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1.
Mol Cell ; 84(2): 202-220.e15, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38103559

RESUMO

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.


Assuntos
Infecções por Papillomavirus , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Papillomavirus Humano , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Proteômica , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Papillomaviridae/genética , Papillomaviridae/metabolismo , Proteínas Virais/genética , Replicação Viral/fisiologia , Reparo do DNA , Proteínas que Contêm Bromodomínio
2.
Cell ; 155(3): 552-66, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24243015

RESUMO

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/farmacologia , Neoplasias Pulmonares/metabolismo , Triazinas/farmacologia , Animais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte , Linhagem Celular Tumoral , Proteína Coatomer/metabolismo , Feminino , Genes ras , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Lisossomos/metabolismo , Camundongos , Terapia de Alvo Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transplante de Neoplasias , Fosforilação Oxidativa
3.
Proc Natl Acad Sci U S A ; 119(49): e2208458119, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36449542

RESUMO

Determining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform Functional Signature Ontology, and pairs these data with untargeted metabolomics analysis for de novo bioactive compound discovery. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using Kolmogorov-Smirnov (KS) tests to compare in-class to out-of-class similarity, we found that SNF retains the ability to identify significant in-class similarity across a diverse set of target classes, and could find target classes not detectable in either platform alone. This confirmed that integration of expression-based and image-based phenotypes can accurately report on MOA. Furthermore, we integrated untargeted metabolomics of complex natural product fractions with the SNF network to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites, including the discovery of the azoxy-containing biaryl compounds parkamycins A and B. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as a powerful approach for advancing natural products drug discovery.


Assuntos
Produtos Biológicos , Produtos Biológicos/farmacologia , Metabolômica , Benchmarking , Fusão Gênica , Biblioteca Gênica
4.
Brain Topogr ; 37(6): 1217-1231, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38955901

RESUMO

Methamphetamine (MA) is a neurological drug, which is harmful to the overall brain cognitive function when abused. Based on this property of MA, people can be divided into those with MA abuse and healthy people. However, few studies to date have investigated automatic detection of MA abusers based on the neural activity. For this reason, the purpose of this research was to investigate the difference in the neural activity between MA abusers and healthy persons and accordingly discriminate MA abusers. First, we performed event-related potential (ERP) analysis to determine the time range of P300. Then, the wavelet coefficients of the P300 component were extracted as the main features, along with the time and frequency domain features within the selected P300 range to classify. To optimize the feature set, F_score was used to remove features below the average score. Finally, a Bidirectional Long Short-term Memory (BiLSTM) network was performed for classification. The experimental result showed that the detection accuracy of BiLSTM could reach 83.85%. In conclusion, the P300 component of EEG signals of MA abusers is different from that in normal persons. Based on this difference, this study proposes a novel way for the prevention and diagnosis of MA abuse.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Eletroencefalografia , Potenciais Evocados P300 , Metanfetamina , Análise de Ondaletas , Humanos , Eletroencefalografia/métodos , Masculino , Potenciais Evocados P300/fisiologia , Potenciais Evocados P300/efeitos dos fármacos , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Feminino , Adulto Jovem , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Encéfalo/efeitos dos fármacos , Redes Neurais de Computação
5.
Neurobiol Dis ; 186: 106279, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37661023

RESUMO

Opioid withdrawal generates extremely unpleasant physical symptoms and negative affective states. A rapid relief of opioid withdrawal-induced anxiety has obvious clinical relevance but has been rarely reported. We have shown that injection of ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) leads to a rapid alleviation of anxiety-like behaviors in male mice undergoing chronic morphine withdrawal. Here we investigated the contribution of nucleus accumbens shell (sNAc) parvalbumin (PV)-neurons to this process. Chronic morphine withdrawal was associated with higher intrinsic excitability of sNAc PV-neurons via reduced voltage-dependent potassium currents. Chemogenetic inhibition of sNAc PV-neurons reversed the enhanced excitability of PV-neurons and anxiety-like behaviors in these morphine withdrawal male mice, while activation of sNAc PV-neurons induced anxiety-like behaviors in naive male mice. (2R,6R)-HNK reversed the altered potassium currents and intrinsic excitability of sNAc PV-neurons. Our findings demonstrate an important contribution of sNAc PV-neurons to modulating morphine withdrawal-induced anxiety-like behaviors and rapid relief of anxiety-like behaviors by (2R,6R)-HNK, this newly identified target may have therapeutic potentials in treating opioid addiction and anxiety disorders.


Assuntos
Ketamina , Masculino , Animais , Camundongos , Parvalbuminas , Morfina , Analgésicos Opioides , Núcleo Accumbens , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade , Neurônios , Potássio
6.
Women Health ; 63(5): 383-391, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37280193

RESUMO

Persistent human papillomavirus (HPV) infection has been associated with the development of cervical cancer. To reduce the incidence of cervical cancer and promote awareness of HPV, a government-sponsored epidemiological study was conducted from 2015 to 2018 in Zhengzhou City. A total of 184,092 women aged 25-64 years were included, of which 19,579 were infected with HPV, reflecting a prevalence of 10.64 percent (19,579/184,092). The HPV genotypes found were classified as high-risk (13 genotypes) and low-risk (8 genotypes). Single and multiple infections were detected in 13,787 (70.42 percent) and 5,792 (29.58 percent) women, respectively. The five most common high-risk genotypes detected, listed in descending order, were HPV52 (2.14 percent; 3,931/184,092), HPV16 (2.04 percent; 3,756/184,092), HPV58 (1.42 percent; 2,607/184,092), HPV56 (1.01 percent; 1,858/184,092), and HPV39 (0.81 percent; 1,491/184,092). Meanwhile, the most common low-risk genotype was HPV53 (0.88 percent; 1,625/184,092). The prevalence of HPV gradually increased with age, with the highest occurring in women aged 55-64 years. The prevalence of single-type HPV infection decreased with age, whereas that of multiple-type HPV infection increased with age. This study indicates a high burden of HPV infection in women in Zhengzhou City.


Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/epidemiologia , Papillomavirus Humano , Infecções por Papillomavirus/epidemiologia , Genótipo , Papillomaviridae/genética , Prevalência , China/epidemiologia
7.
Int J Neuropsychopharmacol ; 25(9): 774-785, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35797010

RESUMO

BACKGROUND: Anxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. Sirtuins 1 (SIRT1) has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety. METHODS: We established a mouse model of anxiety-like behaviors induced by morphine withdrawal and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mitochondrial DNA contents with quantitative real-time PCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by western blot. Then we used virus-mediated downregulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examined the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function. RESULTS: We found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules increased in BLA cells. Virus-mediated downregulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, whereas overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/ peroxisome proliferator activated receptor gamma coactivator 1-alpha pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal. CONCLUSION: Our results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioid withdrawal-associated anxiety.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Sirtuína 1 , Fatores de Transcrição/metabolismo , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Complexo Nuclear Basolateral da Amígdala/metabolismo , DNA Mitocondrial/metabolismo , DNA Mitocondrial/farmacologia , Camundongos , Mitocôndrias/metabolismo , Morfina/farmacologia , Biogênese de Organelas , PPAR gama/metabolismo , PPAR gama/farmacologia , Sirtuína 1/metabolismo
8.
Nature ; 538(7623): 114-117, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27680702

RESUMO

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas Relacionadas à Folistatina/genética , Genes Letais/genética , Via de Sinalização Hippo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/metabolismo , Porfirinas/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Verteporfina , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Proteína Exportina 1
9.
Infection ; 49(6): 1195-1202, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34279816

RESUMO

BACKGROUND: Antiretroviral therapy (ART) regimens containing integrase strand transfer inhibitors (INSTIs) have become the recommended treatment for human immunodeficiency virus type 1 (HIV-1)-infected patients in the updated guidelines in China. In this study, we investigated the prevalence of acquired and transmitted INSTI-associated resistance of HIV-1 strains in the Henan Province (China) to provide guidance on the implementation of routine INSTI-associated HIV-1 genotypic resistance testing. METHODS: Serum samples from HIV-1-infected patients seeking treatment in our hospital from August 2018 to December 2020 were collected and the HIV-1 integrase gene coding sequence was amplified, sequenced and analyzed for INSTI resistance. RESULTS: We obtained integrase sequence data from a total of 999 HIV-1-infected patients, including 474 ART-naive patients, 438 ART-treated patients, and 87 patients with unknown treatment history. We detected INSTI resistance in 12 patients (1.2%, 12/999) of the study group, which included 9 ART-treated patients (2.05%, 9/438), with 6 being INSTI-treated (14.63%, 6/41) and 3 INSTI-naive (0.76%, 3/397) and 3 ART-naive (0.63%, 3/474) patients. The most common major resistance mutation was E138AK (0.5%, 5/999), while the most common accessory resistance mutation was E157Q (1.8%, 18/999). Phylogenetic analysis based on the HIV-1 integrase gene indicated that INSTI resistance was primarily detected in patients infected with HIV-1 subtype B. CONCLUSIONS: In conclusion, our study reveals that INSTI resistance is observed in INSTI-treated patients, as expected, and the prevalence of INSTI resistance in ART-naive patients in Henan Province is low. However, baseline INSTI resistance testing should be considered, as the prescription of INSTI-based regimens is anticipated to increase considerably in the near future.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , China/epidemiologia , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Humanos , Mutação , Filogenia , Prevalência
10.
Biochem J ; 477(17): 3253-3269, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32776146

RESUMO

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood glucose levels ChREBP activity is regulated mainly by nucleocytoplasmic shuttling of ChREBP. Under high glucose ChREBP binds to importin α and importin ß and translocates into the nucleus to initiate transcription. We have previously shown that the nuclear localization signal site (NLS) for ChREBP is bipartite with the NLS extending from Arg158 to Lys190. Here, we report the 2.5 Šcrystal structure of the ChREBP-NLS peptide bound to importin α. The structure revealed that the NLS binding is monopartite, with the amino acid residues K171RRI174 from the ChREBP-NLS interacting with ARM2-ARM5 on importin α. We discovered that importin α also binds to the primary binding site of the 14-3-3 proteins with high affinity, which suggests that both importin α and 14-3-3 are each competing with the other for this broad-binding region (residues 117-196) on ChREBP. We screened a small compound library and identified two novel compounds that inhibit the ChREBP-NLS/importin α interaction, nuclear localization, and transcription activities of ChREBP. These candidate molecules support developing inhibitors of ChREBP that may be useful in treatment of obesity and the associated diseases.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Sinais de Localização Nuclear/química , alfa Carioferinas/química , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cristalografia por Raios X , Células Hep G2 , Humanos , Sinais de Localização Nuclear/genética , Sinais de Localização Nuclear/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismo
11.
BMC Med Genet ; 21(1): 157, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736537

RESUMO

BACKGROUND: Heroin dependence is a complex disease with multiple phenotypes. Classification of heroin users into more homogeneous subgroups on the basis of these phenotypes could help to identify the involved genetic factors and precise treatments. This study aimed to identify the association between genetic polymorphisms of DA synthesis and metabolism genes, including tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), solute carrier family 6 member 3 (SLC6A3) and DA beta-hydroxylase (DBH), with six important phenotypes of heroin dependence. METHODS: A total of 801 heroin dependent patients were recruited and fourteen potential functional single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot. Associations between SNPs with six phenotypes were mainly assessed by binary logistic regression. Generalized multifactor dimensionality reduction was used to analyze the gene-by-gene and gene-by-environment interactions. RESULTS: We found that DBH rs1611114 TT genotype had a protective effect on memory impairment after heroin dependence (P = 0.002, OR = 0.610). We also found that the income-rs12666409-rs129915-rs1611114 interaction yielded the highest testing balance accuracy and cross-validation consistency for memory change after heroin dependence. CONCLUSIONS: Our results suggest that the memory change after heroin dependence was a result of a combination of genetics and environment. This finding could lead to a better understanding of heroin dependence and further improve personalized treatment.


Assuntos
Dopamina/biossíntese , Dopamina/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Dependência de Heroína/genética , Adulto , Euforia , Feminino , Interação Gene-Ambiente , Heroína/efeitos adversos , Dependência de Heroína/fisiopatologia , Humanos , Masculino , Memória , Metadona/efeitos adversos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
12.
Arch Virol ; 165(6): 1453-1461, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279138

RESUMO

Human immunodeficiency virus type 1 (HIV-1) infection remains a severe public health problem worldwide. In this study, we investigated the distribution of HIV-1 subtypes and the prevalence of drug resistance mutations (DRMs) among patients with HIV-1 infection in Henan Province, China. HIV-1 strains in blood samples taken from inpatients and outpatients visiting the Sixth People's Hospital of Zhengzhou from August 2017 to July 2019 with a viral load (VL) greater than 1000 copies/ml were subjected to subtype and DRMs analysis. Out of a total of 769 samples, subtype and DRM data were obtained from 657 (85.43%) samples. Phylogenetic analysis based on partial pol gene sequences indicated that the most commonly found genotype was subtype B (45.51%, 299/657), followed by CRF01_AE (28.61%, 188/657), CRF07_BC (15.68%, 103/657), CRF08_BC (0.76%, 5/657), C (0.61%, 4/657), A (0.30%, 2/657), and others (8.52%, 56/657). Circulating recombinant forms (CRFs) were most commonly found in patients who were naïve to antiretroviral treatment (ART) (68.67%, 160/233). The percentage of patients with one or more major drug-resistance mutations was 50.99% (335/657), and it was 6.44% (15/233) in ART-naive patients that were primarily infected with subtype B (17.74%). Resistance mutations were most common at codons 65, 103, 106, 184, and 190 of the reverse transcriptase gene and codon 46 of the protease gene. Our study provides detailed information about the distribution of HIV-1 subtypes and the incidence of drug resistance mutations of different subtypes in ART-experienced and naïve patients. This can guide policymakers in making decisions about treatment strategies against HIV-1.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirretrovirais/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Filogenia , Filogeografia , Carga Viral , Adulto Jovem
13.
Am J Drug Alcohol Abuse ; 46(1): 68-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31120769

RESUMO

Background: Many experimental studies and theoretical models have tried to explain the multifaceted formation of drug addiction. In most addiction models, social factors are an important component; however, few empirical studies have investigated the social influences on the safe or risky choices of drug-addicted individuals during the abstinence stage. Objectives: To investigate the behavioral patterns of female methamphetamine abstainers under social influence. Methods: Thirty-seven female methamphetamine abstainers (average abstinence time: 8.61 ± 4.75 months) and 40 matched controls performed a gambling task in the presence of peers' choices. We applied both model-free and computational model-based analysis to examine how the decision patterns differed with social influence between the two groups. Results: 1) the choice data from the two groups showed a social influence effect such that participants made more risky choices when others made risky choices; 2) overall, the female methamphetamine abstainers made more risky choices in the social influence task; and 3) in the computational model parameters, the female methamphetamine abstainers exhibited more nonconforming attitudes (with negative other-conferred utility) with respect to peer influence, whereas controls showed higher conformity to peers. Conclusion: Our findings provide the first objective evidence that female methamphetamine abstainers show peer nonconformity. This nonconformist tendency may be a potential behavioral marker to track drug addiction and help to elucidate the mechanisms of decisions made by female methamphetamine abstainers.


Assuntos
Comportamento de Escolha , Tomada de Decisões , Usuários de Drogas/psicologia , Assunção de Riscos , Comportamento Social , Adolescente , Adulto , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Metanfetamina , Modelos Teóricos , Grupo Associado , Conformidade Social , Adulto Jovem
14.
Int J Neuropsychopharmacol ; 22(4): 303-316, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649326

RESUMO

BACKGROUND: Adolescent methamphetamine exposure causes a broad range of neurobiological deficits in adulthood. Glycogen synthase kinase-3ß is involved in various cognitive and behavioral processes associated with methamphetamine exposure. This study aims to investigate the protective effects of the glycogen synthase kinase-3ß inhibitor lithium chloride on adolescent methamphetamine exposure-induced long-term alterations in emotion, cognition, behavior, and molecule and hippocampal ultrastructure in adulthood. METHODS: A behavioral test battery was used to investigate the protective effects of lithium chloride on adolescent methamphetamine exposure-induced long-term emotional, cognitive, and behavioral impairments in mice. Western blotting and immunohistochemistry were used to detect glycogen synthase kinase-3ß activity levels in the medial prefrontal cortex and dorsal hippocampus. Electron microscopy was used to analyze changes in synaptic ultrastructure in the dorsal hippocampus. Locomotor sensitization with a methamphetamine (1 mg/kg) challenge was examined 80 days after adolescent methamphetamine exposure. RESULTS: Adolescent methamphetamine exposure induced long-term alterations in locomotor activity, novel spatial exploration, and social recognition memory; increases in glycogen synthase kinase-3ß activity in dorsal hippocampus; and decreases in excitatory synapse density and postsynaptic density thickness in CA1. These changes were ameliorated by lithium chloride pretreatment. Adolescent methamphetamine exposure-induced working memory deficits in Y-maze spontaneous alternation test and anxiety-like behavior in elevated-plus maze test spontaneously recovered after long-term methamphetamine abstinence. No significant locomotor sensitization was observed after long-term methamphetamine abstinence. CONCLUSIONS: Hyperactive glycogen synthase kinase-3ß contributes to adolescent chronic methamphetamine exposure-induced behavioral and hippocampal impairments in adulthood. Our results suggest glycogen synthase kinase-3ß may be a potential target for the treatment of deficits in adulthood associated with adolescent methamphetamine abuse.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Disfunção Cognitiva/prevenção & controle , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Metanfetamina/farmacologia , Fatores Etários , Animais , Disfunção Cognitiva/induzido quimicamente , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo
15.
Molecules ; 24(5)2019 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832434

RESUMO

The quality and safety of food are important guarantees for the health and legal rights of consumers. As an important special fruitcrop, there are frequently shoddy practices in the kiwifruit (Actinidia chinensis) market, which harms the interests of consumers. However, there is lack of rapid and accurate identification methods for commercial kiwifruit varieties. Here, twelve common commercial varieties of kiwifruit were morphologically discriminated. DNA barcodes of chloroplast regions psbA-trnH, rbcL, matK, rpoB, rpoC1, ycf1b, trnL and rpl32_trnL(UAG), the nuclear region At103 and intergenic region ITS2 were amplified. Divergences and phylogenetic trees were used to analyze the phylogenetic relationship of these twelve commercial kiwifruit varieties. The results showed that matK, ITS2 and rpl32_trnL(UAG) can be utilized as molecular markers to identify CuiYu, JinYan, HuangJinGuo, ChuanHuangJin, HuaYou, YaTe, XuXiang and HongYang. This provides experimental and practical basis to scientifically resolve kiwifruit-related judicial disputes and legal trials.


Assuntos
Actinidia/genética , Frutas/genética , Proteínas de Plantas/genética , Actinidia/anatomia & histologia , Cloroplastos/genética , Código de Barras de DNA Taxonômico , Inocuidade dos Alimentos , Frutas/anatomia & histologia , Humanos
16.
EMBO J ; 33(17): 1960-76, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25024437

RESUMO

The antimitotic anti-cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint-dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31(comet) actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro-apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Mitose , Paclitaxel/farmacologia , RNA Interferente Pequeno/análise , Adaptação Fisiológica , Perfilação da Expressão Gênica , Células HeLa , Humanos , RNA Interferente Pequeno/genética
17.
Int J Neuropsychopharmacol ; 20(3): 257-268, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27815417

RESUMO

Background: Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear. Methods: The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice. Results: Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses. Conclusions: Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors.


Assuntos
Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Receptores de Dopamina D1/biossíntese , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D3/biossíntese , Receptores de Dopamina D3/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Anticorpos/farmacologia , Benzazepinas/farmacologia , Benzopiranos/farmacologia , Heroína , Masculino , Camundongos , Mutação , Neostriado/metabolismo , Núcleo Accumbens , Oxazinas/farmacologia , Córtex Pré-Frontal/metabolismo , Tempo de Reação/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/biossíntese , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/genética
18.
Bioorg Med Chem Lett ; 26(16): 3923-7, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27426302

RESUMO

The MAP3K (Mitogen Activated Protein Kinase Kinase Kinase) TAOK2 (Thousand-And-One Kinase 2) is an activator of p38 MAP kinase cascade that is up-regulated in response to environmental stresses. A synthetic lethal screen performed using a NSCLC (non-small cell lung cancer) cell line, and a second screen identifying potential modulators of autophagy have implicated TAOK2 as a potential cancer therapeutic target. Using a 200,000 compound high throughput screen, we identified three specific small molecule compounds that inhibit the kinase activity of TAOK2. These compounds also showed inhibition of autophagy. Based on SAR (structure-activity relationship) studies, we have predicted the modifications on the reactive groups for the three compounds.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/toxicidade , Relação Estrutura-Atividade , Temperatura de Transição , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Nat Chem Biol ; 9(2): 84-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23292651

RESUMO

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates apoptosis through the death receptors DR4 and DR5. Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic of Smac, the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy.


Assuntos
Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Cinética , Modelos Químicos , Ftalimidas/farmacologia , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Tiazolidinas/farmacologia
20.
Proc Natl Acad Sci U S A ; 109(1): 101-6, 2012 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22184224

RESUMO

The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase Iε in vitro and a unique benzodiazepine derivative acting through a non-GABA(A) receptor target. In addition, two compounds acutely induced Per2lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.


Assuntos
Relógios Circadianos/fisiologia , Ensaios de Triagem em Larga Escala/métodos , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Linhagem Celular , Relógios Circadianos/efeitos dos fármacos , AMP Cíclico/farmacologia , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Fatores de Tempo
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