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Antígenos E da Hepatite B , Hepatite B Crônica , Neoplasias Hepáticas , Carga Viral , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/complicações , Neoplasias Hepáticas/virologia , Antígenos E da Hepatite B/sangue , Estudos de Coortes , Vírus da Hepatite B/imunologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologiaRESUMO
Background and Aims: SARS-CoV-2 vaccines-associated autoimmune liver diseases have been reported in several case reports. However, the safety and immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in patients with autoimmune liver diseases (AILD) is still unknown. Methods: Eighty-four patients with AILD were prospectively followed up after the second dose (primary) of inactivated SARS-CoV-2 vaccine. Some of them received the third dose (booster) of inactivated vaccine. Adverse events (AEs), autoimmune activation, and liver inflammation exacerbation after primary and booster vaccination were recorded. Meanwhile, dynamics of antireceptor-binding-domain IgG (anti-RBD-IgG), neutralizing antibodies (NAbs) and RBD-specific B cells responses were evaluated. Results: The overall AEs in AILD patients after primary and booster vaccination were 26.2% and 13.3%, respectively. The decrease of C3 level and increase of immunoglobulin light chain κ and λ levels were observed in AILD patients after primary vaccination, however, liver inflammation was not exacerbated, even after booster vaccination. Both the seroprevalence and titers of anti-RBD-IgG and NAbs were decreased over time in AILD patients after primary vaccination. Notably, the antibody titers were significantly elevated after booster vaccination (10-fold in anti-RBD-IgG and 7.4-fold in NAbs, respectively), which was as high as in healthy controls. Unfortunately, the inferior antibody response was not enhanced after booster vaccination in patients with immunosuppressants. Changes of atypical memory B cells were inversely related to antibody levels, which indicate that the impaired immune memory was partially restored partly by the booster vaccination. Conclusions: The well tolerability and enhanced humoral immune response of inactivated vaccine supports an additional booster vaccination in AILD patients without immunosuppressants.
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Currently, the relationship between nutritional indices and the prognosis of hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) remains unclear. This study aims to investigate the prognostic value of psoas muscle index (PMI), prognostic nutritional index (PNI), body mass index (BMI), and geriatric nutritional risk index (GNRI) in HCC patients treated with ICIs combined with TKIs. A total of 124 male patients with HCC were included in this study. PNI, PMI, BMI, and GNRI were calculated at the beginning of treatment. The Cox proportional hazards model was used to analyze the effect of various variables. In the univariate analysis, PMI, PNI, GNRI, and ALB were found to impact the outcomes of the patients at different follow-up times. However, the predictive value of these nutritional indices was eliminated when established risk factors were considered. In the multivariate analysis that only included nutrition-related indicators, PMI emerged as an independent prognostic factor for 1-year treatment outcomes. The group with low PMI (≤5.5409 cm2/m2) was found to have a higher risk of death at one year and at the end of the follow-up period.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Idoso , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Músculos Psoas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , DNA Viral , Antígenos E da Hepatite B/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Estudos Prospectivos , Resultado do Tratamento , Neoplasias Hepáticas/epidemiologia , Antivirais/uso terapêutico , Fibrose , Vírus da Hepatite B/genéticaRESUMO
Quinone methides (QMs) are formed as the intermediates during lignin biosynthesis and chemical transformation; the chemical structure of the resulting lignin can then be significantly modified via the corresponding aromatization. Herein, the structure-reactivity relationship of ß-O-4-aryl ether QMs (GS-QM, GG-QM and GH-QM, which are 3-monomethoxylated QMs carrying syringyl, guaiacyl and p-hydroxyphenyl ß-etherified aromatic rings, respectively) was investigated to clarify the formation of alkyl-O-alkyl ether structures in lignin. The structural features of these QMs were characterized by NMR spectroscopy, and their alcohol-addition experiment was well performed at 25 °C to generate alkyl-O-alkyl/ß-O-4 products. The preferential conformation of GS-QM contains a stable directional intramolecular H-bond between γ-OH hydrogen and ß-phenoxy oxygen, which makes the ß-phenoxy group locate on the same side with γ-OH. In contrast, the ß-phenoxy groups in both GG- and GH-QM conformations are distant from the γ-OH; thus, the stable intermolecular H-bond is associated with the γ-OH hydrogen. Based on UV spectroscopy, the addition of methanol and ethanol occurs in QMs with a half-life of 1.7-2.1 and 12.8-19.3 minutes, respectively. With the same nucleophile, these QMs react faster in the order GH-QM > GG-QM > GS-QM. However, the reaction rate appears to be more influenced by the type of nucleophile than by the ß-etherified aromatic ring. Furthermore, the NMR spectra of products indicate that the steric bulkiness of both the ß-etherified aromatic ring and nucleophile contributes to the erythro-preferential formation of adducts from QMs. Moreover, the effect is more pronounced for the ß-etherified aromatic ring of QMs than the nucleophiles. The structure-reactivity relationship study demonstrates that the competition effect between H-bonds and steric hindrance determines the approaching direction and the accessibility of nucleophiles to planar QMs, resulting in stereo-differentiating formation of adducts. This model experiment may provide implications for the biosynthetic route and structural information of the alkyl-O-alkyl ether structure in lignin. Its results can also be further utilized to design innovative extraction methods of organosolv lignins for subsequent selective depolymerization or material preparation.
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Programmed death ligand 1 (PD-L1) plays an important role in the occurrence of hepatocellular carcinoma (HCC). The present study indicated that epithelial-mesenchymal transition (EMT) and induction of cancer stem cell (CSC)-like properties contribute to metastasis of cancers. However, the molecular mechanisms underlying PD-L1 and EMT and CSC phenotypes in HCC remain to be elucidated. Here, we report that PD-L1 regulates not only EMT but also the stem-like transition in liver cancer cells. We observed high PD-L1 expression in CD133+ liver CSCs and CSC-enriched tumor spheres. Altering PD-L1 expression promoted liver CSC phenotypes by increasing the expression of stemness genes, the CD133+ cell population sizes, and the ability to form tumor spheres. Programmed death ligand 1 enhanced HCC cell tumorigenicity and invasion in nude mice. Additionally, PD-L1 overexpression in cells significantly increased cell motility and invasion, as well as the EMT process. Conversely, suppression of PD-L1 in cells had an opposite effect. Prolonged treatment of HCC cells with Akt inhibitor prefosine leads to activation of serum and glucocorticoid kinase 2 (SGK2) and rescued downregulation of PD-L1. Mechanistically, PD-L1 directly interacted with SGK2. Programmed death ligand 1 upregulated SGK2 and activated the SGK2/ß-catenin signaling pathway, and promoted EMT and CSC expansion in liver cancer cells, highlighting the role of SGK2 in PD-L1-mediated EMT and CSC phenotypes in liver cancer cells. In conclusion, our findings suggest that PD-L1 activated the SGK2/ß-catenin signaling pathway, to induce EMT and acquisition of a stem cell phenotype.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Antígeno B7-H1/metabolismo , beta Catenina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Neoplasias Hepáticas/patologia , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Transdução de Sinais , HumanosRESUMO
Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.
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Heterogeneity of antibody responses has been reported in SARS-CoV-2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS-CoV-2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor-binding domain (RBD-IgG) were monitored following a full-course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS-CoV-2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD-IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46-0.93), cancer (OR: 0.65; 95% CI: 0.42-0.99), and diabetes (OR: 0.50; 95% CI: 0.28-0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11-0.76), cancer (OR: 0.38; 95% CI: 0.23-0.62), and diabetes (OR: 0.37; 95% CI: 0.20-0.69) were associated with lower seroconversion of RBD-IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD-IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS-CoV-2 vaccination are impaired in patients with certain chronic diseases.
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COVID-19 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , SARS-CoV-2 , Doença Crônica , China , Anticorpos Neutralizantes , Imunoglobulina G , Vacinação , Anticorpos AntiviraisRESUMO
The antibody and B cell responses after inactivated SARS-CoV-2 vaccination have not been well documented in patients with autoimmune liver disease (AILD). Therefore, we conducted a prospective observational study that included AILD patients and healthy participants as controls between July 1, 2021, and September 30, 2021, at the Second Affiliated Hospital of Chongqing Medical University. All adverse events (AEs) after the COVID-19 vaccination were recorded and graded. Immunoglobulin (Ig)-G antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (anti-RBD-IgG) and neutralizicadng antibodies (NAbs) were tested following full-course vaccination (BBIBP-CorV or CoronaVac). In addition, SARS-CoV-2-specific B cells were detected by flow cytometry. In total, 76 AILD patients and 136 healthy controls (HCs) were included. All AEs were mild and self-limiting, and the incidences were similar between the AILD and HCs. The seropositivity rates of anti-RBD-IgG and NAbs in AILD were 97.4% (100% in HCs, p = 0.13) and 63.2% (84.6% in HCs, p < 0.001), respectively. The titers of anti-RBD-IgG and NAbs were significantly lower in AILD patients than those in HCs. After adjusting for confounders, immunosuppressive therapy was an independent risk factor for low-level anti-RBD-IgG (adjusted odds ratio [aOR]: 4.7; 95% confidence interval [CI], 1.5-15.2; p = 0.01) and a reduced probability of NAbs seropositivity (aOR, 3.0; 95% CI, 1.0-8.9; p = 0.04) in AILD patients. However, regardless of immunosuppressants, the SARS-CoV-2-specific memory B cells responses were comparable between the AILD and HC groups. Our results suggest that inactivated SARS-CoV-2 vaccines (BBIBP-CorV and CoronaVac) are safe, but their immunogenicity is compromised in patients with AILD. Moreover, immunosuppressants are significantly associated with poor antibody responses to the SARS-CoV-2 vaccines. These results could inform physicians and policymakers about decisions on screening the populations at higher risk of poor antibody responses to SARS-CoV-2 vaccines and providing additional vaccinations in patients with AILD.
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Doenças Autoimunes , COVID-19 , Hepatopatias , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , Imunossupressores/efeitos adversos , Formação de Anticorpos , Anticorpos Antivirais , Imunoglobulina GRESUMO
BACKGROUND: High-cost, time-consuming and complex processes of several current approaches limit the use of noninvasive prenatal diagnosis (NIPD) for monogenic disorders in clinical application. Thus, a more cost-effective and easily implementable approach is required. METHODS: We established a low-cost and convenient test to noninvasively deduce fetal genotypes of the mutation and single nucleotide polymorphisms (SNPs) loci by means of targeted amplification combined with deep sequencing of maternal genomic and plasma DNA. The sequential probability ratio test was performed to detect the allelic imbalance in maternal plasma. This method can be employed to directly examine familial pathogenic mutations in the fetal genome, as well as infer the inheritance of parental haplotypes through a group of selected SNPs linked to the pathogenic mutation. RESULTS: The fetal mutations in 17 families with different types of monogenic disorders including hemophilia A, von Willebrand disease type 3, Duchenne muscular dystrophy, hyper-IgM type 1, glutaric acidemia type I, Nagashima-type palmoplantar keratosis, and familial exudative vitreoretinopathy were identified in the study. The mutations included various forms: point mutations, gene inversion, deletions/insertions and duplication. The results of 12 families were verified by sequencing of amniotic fluid samples, the accuracy of the approach in fetal genotyping at the mutation and SNPs loci was 98.85% (172/174 loci), and the no-call rate was 28.98% (71/245 loci). The overall accuracy was 12/12 (100%). Moreover, the approach was successfully applied in plasma samples with a fetal fraction as low as 2.3%. CONCLUSIONS: We have shown in this study that the approach is a cost-effective, less time consuming and accurate method for NIPD of monogenic disorders.
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Feto , Diagnóstico Pré-Natal , Feminino , Genótipo , Haplótipos , Humanos , Nucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Diagnóstico Pré-Natal/métodosRESUMO
Baicalein (BE) is a promising antifungal small-molecule compound with an extended antifungal spectrum, good synergy with fluconazole, and low toxicity, but its target protein and antifungal mechanism remain elusive. In this study, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. Eno1 acts as a key therapeutic target of the drug, as BE had no antifungal activity against the eno1 null mutant in a Galleria mellonella model of C. albicans infection. To investigate the mechanism of action, we solved the crystal structure of C. albicans Eno1(CaEno1) and then compared the difference between this structure and that of Eno1 from humans. The predicted primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Both positions S269 and K273 have different residues in the human Eno1 (hEno1). This finding suggests that BE may bind selectively to CaEno1, which would limit the potential for side effects in humans. Our findings demonstrate that Eno1 is a target protein of BE and thus may serve as a novel target for the development of antifungal therapeutics acting through the inhibition of glycolysis. IMPORTANCE Baicalein (BE) is a promising antifungal agent which has been well characterized, but its target protein is still undiscovered. The protein Eno1 plays a crucial role in the survival of Candida albicans. However, there are few antifungal agents which inhibit the functions of Eno1. Here, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. We further solved the crystal structure of C. albicans Eno1(CaEno1) and predicted that the primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Our findings will be helpful to get specific small-molecule inhibitors of CaEno1 and open the way for the development of new antifungal therapeutics targeted at inhibiting glycolysis.
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Antifúngicos , Candida albicans , Aminoácidos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/farmacologia , Proteínas de Ligação a DNA/metabolismo , Flavanonas , Proteínas Fúngicas , Glicólise , Humanos , Testes de Sensibilidade Microbiana , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/farmacologiaRESUMO
Multiple morphological abnormalities of the sperm flagella (MMAF), characteristic with bent, short, coiled, absent, and abnormal caliber flagella, is an important basis of male infertility. Genetic factors account for a large proportion of patients with MMAF. The fibrous sheath interacting protein 2 (FSIP2) has a significant function in the spermatogenesis and flagellar motility. In our study, a novel compound heterozygous mutation (c.1494C > A, p.C498* and c.11020_11024del, p.Tyr3675Cysfs*3) in FSIP2 gene was identified in an infertile male patient with MMAF. H&E staining presented typical MMAF phenotype and thick neck, midpiece in the patient's sperm cells. Transmission electron microscopy observation showed abnormal mitochondrial arrangement and disorganization and dysplastic of the fibrous sheath (FS), which were verified again under light microscopy. Immunofluorescence (IF) analysis of FISP2 expression showed that FSIP2 was absent in the flagellum of the patient's sperm cells. Our findings will be helpful to the precise diagnosis of MMAF and male infertility and enrich the mutational spectrum of FSIP2 gene.
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Dineínas do Axonema , Infertilidade Masculina , Proteínas de Plasma Seminal , Cauda do Espermatozoide , Espermatozoides , Dineínas do Axonema/genética , Heterozigoto , Humanos , Infertilidade Masculina/genética , Masculino , Mutação , Proteínas de Plasma Seminal/genética , Espermatozoides/anormalidadesRESUMO
BACKGROUND & AIMS: Worldwide, hepatocellular carcinoma (HCC) is one of the most common causes of death in people. Albumin (ALB) is considered as an important indicator for HCC prognosis, and evidence has shown HCC cell growth can be regulated by ALB. However, the role of ALB in hepatocarcinogenesis and the mechanism of action is still unknown. METHODS: The expression of ALB was determined by clinical profiles, immunohistochemistry, and western blot. Wound healing and Transwell assays were conducted to evaluate the effects of ALB during migration and invasion in HCC. We used mass spectrometry coupled isobaric tags for relative and absolute quantitation (iTRAQ)-technology to identify secretory differentially expressed proteins (DEPs) in ALB knockdown HepG2 cells. Western blot, reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay techniques were used for verification. RESULTS: We suggested that ALB was associated with aggressive metastasis and depleting ALB significantly promoted invasion and migration of HCC. A total of 210 DEPs were identified after silencing of ALB. We observed that a negative correlation between ALB and urokinase plasminogen activator surface receptor (uPAR) expression levels. CONCLUSIONS: ALB acts as a tumour suppressor and plays a key role in HCC progression, particularly in invasion and metastasis. Suppression of ALB promoted migration and invasion of HCC cells by increasing uPAR, matrix metalloproteinase (MMP2), and MMP9.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Albuminas , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Invasividade Neoplásica/patologia , Metástase NeoplásicaRESUMO
BACKGROUND: Dexmedetomidine promotes normal sleep architecture; the drug also improves analgesia. We therefore tested the hypothesis that supplementing intravenous analgesia with dexmedetomidine reduces delirium in older patients recovering from orthopedic surgery. METHODS: In this double-blinded randomized controlled trial, we enrolled 712 older (aged 65-90 years) patients scheduled for major orthopedic surgery. Postoperative analgesia was provided by patient-controlled intravenous sufentanil, supplemented by randomly assigned dexmedetomidine (1.25 µg/mL) or placebo, for up to three days. The primary outcome was the incidence of delirium assessed twice daily with the Confusion Assessment Method. Among secondary outcomes, pain severity was assessed twice daily and sleep quality once daily, each with an 11-point scale where 0 = no pain/the best possible sleep and 10 = the worst pain/the worst possible sleep. RESULTS: The incidence of postoperative delirium was 7.3% (26 of 354) with placebo and 4.8% (17 of 356) with dexmedetomidine; relative risk 0.65, 95% CI 0.36 to 1.18; P = 0.151. Dexmedetomidine reduced pain both at rest (median difference -1 to 0 points, P ≤ 0.001) and with movement (-1 points, P < 0.001) throughout the first 5 postoperative days; it also improved subjective sleep quality during the first 3 postoperative days: day one median difference -1 point (95% CI -1 to 0), P = 0.007; day two 0 point (-1 to 0), P = 0.010; and day three 0 point (-1 to 0), P = 0.003. The incidence of adverse events was similar in each group. CONCLUSIONS: Supplementing sufentanil intravenous analgesia with low-dose dexmedetomidine did not significantly reduce delirium, but improved analgesia and sleep quality without provoking adverse events. TRIAL REGISTRATION: www.chictr.org.cn : ChiCTR1800017182 (Date of registration: July 17, 2018); ClinicalTrials.gov: NCT03629262 (Date of registration: August 14, 2018).
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Analgesia/métodos , Analgésicos não Narcóticos/farmacologia , Delírio/epidemiologia , Dexmedetomidina/farmacologia , Procedimentos Ortopédicos , Complicações Pós-Operatórias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Pequim/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Incidência , Masculino , Dor Pós-Operatória/tratamento farmacológico , Sufentanil/administração & dosagemRESUMO
Lack of novel antifungal agents and severe drug resistance has led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with anti-resistant potency are highly desirable. Thus, derivatives of curcumin were synthesized to restore the effectiveness of fluconazole (FLC) against FLC-resistant Candida spp. and structure-activity relationships were then discussed. Some novel derivatives showed promising features as novel antifungal lead compounds. Of them, compound 4 showed good alone or synergistic antifungal activity against FLC-resistant Candida spp. Moreover, compound 4 was proven as a potent inhibitor of Candida albicans biofilm formation and yeast-to-hypha morphological transition whether used alone or in combination with FLC, which was further confirmed by the inhibitory effect on cellular surface hydrophobicity of C. albicans. Compound 4 also inhibits intracellular ATP production of C. albicans and disrupts membrane permeability of C. albicans when used in combination with FLC. The results highlighted the potential of curcumin derivatives to overcome fluconazole-related and biofilm-related drug resistance.
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Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Curcumina/análogos & derivados , Fluconazol/farmacologia , Trifosfato de Adenosina/metabolismo , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Candida/metabolismo , Candida/fisiologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Schisandronic acid (SA), a triterpenoid from fruits of Schisandra sphenanthera, inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion. It was a promising lead compound for the development of novel HCV entry inhibition agents. OBJECTIVE: The aim of the present study is to search for compounds with more potent anti-HCV and antitumor activities and explore SARs. A series of novel derivatives of SA were designed and synthesized and evaluated for in vitro, their anti-HCV and antitumor activities. METHODS: SA derivatives were synthesized by reduction, condensation, esterification or amidation. The anti-HCV activity of title compounds was tested by inhibition on HCVcc infection of Huh7 cells, and a preliminary MOA study was conducted by determining inhibition on HCVpp entry into Huh7 cells. The antitumor activity in vitro was determined by MTT methods. RESULTS: In total, 24 novel derivatives were synthesized. Most of the compounds inhibited HCVcc infection. Compounds 5h and 6 showed the most potent anti-HCVcc activities and inhibition of HCVpp entry into Huh7 cells without obvious cytotoxicity. Most of the title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive control SA and DOX. CONCLUSION: Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 were promising lead compounds for development of novel HCV entry inhibition or antitumor agents.
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Antineoplásicos Fitogênicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Triterpenos/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Relação Estrutura-Atividade , Internalização do Vírus/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: A proportion of chronic hepatitis B virus (HBV) infection patients with normal alanine aminotransferase (ALT) should start antiviral therapy based on liver biopsy. We aim to evaluate the proportion of such patients, find noninvasive methods for identifying and then evaluate antiviral efficacy. METHODS: 253 chronic HBV infection patients with normal ALT were analyzed at baseline and 57 patients with histological indication for antiviral therapy (Histology activity index ≥5 and/or Ishak fibrosis score ≥3) and 140 patients with elevated ALT received entecavir therapy and were followed-up to 78 weeks with a second liver biopsy in this multi-center study. RESULTS: 127 (50.2%) of 253 patients with normal ALT fulfilled histological indication for antiviral therapy. Aspartate aminotransferase (P=0.049), anti-hepatitis B virus core antibody (P=0.001) and liver stiffness measurement (P=0.000) were independent variables for identifying histological indication for antiviral therapy. A noninvasive model (AAF) performed best among independent variables and other noninvasive models with area under the operating characteristic curve of 0.887. Antiviral efficacy showed that 38 (66.7%) of 57 patients had undetectable HBV DNA. 12 (41.4%) of 29 patients who were hepatitis B e antigen (HBeAg)-positive at baseline achieved HBeAg loss and 3 (10.3%) achieved HBeAg seroconversion. 25 (43.9%) of 57 patients achieved histological response. Moreover, 57 patients with normal ALT had a similar antiviral therapy efficacy with 140 patients with elevated ALT (P>0.1) except proportion of inflammation improvement and histological response (P=0.005, P=0.049). CONCLUSIONS: Half of chronic HBV patients with normal ALT should start antiviral therapy based on liver biopsy. A noninvasive model could be used as a reliable tool for antiviral therapy decision. Patients with normal or elevated ALT had a similar antiviral efficacy.
Assuntos
Hepatite B Crônica , Alanina Transaminase , Antivirais/uso terapêutico , DNA Viral , Anticorpos Anti-Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , HumanosRESUMO
A gradual rise in immunocompromised patients over past years has led to the increasing incidence of invasive fungal infections. Development of effective fungicides can not only provide new means for clinical treatment, but also reduce the occurrence of fungal resistance. We identified a new antifungal agent (4-phenyl-1, 3-thiazol-2-yl), hydrazine (numbered as 31C) which showed high-efficiency, broad-spectrum and specific activities. The minimum inhibitory concentration of 31C against pathogenic fungi was between 0.0625-4 µg/ml in vitro, while 31C had no obvious cytotoxicity to human umbilical vein endothelial cells with the concentration of 4 µg/ml. In addition, 31C of 0.5 µg/ml could exhibit significant fungicidal activity and inhibit the biofilm formation of C. albicans. In vivo fungal infection model showed that 31C of 10 mg/kg significantly increased the survival rate of Galleria mellonella. Further study revealed that 31C-treatment increased the reactive oxygen species (ROS) in C. albicans and elevated the expression of some genes related to anti-oxidative stress response, including CAP1, CTA1, TRR1, and SODs. Consistently, 31C-induced high levels of intracellular ROS resulted in considerable DNA damage, which played a critical role in antifungal-induced cellular death. The addition of ROS scavengers, such as glutathione (GSH), N-Acetyl-L-cysteine (NAC) or oligomeric proanthocyanidins (OPC), dramatically reduced the antifungal activities of 31C and rescued the 31C-induced filamentation defect. Collectively, these results showed that 31C exhibited strong antifungal activity and induced obvious oxidative damage, which indicated that compounds with a structure similar to 31C may provide new sight for antifungal drug development.
Assuntos
Antifúngicos , Candida albicans , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Células Endoteliais , Humanos , Hidrazinas/farmacologia , Testes de Sensibilidade Microbiana , Estresse OxidativoRESUMO
BACKGROUND: Rabdosia japonica has been historically used in China as a popular folk medicine for the treatment of cancer, hepatitis, and gastricism. Glaucocalyxin A (GLA), an ent-kaurene diterpene isolated from Rabdosia japonica, is one of the main active ingredients showing potent inhibitory effects against several types of tumor cells. To the best of our knowledge, studies regarding the structural modification and Structure- Activity Relations (SAR) of this compound have not yet been reported. OBJECTIVE: The aim of this study was to discover more potent derivatives of GLA and investigate their SAR and cytotoxicity mechanisms. METHODS: Novel 7-O- and 14-O-derivatives of GLA were synthesized by condensation of acids or acyl chloride. The anti-tumor activities of these derivatives against various human cancer cell lines were evaluated in vitro by MTT assays. Apoptosis assays of compound 17 (7,14-diacylation product) were performed on A549 and HL-60 cells by flow cytometry and TUNNEL. The acute toxicity of this compound was tested on mice, at the dose of 300mg per kg body weight. RESULTS: Seventeen novel 7-O- and 14-O-derivatives of GLA (1-17) were synthesized. These compounds showed potent cytotoxicity against the tested cancer cell lines, and almost all of them were found to be more cytotoxic than GLA and oridonin. Of the synthesized derivatives, compound 17 presented the greatest cytotoxicity, with IC50 values of 0.26µM and 1.10µM in HL-60 and CCRF-CEM cells, respectively. Furthermore, this compound induced weak apoptosis of A549 cells but showed great potential in stimulating the apoptosis of HL- 60 cells. Acute toxicity assays indicated that compound 17 is relatively safer. CONCLUSION: The results reported herein indicate that the synthesized GLA derivatives exhibited greater cytotoxicity against leukemia cells than against other types of tumors. In particular, 7,14-diacylation product of GLA was found to be an effective anti-tumor agent. However, the cytotoxicity mechanism of this product in A549 cells is expected to be different than that in other tumor cell lines. Further research is needed to confirm this hypothesis.