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1.
BMC Med ; 18(1): 267, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33012286

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is effective in patients with ovarian cancer. Whether adipose tissue (AT) could predict the efficacy of VEGF receptor (VEGFR) inhibitors in ovarian cancer is unknown. We aimed to evaluate the ability of distinct AT depots to predict the efficacy of apatinib, a VEGFR inhibitor, in recurrent ovarian cancers included in the AEROC trial. METHODS: The AEROC was a single-arm phase 2 trial of apatinib and oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer. Apatinib was administered continuously, and oral etoposide was administered every 21 days for a maximum of six cycles. This was a post hoc study based on the AEROC trial. Areas of visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) were measured using computed tomography scan at baseline to assess their association with the objective response rate, progression-free survival, and overall survival. RESULTS: Of the 35 treated patients, 31 patients with at least one post-baseline efficacy assessment by computed tomography scan were included in this study. After adjusting for apatinib exposure, high VAT (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.03-0.90, P = 0.037) and SAT (OR, 0.16; 95% CI, 0.03-0.87, P = 0.034) were significantly associated with a higher objective response rate. Further, decreased risks of disease progression and death were associated with high VAT (hazard ratio [HR], 0.39; 95% CI, 0.17-0.92, P = 0.031, and HR, 0.12; 95% CI, 0.04-0.40, P < 0.001, respectively), SAT (HR, 0.35; 95% CI, 0.15-0.83, P = 0.027, and HR, 0.24; 95% CI, 0.08-0.67, P = 0.007, respectively), and IMAT (HR, 0.20; 95% CI, 0.06-0.74, P = 0.016, and HR, 0.13; 95% CI, 0.03-0.62, P = 0.011, respectively). CONCLUSIONS: High areas of VAT, SAT, and IMAT were significantly associated with better outcomes in patients with platinum-resistant or platinum-refractory ovarian cancer who received VEGFR inhibitors. AT assessments may be valuable as patient-specific imaging biomarkers for predicting response to VEGFR inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02867956 .

2.
Food Chem ; : 128243, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33069529

RESUMO

Tea saponins from Camellia oleifera Abel. seed pomace are new sources of commercial saponins. This study established an eco-friendly and efficient extraction method for tea saponins from C. oleifera seed pomace. A ternary deep eutectic solvent (DES) composed of l-proline, glycerol and sucrose (4:10:1 in molar ratio, abbreviated as PGS-5) achieved the highest extraction yield of tea saponins among all screened DESs. A maximum extraction yield of 23.22 ± 0.28% was obtained using PGS-5 under the optimized extraction time, DES concentration and liquid-solid ratio. Through ultraviolet, Fourier transform infrared spectroscopy and ultrahigh-performance liquid chromatography-Q Exactive HF mass spectroscopy, as well as analyses of antioxidant and antimicrobial activities, it was determined that extracted saponins did not altered during processing. Therefore, PGS-5 can serve as a solvent to obtain stable and beneficial tea saponins from C. oleifera seed pomace.

3.
J Ultrasound Med ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33035374

RESUMO

OBJECTIVES: To conduct a quantitative analysis of renal microvascular perfusion in diabetic patients with kidney injury using contrast-enhanced ultrasound (CEUS). METHODS: A total of 172 patients with type 2 diabetes mellitus and kidney injury were recruited from May 2017 to November 2019. After collection of clinical characteristics, a CEUS examination was performed after injection of the contrast agent SonoVue (Bracco SpA, Milan, Italy). Time-intensity curves and renal perfusion parameters were analyzed. Ultrasound-guided renal biopsy was performed. The patients were divided into a diabetic nephropathy (DN) group and a nondiabetic renal disease (NDRD) group according to renal pathologic results. The discrimination of perfusion parameters between the groups was analyzed statistically with SPSS version 19.0 software (IBM Corporation, Armonk, NY). Receiver operating characteristic curves were used to illustrate the diagnostic performance of indicators. RESULTS: Ninety-eight patients, including 45 with DN (29 male; mean age ± SD, 57.76 ± 10.47 years) and 53 with NDRD (40 male; mean age, 48.7 ± 13.88 years) were included in this study. The peak enhancement (PE), wash-in the area under the curve (AUC), wash-in rate, wash-in perfusion index, wash-out AUC, wash-in and wash-out AUC, and wash-out rate were significantly different between the groups (P < .05). There were no differences in time-related parameters between the DN and NDRD groups (P > .05). The receiver operating characteristic curve analysis showed that the AUC for PE was 0.727, and PE lower than 7712.426 had diagnostic potential, with sensitivity of 81% and specificity of 40% in discriminating between NDRD and DN. CONCLUSIONS: The quantification of CEUS parameters can discriminate DN in diabetic patients with kidney injury. The PE and AUC may be feasible parameters.

4.
Comput Biol Chem ; 89: 107385, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33032038

RESUMO

PURPOSE: The aim of the study was to comprehensively evaluate the associations between tumor necrosis factor (TNF) gene polymorphism and influenza A (H1N1) susceptibility. METHODS: The relevant studies were identified through a search of PubMed, Embase, and Cochrane library database until February 29, 2020, without language restrictions. Two independent reviewers extracted the data, and any discrepancies were resolved by consensus. The quality of the eligible article was evaluated by Newcastle-Ottawa Quality Assessment Scale (NOS). Egger's test was applied to evaluate publication bias. All these analyses were performed using Stata15.1 software. RESULTS: A total of 5 studies with 474 cases and 805 controls were included. The results of meta-analysis showed that there were statistically significant for rs361525 in allelic model (A vs. G) [OR = 2.46 (1.10, 5.52)] and for rs1800750 in dominant model (AA + GA vs. GG) [OR = 2.42 (1.24, 4.71)] in cases vs. controls. Furthermore, subgroup analysis for race showed that for rs361525 in allelic model (A vs. G), there were significant differences for Caucasian [OR = 3.64 (1.18, 11.23)] and no significant difference for Mexican [OR = 2.25 (0.82, 6.13)] in cases vs. controls. There was publication bias for rs361525 in dominant model (AA + GA vs. GG, p = 0.042) and rs1800629 in recessive model (AA vs. GG + GA, p < 0.001). CONCLUSIONS: Caucasian with A site mutation of -238TNF G/A (rs361525) was more susceptible to influenza A (H1N1).The -376 dominant model AA + GA of TNF genes was associated with the susceptibility to influenza A (H1N1). However, more studies with large sample size are needed to confirm the results.

5.
BMC Health Serv Res ; 20(1): 942, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046076

RESUMO

BACKGROUND: The asymmetry of information brings difficulty for government to manage public hospitals. Therefore, Jiading District of Shanghai has been establishing DRGs-based inpatient service management system (ISMS) to effectively compare the output of different hospitals through DRGs, reward desired hospital performance and enhance inpatient service capacity. However, the impact of the implementation of DRGs-based inpatient service management (ISM) policy in Jiading district is still unknow. We therefore conducted this study to evaluate the impact of DRGs-based ISM policy on the performance of inpatient service since its implementation in Jiading District, Shanghai, China in 2017. METHODS: Using an interrupted time series design, we analyzed quarterly data of seven DRGs-based performance measures from the ISMS which covered all five public hospitals in Jiading District from 2013 to 2019. We utilized the segmented linear regression model to assess the change of level and trend of performance indicators before and after ISM policy. Dickey-Fuller test was used to examine the stationary of the data. Durbin-Watson test was performed to check the series autocorrelation of indicators. RESULTS: Significant changes in the following indicators were observed since the implementation of ISM policy. The case-mix index (CMI) level decreased by 0.103 (P < 0.05), the trend increased by 0.008 (P < 0.05). The total weight level decreased by 3719.05 (P < 0.05), and the trend increased by 250.13 (P < 0.05). The time efficiency index (TEI) level increased by 0.12 (P < 0.05), and the trend decreased by 0.01 (P < 0.05). The cost efficiency index (CEI) level increased by 0.31 (P < 0.05), and the trend decreased by 0.02 (P < 0.05). No significant difference was found in the change of DRGs number, inpatient mortality of low-risk group cases (IMLRG) and inpatient mortality of medium-to-low risk group cases (IMMLRG). CONCLUSIONS: Findings highlight the role of ISM policy in improving the capacity and efficiency of regional inpatient service. Three prerequisites, including a good information system, high-quality EMR data, and a management team, are needed for other countries to implement their own ISM policy to help government manage public hospitals and improve the performance of regional inpatient service.

6.
Curr Neuropharmacol ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32888272

RESUMO

Multiple studies on the pathomechanisms of depressive disorder and antidepressants have been reported. However, literature involving scientometric analysis of depressive disorder is sparse. Here, we use scientometric analysis and a historical review to highlight recent research on depression. We use the former to examine research on depressive disorders from 1998 to 2018. The latter is used to identify the most frequent keywords in keyword analysis, as well as explore hotspots and depression trends. Scientometric analysis uncovered field distribution, knowledge structure, research topic evolution, and topics emergence as main explorations in depressive disorder. Induction factor, comorbidity, pathogenesis, therapy and animal models of depression help illustrate occurrence, development and treatment of depressive disorder. Scientometric analysis found 231,270 research papers on depression, a 4-fold increase over the last 20 years. These findings offer a vigorous roadmap for further studies in this field.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32929805

RESUMO

RATIONALE: Piperine, an alkaloid isolated from Piper nigrum L, has been demonstrated to have many pharmacological effects and several health benefits. The aim of this study was to study the metabolic profiles of piperine in mouse, rat, dog and human hepatocytes. METHODS: The biotransformation was carried out by incubating piperine with hepatocyte at 37 o C. After incubation for 2 h, the samples were pretreated and analyzed by liquid chromatography combined with diode array detection and high-resolution mass spectrometry (LC/DAD-HRMS). The structures of the metabolites were assigned through comparison of their accurate masses and product ions with those of the parent compound. RESULTS: A total of twenty metabolites were detected and the structures were proposed. Piperine was metabolized through the following pathways: 1) oxidation to form a catechol derivative, which further underwent methylation, glucuronidation, glutathione (GSH) conjugation and hydroxylation followed by opening of the piperidine ring; 2) hydroxylation to form a carbinolamine intermediate followed by opening of the piperidine ring and the formation of alcohol and acid derivatives; and 3) hydroxylation to form stable hydroxylated metabolites. In mouse, formation of the catechol derivative (M12) and hydroxylation (M11) were the major metabolic pathways; in rat, formation of the catechol derivative (M12) and glucuronidation (M9) were the main pathways; and in dog and human, formation of the catechol derivative (M12) was the predominant pathway. No human-specific metabolite was observed. CONCLUSIONS: This study provided some new information on the metabolic profiles of piperine, which should be of great importance in the study of the pharmacology and toxicity of this compound.

8.
R I Med J (2013) ; 103(8): 24-28, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32900008

RESUMO

BACKGROUND: Acute kidney injury (AKI) has been reported as a complication of COVID-19. However, the epidemiology, management, and associated outcomes have varied greatly between studies. The pathophysiology remains unclear.  Summary: The etiology of AKI in the setting of COVID-19 appears multifactorial. Systemic effects of sepsis, inflammation, and vascular injury likely play some role. Furthermore, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 receptor, highly expressed in the kidney, providing a route for direct infection. Older age, baseline comorbidities, and respiratory failure are strong risk factors for the development of AKI. Regardless of etiology, AKI carries a significantly increased risk for in-hospital mortality, especially in those with critical illness. Currently, management of AKI in patients with COVID-19 remains supportive. Key Messages: AKI is common in patients with COVID-19. Future studies are needed to examine the response to anti-viral treatment as well as long-term renal outcomes in patients with AKI.


Assuntos
Lesão Renal Aguda , Betacoronavirus , Infecções por Coronavirus , Estado Terminal , Rim , Pandemias , Administração dos Cuidados ao Paciente/métodos , Pneumonia Viral , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/terapia , Lesão Renal Aguda/virologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Estado Terminal/mortalidade , Estado Terminal/terapia , Mortalidade Hospitalar , Humanos , Rim/metabolismo , Rim/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Prognóstico , Medição de Risco , Fatores de Risco , Internalização do Vírus
10.
Mol Med Rep ; 22(4): 3161-3172, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945431

RESUMO

Lung adenocarcinoma (LUAD), a major subtype of lung cancer, is the leading cause of cancer­related mortality worldwide. Previous studies have determined the role of the protein arginine methyltransferases (PRMTs) in the physiology and pathology of LUAD. However, to the best of our knowledge, no empirical studies have been performed determining the association between protein arginine methyltransferase 6 (PRMT6) and LUAD. The present study aimed to determine the expression levels of PRMT6 in LUAD and its association with the clinicopathological characteristics. The effect of PRMT6 knockdown on cell growth was analyzed and chromatin immunoprecipitation (ChIP) assay was used to investigate the regulatory mechanisms of PRMT6 on downstream gene expression. In addition, a xenograft model was used to determine whether the PRMT6­regulated expression levels of p18 in vitro could be validated in vivo. PRMT6 overexpression in LUAD is associated with high clinical stage, lymph node metastasis and poor clinical outcomes. Furthermore, the silencing of PRMT6 significantly reduced the enrichment of Histone H3 asymmetric demethylation at arginine 2 in the promoter region of the p18 gene, thereby activating the expression of the gene. This, in turn, induced G1/S phase cell cycle arrest, resulting in the inhibition of cell proliferation. The xenograft model also suggested that PRMT6 suppressed LUAD development by activating p18 expression in vivo. In conclusion, the findings of the present study suggested that PRMT6 may serve as an oncogene in the progression of LUAD through epigenetically suppressing p18 expression. Thus, PRMT6 may represent a novel potential therapeutic target for LUAD.

11.
Cells ; 9(10)2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993109

RESUMO

MiR-146a is upregulated in the stem cell-enriched limbal region vs. central human cornea and can mediate corneal epithelial wound healing. The aim of this study was to identify miR-146a targets in human primary limbal epithelial cells (LECs) using genomic and proteomic analyses. RNA-seq combined with quantitative proteomics based on multiplexed isobaric tandem mass tag labeling was performed in LECs transfected with miR-146a mimic vs. mimic control. Western blot and immunostaining were used to confirm the expression of some targeted genes/proteins. A total of 251 differentially expressed mRNAs and 163 proteins were identified. We found that miR-146a regulates the expression of multiple genes in different pathways, such as the Notch system. In LECs and organ-cultured corneas, miR-146a increased Notch-1 expression possibly by downregulating its inhibitor Numb, but decreased Notch-2. Integrated transcriptome and proteome analyses revealed the regulatory role of miR-146a in several other processes, including anchoring junctions, TNF-α, Hedgehog signaling, adherens junctions, TGF-ß, mTORC2, and epidermal growth factor receptor (EGFR) signaling, which mediate wound healing, inflammation, and stem cell maintenance and differentiation. Our results provide insights into the regulatory network of miR-146a and its role in fine-tuning of Notch-1 and Notch-2 expressions in limbal epithelium, which could be a balancing factor in stem cell maintenance and differentiation.

12.
Chemosphere ; 254: 126849, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957276

RESUMO

Black carbon (BC), which is a by-product with incomplete combustion of carbonaceous materials, can be used as an indicator of combustion emissions and is an important climate forcer. In this study, a spatial-temporal synthesis of BC aerosols and the affecting factors was conducted in urban Beijing. As observed, BC showed a spatial pattern with high concentration in south and low in north. BC concentration evidently decreased by approximately 61% between 2005 and 2017. From 2015 to 2017, the mass ratio of BC/PM2.5 dropped by 28%, which suggested a more efficient effect of control measures to BC than PM2.5. The BC/CO ratio dropped by 22%, which indicated the decreasing emission from fossil fuel sources. With regard to BC loading, the spectral dependence of absorption aerosol exhibited significant seasonal variations. High absorption Ångström exponent (α) was observed during heating season, which reflected the increasing contribution of brown carbon (BrC) to light absorption. Backward trajectory analysis showed that the levels of BC and PM2.5 were high in Cluster-South and Cluster-West. BrC absorption was high in Cluster-West, Cluster-Northwest and Cluster-Northeast, due to the biomass and coal burning for domestic heating and aging processes on a regional scale. The effects of emission control and transport variability on pollutant variation were estimated on the basis of the cluster analysis. Results indicated that the effect of emission reduction was the major reason for the decrease of BC from 2015 to 2017, which resulted in a 34% reduction of BC concentration. Meanwhile, transport variability caused a 15% reduction.

13.
Eur J Pharm Biopharm ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32980448

RESUMO

Liposomal Amphotericin B, known as AmBisome®, is a life-saving antifungal product that sold $407 million in 2019. AmBisome® has a rather complex physical structure in that Amphotericin B (AmpB) forms a stable ionic complex with the lipid bilayer to maintain AmBisome®'s low toxicity and high stability in systemic circulation. Failed attempts to reproduce AmBisome®'s precise structure has resulted in faster drug release and higher toxicity both in vitro and in vivo. In this study, we established several analytical methodologies to quantify liposomal AmpB components, characterize thermal properties of the liposome, and determine particle size distribution, AmpB aggregation state, and drug release kinetics. We applied these methodologies together with in vitro hemolytic potential and antifungal activity tests to characterize multiple lots of AmBisome® and two generic products approved in India, Phosome® and Amphonex®. We also used Fungizone®, a micellar AmpB formulation, and "leaky" AmpB liposomes as negative controls. Our results showed that Phosome® and Amphonex® were both similar to AmBisome®, while Fungizone® and 'leaky" liposomes exhibited differences in both thermal properties and AmpB aggregation state, leading to faster drug release and higher toxicity. Due to the increased interest of the pharmaceutical industry in making generic AmBisome® and the lack of standard analytical methods to characterize liposomal AmpB products, the methodologies described here are valuable for the development of generic liposomal AmpB products.

14.
ChemMedChem ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32964625

RESUMO

Since the initial discovery as nicotinic acetylcholine receptor ligands, the 3-alkoxyisoxazole scaffold has now been shown as a versatile platform for the development of potent σ1 and σ2 receptor ligands. Herein we report a further SAR exploration on the 3-alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands. Various substitutions on the benzene ring and the basic amino regions resulted in a total of 21 compounds that were tested for their binding affinities to σ2 receptor. In particular, compound 51 was identified as one of the most potent σ2 ligands within the series with a K i value of 7.9 nM, and demonstrated potent anti-proliferative effects on the both osteosarcoma cell lines 143B and MOS-J (IC 50 values of 0.89 and 0.71 µM, respectively), compared to siramesine (IC 50 values of 1.81 and 2.01 µM). Moreover, compound 51 inhibited the clonal formation of the osteosarcoma 143B cells at 1 µM concentration, corresponding to half the dose required of siramesine for similar effects. The general cytotoxicity profile of compound 51 was assessed in a number of normal cell lines, including HaCaT, HAF, and LO2 cells. Furthermore, FACS analysis showed that compound 51 likely inhibits the osteosarcoma cell growth by disruption of the cell cycle and promotion of cell apoptosis.

15.
Neuropharmacology ; 181: 108326, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32966847

RESUMO

We have previously shown that sphingosine kinase 2 (SPK2) interacts with Bcl-2 via its BH3 domain, activating autophagy by inducing the dissociation of Beclin-1/Bcl-2 complexes, and that a TAT-SPK2 peptide containing the BH3 domain of SPK2 protects neurons against ischemic injury. The goals of the present study were to establish the functional significance of these findings, by testing whether TAT-SPK2 was effective in a mouse model of ischemic stroke, and to explore potential underlying mechanisms. Mice were administered with TAT-SPK2 by intraperitoneal injection before or after transient middle cerebral artery occlusion (tMCAO). Infarct volume, neurological deficit and brain water content were assessed 24 h after reperfusion. Mitophagy inhibitor Mdivi-1 and BNIP3 siRNAs were used to examine the involvement of BNIP3-dependent mitophagy in the neuroprotection of TAT-SPK2. Mitophagy was quantified by immunoblotting, immunofluorescence and electron microscopy. The interaction between TAT-SPK2 and Bcl-2, Bcl-2 and BNIP3 was detected by co-immunoprecipitation. In the tMCAO model, pre-treatment with TAT-SPK2 significantly reduced infarct volume, improved neurological function and decreased brain edema. Neuroprotection by TAT-SPK2 was still seen when the peptide was administered 3 h after reperfusion. TAT-SPK2 also significantly improved functional recovery and reduced long-term brain atrophy of the ischemic hemisphere 30 days after administration. Our studies further showed that TAT-SPK2 directly binds to Bcl-2 and disrupts Bcl-2/Beclin-1 or Bcl-2/BNIP3 complexes to induce mitophagy. These results suggest that TAT-SPK2 protects neurons against ischemia reperfusion injury by activating BNIP3-mediated mitophagy. Agents exploiting this molecular mechanism are potential candidates for the treatment of ischemic stroke.

16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 680-686, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958123

RESUMO

Objective To investigate the role of butyrophilin 3A1 (BTN3A1) in the activation and proliferation of human peripheral blood Vγ9Vδ2 T cells induced by M. tuberculosis heat resistant antigen (MTB-HAg). Methods Human peripheral blood mononuclear cells (PBMCs) were treated with BTN3A1 blocking antibody for 3 hours and then stimulated with MTB-HAg or phosphoantigen (PAg). At 24 hours of stimulation, the cells were collected to detect the expression of CD69 in Vγ9Vδ2 T cells by flow cytometry. At 20 hours of stimulation, the cells were collected to detect the proportions of cells producing helper T cell type I (Th1) cytokines IFN-γ and tumor necrosis factor α (TNF-α) in the Vγ9Vδ2 T cells. The PBMCs were also stimulated and cultured in IL-2-containing medium for 10 days, and the expansion and proliferation activity of Vγ9Vδ2 T cells were detected. Results After stimulated with MTB-HAg, the average fluorescence intensity of CD69 and the proportion of CD69 positive cells in Vγ9Vδ2 T cells decreased significantly in BTN3A1 blocked group, being 13.84% and 43.00% of those in the stimulated group, respectively. However, the average fluorescence intensity of CD69 molecules and the proportion of positive cells in PAg blocked group were significantly inhibited (3.10%, 4.47% and 9.53%, 10.91% of those in the stimulated group). The proportions of IFN-γ and TNF-α producing Vγ9Vδ2 T cells stimulated with MTB-HAg decreased significantly in the BTN3A1 blocked group, and the expansion number and cell proliferation activity of Vγ9Vδ2 T cells were also reduced significantly in the BTN3A1 blocked group. The results were similar to those of the PAg blocked group. Conclusion BTN3A1 promotes activation and proliferation of peripheral blood Vγ9Vδ2 T cells induced by MTB-HAg.

18.
Angew Chem Int Ed Engl ; 59(44): 19610-19617, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-32876984

RESUMO

Aluminum-containing adjuvants used in vaccine formulations suffer from low cellular immunity, severe aggregation, and accumulation in the brain. Conventional aluminosilicates widely used in the chemical industry focus mainly on acidic sites for catalytic applications, but they are rarely used as adjuvants. Reported here is an innovative "ligand-assisted steric hindrance" strategy to create a high density of six-coordinate VI Al-OH groups with basicity on dendritic mesoporous silica nanoparticles as new nanoadjuvants. Compared to four-coordinate IV Al-modified counterparts, VI Al-OH-rich aluminosilicate nanoadjuvants enhance cellular delivery of antigens and provoke stronger cellular immunity. Moreover, the aluminum accumulation in the brain is more reduced than that with a commercial adjuvant. These results show that coordination chemistry can be used to control the adjuvanticity, providing new understanding in the development of next-generation vaccine adjuvants.

19.
Transplant Proc ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768286

RESUMO

BACKGROUND: The main cause of chronic renal allograft dysfunction (CRAD) still remains unclear. Insulin resistance (IR) may be a potential inducement, but there is insufficient evidence about this association. We aimed to establish a rat model of CRAD complicated with IR and to explore the function and pathologic changes of the renal allograft induced by IR. METHODS: F344-to-Lewis rats of CRAD were fed a high-fat diet to induce IR. They were divided into 3 groups: IR (CRAD+IR), CRAD, and control (CTL). Serum levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were measured to evaluate the renal function. The Homeostasis Model Assessment (HOMA)-IR index was detected by comparing the values of fasting serum insulin levels (FINS) with fasting blood glucose levels (FBG). The pathologic analysis was conducted by the degree of renal lesions including glomerular lesions, renal tubular lesions, hemorrhage, inflammatory cell infiltration, fibrillation, and hyperplasia of the renal interstitium. RESULTS: In the second, third, and fourth month after surgery, serum levels of Scr and BUN in the IR group were reduced more than those in the CRAD group, while they were both higher compared to the CTL group, suggesting that renal function in the CRAD group was declined. The HOMA-IR in the IR group was greater than that in the CRAD and CTL groups, showing that simple high-fat diet feeding significantly and steadily increased FINS and FBG in CRAD complicated with IR rats. Pathologic changes indicated that the CRAD rat model was successfully constructed and was still in the early-middle stages of renal lesions 4 months after surgery, yet IR presented a significant effect on CRAD. CONCLUSION: These results indicate that the stable CRAD complicated with IR rat model can be established through a high-fat diet in CRAD rats in 4 months, and IR could be an influencing factor.

20.
Protein Cell ; 2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772249

RESUMO

TANK-binding kinase 1 (TBK1), a core kinase of antiviral pathways, activates the production of interferons (IFNs). It has been reported that deacetylation activates TBK1; however, the precise mechanism still remains to be uncovered. We show here that during the early stage of viral infection, the acetylation of TBK1 was increased, and the acetylation of TBK1 at Lys241 enhanced the recruitment of IRF3 to TBK1. HDAC3 directly deacetylated TBK1 at Lys241 and Lys692, which resulted in the activation of TBK1. Deacetylation at Lys241 and Lys692 was critical for the kinase activity and dimerization of TBK1 respectively. Using knockout cell lines and transgenic mice, we confirmed that a HDAC3 null mutant exhibited enhanced susceptibility to viral challenge via impaired production of type I IFNs. Furthermore, activated TBK1 phosphorylated HDAC3, which promoted the deacetylation activity of HDAC3 and formed a feedback loop. In this study, we illustrated the roles the acetylated and deacetylated forms of TBK1 play in antiviral innate responses and clarified the post-translational modulations involved in the interaction between TBK1 and HDAC3.

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