Fluconazol/efeitos adversos , Flucitosina/administração & dosagem , Flucitosina/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/epidemiologia , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Adulto Jovem
17.
Acta Pharmacol Sin ; 39(4): 649-658, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29219946

RESUMO

4-(4-Pyridinyl methylene) curcumin (C1206) is a new derivative of curcumin that is more active than curcumin in inhibition of heat shock protein 90 (Hsp90) and antitumor action. In this study we investigated the relationship between C1206-induced inhibition of Hsp90 and its anti-leukemic effects. The fluorescence quenching experiments showed that C1206 seemed to bind the middle dimerization domain of Hsp90. The interaction between C1206 and Hsp90 was driven mainly by electrostatic interaction. In in vitro enzyme activity assay, C1206 dose-dependently inhibited Hsp90 ATPase activity with an IC50 value of 4.17 µmol/L. In both imatinib-sensitive K562 chronic myeloid leukemia cells and imatinib-resistant K562/G01 chronic myeloid leukemia cells, C1206 (0.4-3.2 µmol/L) dose-dependently caused the degradation of Hsp90 client proteins and downstream proteins (AKT, MEK, ERK, C-RAF, P-AKT, P-MEK and P-ERK). Furthermore, C1206 (0.4-3.2 µmol/L) dose-dependently induced apoptosis of K562 and K562/G01 cells through triggering mitochondrial pathway. Consistent with this result, C1206 inhibited the proliferation of K562 and K562/G01 cells with IC50 values of 1.10 and 0.60 µmol/L, respectively. These results suggest that C1206 is a novel Hsp90 inhibitor and a promising therapeutic agent for chronic myeloid leukemia.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Antineoplásicos/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adenosina Trifosfatases/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Curcumina/química , Ensaios Enzimáticos , Proteínas de Choque Térmico HSP90/química , Humanos , Células K562 , Mitocôndrias/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
18.
Microb Cell Fact ; 16(1): 179, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29084554

RESUMO

BACKGROUND: 3-Hydroxypropionic acid (3-HP) is an important platform chemical, serving as a precursor for a wide range of industrial applications such as the production of acrylic acid and 1,3-propanediol. Although Escherichia coli or Saccharomyces cerevisiae are the primary industrial microbes for the production of 3-HP, alternative engineered hosts have the potential to generate 3-HP from other carbon feedstocks. Methylobacterium extorquens AM1, a facultative methylotrophic α-proteobacterium, is a model system for assessing the possibility of generating 3-HP from one-carbon feedstock methanol. RESULTS: Here we constructed a malonyl-CoA pathway by heterologously overexpressing the mcr gene to convert methanol into 3-HP in M. extorquens AM1. The engineered strains demonstrated 3-HP production with initial titer of 6.8 mg/l in shake flask cultivation, which was further improved to 69.8 mg/l by increasing the strength of promoter and mcr gene copy number. In vivo metabolic analysis showed a significant decrease of the acetyl-CoA pool size in the strain with the highest 3-HP titer, suggesting the supply of acetyl-CoA is a potential bottleneck for further improvement. Notably, 3-HP was rapidly degraded after the transition from exponential phase to stationary phase. Metabolomics analysis showed the accumulation of intracellular 3-hydroxypropionyl-CoA at stationary phase with the addition of 3-HP into the cultured medium, indicating 3-HP was first converted to its CoA derivatives. In vitro enzymatic assay and ß-alanine pathway dependent 13C-labeling further demonstrated that a reductive route sequentially converted 3-HP-CoA to acrylyl-CoA and propionyl-CoA, with the latter being reassimilated into the ethylmalonyl-CoA pathway. The deletion of the gene META1_4251 encoding a putative acrylyl-CoA reductase led to reduced degradation rate of 3-HP in late stationary phase. CONCLUSIONS: We demonstrated the feasibility of constructing the malonyl-CoA pathway in M. extorquens AM1 to generate 3-HP. Furthermore, we showed that a reductive route coupled with the ethylmalonyl-CoA pathway was the major channel responsible for degradation of the 3-HP during the growth transition. Engineered M. extorquens AM1 represents a good platform for 3-HP production from methanol.


Assuntos
Ácido Láctico/análogos & derivados , Methylobacterium extorquens/metabolismo , Acil Coenzima A/genética , Acil Coenzima A/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Técnicas de Cultura Celular por Lotes , Isótopos de Carbono/química , Isótopos de Carbono/metabolismo , Cromatografia Líquida de Alta Pressão , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Transportadores de Ácidos Dicarboxílicos/deficiência , Transportadores de Ácidos Dicarboxílicos/genética , Engenharia Genética , Marcação por Isótopo , Ácido Láctico/análise , Ácido Láctico/biossíntese , Espectrometria de Massas , Metabolômica , Metanol/metabolismo , Methylobacterium extorquens/genética , Methylobacterium extorquens/crescimento & desenvolvimento , Regiões Promotoras Genéticas
19.
BMC Infect Dis ; 17(1): 463, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28673256

RESUMO

BACKGROUND: Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare. METHODS: HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed. RESULTS: In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events. CONCLUSIONS: CNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases.


Assuntos
Antifúngicos/uso terapêutico , Criptococose/etiologia , Doenças Hematológicas/microbiologia , Adolescente , Adulto , Idoso , Anfotericina B/uso terapêutico , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Criptococose/tratamento farmacológico , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Doenças Hematológicas/complicações , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Meningite Criptocócica/tratamento farmacológico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Adulto Jovem
20.
J Ultrasound Med ; 36(3): 485-492, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28133769

RESUMO

OBJECTIVES: The purpose of this study was to assess the diagnostic performance of ultrasound-guided diffuse optical tomography for differentiation of benign and malignant breast lesions. METHODS: The Cochrane Library, PubMed, and Embase databases were searched from inception to February 14, 2016. Sensitivity, specificity, and other information were extracted from the included studies. Sensitivity and specificity were pooled by a bivariate mixed-effects binary regression model. A summary receiver operating characteristic curve was constructed. Heterogeneity and publication bias were explored by Higgins and Deeks tests, respectively. RESULTS: Seven studies including 768 women with 886 lesions were analyzed. The summary sensitivity, specificity, and diagnostic odds ratio were 95% (95% confidence interval [CI], 85%-98%), 77% (95% CI, 66%-85%), and 57 (95% CI, 12-267), respectively. The area under the summary receiver operating characteristic curve was 91% (95% CI, 89%-94%). No significant heterogeneity or publication bias existed. CONCLUSIONS: Ultrasound-guided diffuse optical tomography is useful for differentiating breast lesions. Especially, its sensitivity is excellent.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Tomografia Óptica/métodos , Ultrassonografia Mamária/métodos , Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Sensibilidade e Especificidade
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