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1.
JCI Insight ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954484

RESUMO

Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

2.
World J Surg Oncol ; 22(1): 39, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38297355

RESUMO

BACKGROUND: The peritoneal cancer index (PCI) has been used to predict surgical outcomes for pseudomyxoma peritonei (PMP). The present study aimed to establish the optimal cutoff point for PCI to predict surgical resectability of PMP. METHODS: A total of 366 PMP patients were included. The patients were divided into low-grade and high-grade groups. Based on the completeness of the cytoreduction (CC) score, both low-grade and high-grade PMP patients were further divided into complete cytoreductive surgery (CRS) and maximal tumor debulking (MTD) subgroups. The ability to predict surgical resectability of total and selected PCI (regions 2 + 9 to 12) was analyzed through receiver operating characteristic (ROC) curves. RESULTS: Both total and selected PCI demonstrated excellent discriminative ability in predicting surgical resectability for low-grade PMP patients (n = 266), with the ROC-AUC of 0.940 (95% CI: 0.904-0.965) and 0.927 (95% CI: 0.889-0.955). The corresponding optimal cutoff point was 21 and 5, respectively. For high-grade PMP patients (n = 100), both total and selected PCI exhibited good performance in predicting surgical resectability, with the ROC-AUC of 0.894 (95% CI: 0.816-0.946) and 0.888 (95% CI: 0.810-0.943); correspondingly, the optimal cutoff point was 25 and 8, respectively. The discriminative ability between total and selected PCI in predicting surgical resectability did not show a statistical difference. CONCLUSIONS: Both total and selected PCI exhibited good performance and similarity in predicting complete surgical resection for both low-grade and high-grade PMP patients. However, the selected PCI was simpler and time-saving in clinical practice. In the future, new imaging techniques or predictive models may be developed to better predict PCI preoperatively, which might assist in confirming whether complete surgical resection can be achieved.


Assuntos
Hipertermia Induzida , Neoplasias Peritoneais , Pseudomixoma Peritoneal , Humanos , Pseudomixoma Peritoneal/patologia , Neoplasias Peritoneais/patologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos
3.
Sci Rep ; 13(1): 21520, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057378

RESUMO

Peritoneal cancer index (PCI) is the surgical variable most commonly used to quantify the extent of peritoneal metastases for pseudomyxoma peritonei (PMP) patients. The present study aimed to investigate the agreement between CT predicted and surgical PCI by the Bland-Altman method for PMP of appendiceal origin. A total of 167 PMP patients of appendiceal origin were included between 2016 and 2021. Bland-Altman analysis was performed for both total PCI and selected PCI (regions 2 + 9-12). After the Bland-Altman plot was drawn, the mean bias and its 95% limit of agreements (LoAs) was quantified. Besides, the correlation coefficients between CT-PCI and surgical PCI were also been calculated. The Bland-Altman plot showed the mean bias ± SD between total CT-PCI and surgical PCI as 0.431 ± 3.005, with the LoAs from - 5.459 to 6.321. There were nine points of difference in total PCI exceeded the 95% LoAs, with the rate of 5.39% (9/167). As for selected CT-PCI, Bland-Altman plot showed the mean bias ± SD between selected CT-PCI and surgical PCI as - 0.287 ± 1.955, with the LoAs from - 4.118 to 3.544. There were ten points of difference in selected PCI exceeded the 95% LoAs, with the rate of 5.99% (10/167). The Spearman's rank correlation coefficient between total CT-PCI and surgical PCI was 0.911, P < 0.001, as for selected CT-PCI and surgical PCI, the coefficient was 0.909, P < 0.001. Although there was a strong correlation for both total and selected CT-PCI with surgical PCI, however, the agreement is still not good in Bland-Altman analysis, which suggested that CT-PCI cannot predict surgical PCI accurately even in professional PMP treatment centers. In brief explanation, CT makes it difficult to distinguish the borderline between tumor tissue and mucus and to detect tumor lesions in the small intestine regions, which caused overestimation or underestimation by CT-PCI. In the future, a multiple linear regression model based on CT-PCI might accurately predict surgical PCI preoperatively.


Assuntos
Apêndice , Neoplasias Peritoneais , Pseudomixoma Peritoneal , Humanos , Pseudomixoma Peritoneal/diagnóstico por imagem , Pseudomixoma Peritoneal/cirurgia , Pseudomixoma Peritoneal/patologia , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/cirurgia , Peritônio/diagnóstico por imagem , Peritônio/patologia , Tomografia Computadorizada por Raios X , Estudos Retrospectivos
4.
Pharmgenomics Pers Med ; 16: 835-846, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37724294

RESUMO

Purpose: Chromosomal abnormalities represent genomic signatures linked to cancer prognosis and responses to chemotherapy, immunotherapy, and drug resistance. This study aimed to investigate the impact of chromosome copy number variants (CNVs) on the efficacy of tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC) patients, as well as its prognostic implications for progression-free survival (PFS) and overall survival (OS) in EGFR wild-type patients. Methods: A total of 110 patients with advanced NSCLC were enrolled in this study and categorized into EGFR-mutated and wild-type groups. Utilizing next-generation sequencing (NGS) technology, we assessed 24 genes and chromosome CNVs associated with lung cancer pathways in patients' tissue samples. Results: Within the EGFR-mutated group, patients with a gain in Chr 1p13.3-p13.1 exhibited poor TKI responses, a high relapse rate, and shortened PFS (P = 0.002). Conversely, EGFR-mutated patients with a gain in 14q31.1-q31.3 demonstrated favorable TKI responses and relatively extended PFS (P = 0.005). Among EGFR wild-type patients, the presence of 7q31.1-q31.31 CNV emerged as an independent factor influencing both PFS and OS (P = 0.013, P = 0.004). Notably, patients with a gain in 7q31.1-q31.31 exhibited prolonged PFS and OS. Additionally, independent prognostic significance for OS in EGFR wild-type patients was observed for CNVs in 9q21.31-q22.2 and 11p11.11-q12.1 regions (P = 0.001). Patients with gains in these regions experienced extended OS, while losses were predictive of poorer outcomes. Conclusion: Our results suggested that chromosomal copy number variation is a practical indicator for predicting the response of EGFR-targeted therapy and prognosis for NSCLC patients.

5.
ISME Commun ; 3(1): 34, 2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37081217

RESUMO

Acinetobacter is present in the livestock environment, but little is known about their antibiotic resistance and pathogenic species in the farm groundwater. Here we investigated antibiotic resistance of Acinetobacter in the swine farm groundwater (JZPG) and residential groundwater (JZG) of a swine farming village, in comparison to a nearby (3.5 km) non-farming village (WTG) using metagenomic and culture-based approaches. Results showed that the abundance of antibiotic resistome in some JZG and all JZPG (~3.4 copies/16S rRNA gene) was higher than that in WTG (~0.7 copies/16S rRNA gene), indicating the influence of farming activities on both groundwater types. Acinetobacter accounted for ~95.7% of the bacteria in JZG and JZPG, but only ~8.0% in WTG. They were potential hosts of ~95.6% of the resistome in farm affected groundwater, which includes 99 ARG subtypes against 23 antibiotic classes. These ARGs were associated with diverse intrinsic and acquired resistance mechanisms, and the predominant ARGs were tetracyclines and fluoroquinolones resistance genes. Metagenomic binning analysis elucidated that non-baumannii Acinetobacter including A. oleivorans, A. beijerinckii, A. seifertii, A. bereziniae and A. modestus might pose environmental risks because of multidrug resistance, pathogenicity and massive existence in the groundwater. Antibiotic susceptibility tests showed that the isolated strains were resistant to multiple antibiotics including sulfamethoxazole (resistance ratio: 96.2%), levofloxacin (42.5%), gatifloxacin (39.0%), ciprofloxacin (32.6%), tetracycline (32.0%), doxycycline (29.0%) and ampicillin (12.0%) as well as last-resort polymyxin B (31.7%), colistin (24.1%) and tigecycline (4.1%). The findings highlight potential prevalence of groundwater-borne antibiotic-resistant pathogenic Acinetobacter in the livestock environment.

6.
Virol Sin ; 38(3): 398-408, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36907331

RESUMO

Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50-1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4+ T cell pool is a source of LLV. However, the intrinsic characteristics of CD4+ T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4+ T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4+ T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1ß factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4+ T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , HIV-1/genética , Linfócitos T , Viremia/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , Carga Viral , Fatores de Transcrição/genética , Perfilação da Expressão Gênica , Linfócitos T CD4-Positivos , Fármacos Anti-HIV/farmacologia , Proteínas de Ligação a DNA/genética
7.
Clin Exp Pharmacol Physiol ; 49(3): 360-369, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34757657

RESUMO

Ensartinib is a promising, aminopyridazine-based small molecule that potently inhibits anaplastic lymphoma kinase. This random, two-period, crossover study evaluated the effects of food on the pharmacokinetics of ensartinib after a single dose (225 mg) in healthy Chinese subjects. The pharmacokinetic parameters of ensartinib were calculated using non-compartmental analysis. Twenty-four healthy Chinese subjects age 20-44 years were included in this study. The area under the concentration-time curve of ensartinib was ~25% lower after the intake of a high-fat, high-calorie meal before dosing, whereas the maximum plasma concentration was decreased by ~37%, illustrating the statistically significant effect of food on ensartinib pharmacokinetics. In addition, food intake prolonged the absorption phase of ensartinib (median time to maximum plasma concentration, from 4.5 to 6 hours). Population pharmacokinetic (PopPK) analysis was conducted using NONMEM, and the influences of food, age, sex, body weight and body mass index were studied via covariate analysis. In this analysis, ensartinib plasma concentrations were best described by a one-compartment model with Weibull absorption. The final model included food and age as covariates on apparent distribution and apparent clearance. Based on the final PopPK model, food was identified as a significant covariate for apparent clearance, apparent volume of distribution and absorption rate constant, consistent with the results of non-compartmental pharmacokinetic analysis.


Assuntos
Antineoplásicos/farmacocinética , Povo Asiático , Interações Alimento-Droga/genética , Piperazinas/farmacocinética , Piridazinas/farmacocinética , Adulto , Antineoplásicos/administração & dosagem , Área Sob a Curva , China , Estudos Cross-Over , Gorduras na Dieta , Ingestão de Energia , Feminino , Meia-Vida , Humanos , Masculino , Piperazinas/administração & dosagem , Piridazinas/administração & dosagem , Adulto Jovem
8.
Sensors (Basel) ; 21(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206541

RESUMO

Transient magnetic field sensors are used in various electromagnetic environment measurement scenarios. In this paper, a novel magnetic field sensor based on a digital integrator was developed. The antenna was a small B-DOT loop. It was designed optimally for the simulation. The magnetic field signal was digitally integrated with the improved Al-Alaoui algorithm, resulting in less integration error. To compensate for the bandwidth loss of the optical fiber system, we specially designed an FIR (finite impulse response) filter for frequency compensation. The circuit was described, and the transimpedance amplifier was specially designed to ensure the low noise characteristic of the receiver. The sensitivity of the sensor was calibrated at 68.2 A·m-1/mV, the dynamic range was 50 dB (1-300 kA/m), the linear correlation coefficient was 0.96, and the bandwidth was greater than 100 MHz. It was tested and verified under the action of an A-type lightning current. The sensor exhibited high-precision performance and flat amplitude-frequency characteristics. Therefore, it is suitable for lightning positioning, partial discharge testing, electromagnetic compatibility management, and other applications.

9.
J Viral Hepat ; 28(10): 1355-1361, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34185938

RESUMO

We studied the characteristics of immune activation and investigated the underlying mechanisms in patients with human immunodeficiency virus-1/hepatitis B virus (HIV/HBV) coinfection after receiving HBV-active antiretroviral therapy. Forty patients with HIV/HBV coinfection, 38 patients with HIV monoinfection and 20 healthy controls were enrolled. CD4+ count, HIV load, HBV load, markers of immune activation and regulatory T-cell (Treg cell) frequency were assessed and compared between HIV-monoinfected and HIV/HBV-coinfected patients at week 0 (baseline), 12, 24, 36 and 48 after the onset of HBV-active antiretroviral therapy. Before antiretroviral therapy, frequencies of CD4+ HLADR+ CD38+ , CD8+ HLADR+ CD38+ , and Treg cells, and sCD163 and sCD14 levels were significantly higher in both HIV/HBV-coinfected patients and HIV-monoinfected patients, compared with healthy controls. Frequencies of CD4+ HLADR+ CD38+ and CD8+ HLADR+ CD38+ cells decreased following antiretroviral therapy in both groups. sCD163 levels did not change significantly in both groups and no significant difference was observed between the two groups at each time point during the 48-week antiretroviral therapy. In week 24, levels of sCD14 and frequencies of Treg cells appeared significantly higher in HIV/HBV-coinfected patients than in HIV-monoinfected patients, in which sCD14 levels and Treg cell frequencies declined to those in healthy controls. The Treg cell frequency was consistent with that of sCD14 levels in HIV/HBV-coinfected patients. Coinfection with HBV significantly increases sCD14 levels in HIV-infected patients during HBV-active antiretroviral therapy, which may potentially contribute to liver inflammation.


Assuntos
Coinfecção , Infecções por HIV , HIV-1 , Contagem de Linfócito CD4 , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Vírus da Hepatite B , Humanos , Linfócitos T Reguladores
10.
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980808

RESUMO

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Exossomos/metabolismo , Interferon-alfa/farmacologia , Interferon beta/farmacologia , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/genética , Animais , Chlorocebus aethiops , Exossomos/genética , Exossomos/virologia , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Células Vero
11.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34021074

RESUMO

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.


Assuntos
Apresentação de Antígeno , COVID-19/imunologia , Regulação para Baixo/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Evasão da Resposta Imune , SARS-CoV-2/imunologia , Proteínas Virais/imunologia , Animais , Autofagia/genética , Autofagia/imunologia , COVID-19/genética , Chlorocebus aethiops , Células HEK293 , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Lisossomos/genética , Lisossomos/imunologia , Lisossomos/virologia , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genética , Células Vero , Proteínas Virais/genética
12.
J Virol ; 94(10)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32161174

RESUMO

Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/ß/γ, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4+ T lymphocytes and resting CD4+ T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5' long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs).IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.


Assuntos
Proteínas Argonautas/metabolismo , Proteínas Argonautas/farmacologia , Epigênese Genética , Regulação Viral da Expressão Gênica/efeitos dos fármacos , HIV-1/fisiologia , Latência Viral/efeitos dos fármacos , Antirretrovirais/uso terapêutico , Proteínas Argonautas/genética , Linfócitos T CD4-Positivos/virologia , Células HEK293 , Infecções por HIV/virologia , HIV-1/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Células Jurkat , Proteínas de Ligação a RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Virais/metabolismo , Latência Viral/genética , Replicação Viral/efeitos dos fármacos
13.
Ci Ji Yi Xue Za Zhi ; 32(1): 5-13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110513

RESUMO

Male lower urinary tract symptoms (LUTSs) are highly prevalent in men and the incidence increases with aging. The pathophysiology of male LUTSs might be bladder outlet dysfunctions such as bladder neck (BN) dysfunction, benign prostatic obstruction, and poor relaxation of external sphincter and bladder dysfunctions such as detrusor overactivity (DO), detrusor underactivity, DO, and inadequate contractility. Male LUTSs include voiding and storage symptoms, and precision diagnosis should not be done based on the symptoms alone. Videourodynamic study provides a thorough look at the bladder and bladder outlet and can clearly demonstrate the underlying pathophysiology when the initial medication fails to relieve LUTS. Medical treatment should be given based on the underlying pathophysiology of LUTS, and surgical intervention to remove prostate should only be performed when a definite bladder outlet obstruction due to prostatic obstruction has been confirmed by invasive urodynamic study.

14.
Investig Clin Urol ; 61(Suppl 1): S33-S42, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32055752

RESUMO

After decades of clinical and basic science research, the clinical application of botulinum toxin A (Botox) in urology has been extended to neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity, refractory overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), lower urinary tract symptoms, benign prostatic hyperplasia, and neurogenic or non-neurogenic lower urinary tract dysfunction in children. Botox selectively disrupts and modulates neurotransmission, suppresses detrusor overactivity, and modulates sensory function, inflammation, and glandular function. In addition to motor effects, Botox has been found to have sensory inhibitory effects and anti-inflammatory effects; therefore, it has been used to treat IC/BPS and OAB. Currently, Botox has been approved for the treatment of NDO and OAB. Recent clinical trials on Botox for the treatment of IC/BPS have reported promising therapeutic effects, including reduced bladder pain. Additionally, the therapeutic duration was found to be longer with repeated Botox injections than with a single injection. However, the use of Botox for IC/BPS has not been approved. This paper reviews the recent advances in intravesical Botox treatment for OAB and IC/BPS.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Cistite Intersticial/tratamento farmacológico , Fármacos Neuromusculares/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Administração Intravesical , Toxinas Botulínicas Tipo A/efeitos adversos , Humanos , Fármacos Neuromusculares/efeitos adversos
15.
Emerg Microbes Infect ; 8(1): 1347-1360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31516086

RESUMO

The polymerase complex of Ebola virus (EBOV) is the functional unit for transcription and replication of viral genome. Nucleoprotein (NP) is a multifunctional protein with high RNA binding affinity and recruits other viral proteins to form functional polymerase complex. In our study, we investigated host proteins associated with EBOV polymerase complex using NP as bait in a transcription and replication competent minigenome system by mass spectrometry analysis and identified SET and MYND domain-containing protein 3 (SMYD3) as a novel host protein which was required for the replication of EBOV. SMYD3 specifically interacted with NP and was recruited to EBOV inclusion bodies through NP. The depletion of SMYD3 dramatically suppressed EBOV mRNA production. A mimic of non-phosphorylated VP30, which is a transcription activator, could partially rescue the viral mRNA production downregulated by the depletion of SMYD3. In addition, SMYD3 promoted NP-VP30 interaction in a dose-dependent manner. These results revealed that SMYD3 was a novel host factor recruited by NP to supporting EBOV mRNA transcription through increasing the binding of VP30 to NP. Thus, our study provided a new understanding of mechanism underlying the transcription of EBOV genome, and a novel anti-EBOV drug design strategy by targeting SMYD3.


Assuntos
Ebolavirus/fisiologia , Histona-Lisina N-Metiltransferase/metabolismo , Interações Hospedeiro-Patógeno , Proteínas do Nucleocapsídeo/metabolismo , RNA Mensageiro/biossíntese , RNA Viral/biossíntese , Transcrição Gênica , Células HEK293 , Humanos , Espectrometria de Massas , Ligação Proteica , Mapeamento de Interação de Proteínas
16.
Electromagn Biol Med ; 38(3): 185-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055982

RESUMO

In recent years, using electromagnetic fields as a targeted therapy for tumors has become a new idea. This paper aims to study the response of rat glioma cells (C6) when the external electromagnetic field parameters change and to obtain a complete working range of magnetic field parameters. Four-day, 4-h daily millisecond magnetic field exposure experiments were performed with C6 cells. The peak values of magnetic field intensity were 260 mT, 90 mT, 19 mT and 6 mT. Each day after exposure, cell morphology and cell viability assay (MTT method) were measured. The response of C6 cells shows a significant window effect and time cumulative effect on the cell, and it is non-destructive. The working inhibited magnetic field range of magnetic field increase rate dB/dt (T/s) is [34, 119.5] and [166.75, 527.25], the magnetic field amplitude B (mT) is [6, 260], the magnetic field integral Bt (mT·s) is [0.1649, 0.8085] and the energy integral B2t (mT2·s) is [2.317, 53.328]. Our findings provide the theoretical and experimental basis for clinical applications of electromagnetic fields.


Assuntos
Campos Eletromagnéticos , Glioma/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Humanos , Potenciais da Membrana/efeitos da radiação , Ratos , Fatores de Tempo
17.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013676

RESUMO

The traditional biochemical methods for analyzing cellular composition of oleaginous microorganisms are time-consuming, polluting, and expensive. In the present study, an FT-IR method was used to analyze the cellular composition of the marine oleaginous protist Aurantiochytrium sp. during various research processes, such as strains screening, medium optimization, and fermentation, and was evaluated as a green, low-cost, high throughput, and accurate method compared with the traditional methods. A total of 109 Aurantiochytrium sp. strains were screened for lipid and carbohydrate production and the best results were found for the strains No. 6 and No. 32. The yields and productivities could reach up to 47.2 g/L and 0.72 g/L/h for lipid, 21.6 g/L and 0.33 g/L/h for docosahexaenoic acid (DHA) in the strain No. 6, and 15.4 g/L and 0.18 g/L/h for carbohydrate in the strain No. 32, under the optimal conditions, respectively. These results confirmed potentials of the two Aurantiochytrium sp. strains for lipid, DHA, and carbohydrate productions at industrial scales. The FT-IR method in this study will facilitate research on the oleaginous Aurantiochytrium sp., and the obtained two strains for lipid and carbohydrate productions will provide the foundations for their applications in medical, food, and feed industries.


Assuntos
Carboidratos/biossíntese , Ácidos Docosa-Hexaenoicos/biossíntese , Estramenópilas/metabolismo , Carboidratos/análise , Ácidos Docosa-Hexaenoicos/análise , Espectroscopia de Infravermelho com Transformada de Fourier , Estramenópilas/química
18.
J Immunother ; 41(6): 274-283, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29864078

RESUMO

Memory stem T (TSCM) cells, a new subset of memory T cells with self-renewal and multipotent capacities, are considered as a promising candidates for adoptive cellular therapy. However, the low proportion of human TSCM cells in total CD8 T cells limits their utility. Here, we aimed to induce human CD8 TSCM cells by stimulating naive precursors with interleukin-21 (IL-21). We found that IL-21 promoted the generation of TSCM cells, described as CD45RACD45ROCD62LCCR7CD122CD95 cells, with a higher efficiency than that observed with other common γ-chain cytokines. Upon adoptive transfer into an A375 melanoma mouse model, these lymphocytes mediated much stronger antitumor responses. Further mechanistic analysis revealed that IL-21 activated the Janus kinase signal transducer and activator of transcription 3 pathway by upregulating signal transducer and activator of transcription 3 phosphorylation and consequently promoting the expression of T-bet and suppressor of cytokine signaling 1, but decreasing the expression of eomesodermin and GATA binding protein 3. Our findings provide novel insights into the generation of human CD8 TSCM cells and reveal a novel potential clinical application of IL-21.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Interleucinas/metabolismo , Melanoma/terapia , Células-Tronco Multipotentes/fisiologia , Animais , Linfócitos T CD8-Positivos/transplante , Processos de Crescimento Celular , Linhagem Celular , Autorrenovação Celular , Modelos Animais de Doenças , ELISPOT , Humanos , Memória Imunológica , Janus Quinases/metabolismo , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos NOD , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Cell Mol Med ; 22(3): 1826-1839, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29193684

RESUMO

Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug-resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti-influenza compound, ZBMD-1, from a library of 20,000 compounds using cell-based influenza A infection assays. We found that ZBMD-1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC50 ranging from 0.41-1.14 µM. Furthermore, ZBMD-1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD-1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD-1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro-inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD-1 is a promising anti-influenza compound which can be further investigated as a useful strategy against IAVs in the future.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas do Core Viral/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A/metabolismo , Concentração Inibidora 50 , Masculino , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Proteínas de Ligação a RNA/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas do Core Viral/metabolismo
20.
Mol Ther ; 24(9): 1528-37, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27434587

RESUMO

Although combined antiretroviral therapy (cART) successfully decreases plasma viremia to undetectable levels, the complete eradication of human immunodeficiency virus type 1 (HIV-1) remains impractical because of the existence of a viral reservoir, mainly in resting memory CD4(+) T cells. Various cytokines, protein kinase C activators, and histone deacetylase inhibitors (HDACi) have been used as latency-reversing agents (LRAs), but their unacceptable side effects or low efficiencies limit their clinical use. Here, by a mutation accumulation strategy, we generated an attenuated HIV-1 Tat protein named Tat-R5M4, which has significantly reduced cytotoxicity and immunogenicity, yet retaining potent transactivation and membrane-penetration activity. Combined with HDACi, Tat-R5M4 activates highly genetically diverse and replication-competent viruses from resting CD4(+) T lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Thus, Tat-R5M4 has promising potential as a safe, efficient, and specific LRA in HIV-1 treatment.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Ativação Viral , Latência Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Alelos , Substituição de Aminoácidos , Terapia Antirretroviral de Alta Atividade , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Peptídeos Penetradores de Células/metabolismo , Peptídeos Penetradores de Células/farmacologia , Citocinas/biossíntese , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Mutação , Ativação Viral/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia
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