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1.
Exp Parasitol ; 242: 108376, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36089006

RESUMO

Aminopeptidases P are metalloproteases belonging to the M24 peptidase family. It specifically hydrolyzes the N-terminus of polypeptides free of acidic amino acids, and plays an important role in the nutrition, metabolism and growth of parasites. The aim of this study was to characterize a novel Trichinella spiralis aminopeptidase P (TsAPP) and to investigate its functions in the invasion of T. spiralis. TsAPP contained two domains of creatinase (a creatinase N and creatinase N2) and a domain of peptidase M24C and APP. The complete TsAPP sequence was cloned and expressed in Escherichia coli BL21 cells. The recombinantly produced TsAPP was used to raise polyclonal antibodies that were subsequently used to detect the expression of the protein in the different life stages of T. spiralis. TsAPP was expressed in various T. spiralis stages. TsAPP was primarily localized in the cuticle, stichosome and intrauterine embryos of this nematode. rTsAPP has an enzymatic activity of a natural aminopeptidase P to hydrolyze the substrate H-Ala-Pro-OH. rTsAPP promoted the larval intrusion of intestinal epithelium cells (IECs). The results showed that TsAPP is involved in the T. spiralis intrusion of IECs and it might be a potential candidate vaccine target against Trichinella infection.

2.
Sci Rep ; 12(1): 15899, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36151134

RESUMO

Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Congenital heart disease (CHD) is the most common structural abnormality in patients with ARSA. We aimed to assess the prevalence of genetic abnormalities, particularly sequence variants, in fetuses with CHD and ARSA. By clinical phenotyping and genomic sequencing, we retrospectively reviewed all fetuses with a prenatal diagnosis of CHD combined with ARSA at a single center. As a result, we identified 30 fetuses with ARSA combined with CHD, with conotruncal anomalies being the most common (n = 12, 40%), followed by left ventricular outflow tract obstruction (n = 6, 20%) and atrioventricular septal defects (n = 6, 20%). Overall, 18 (60%) cases had a genetic diagnosis. Copy number variation sequencing analysis identified six (20%) fetuses with aneuploidy and seven (23%) with pathogenic copy-number variants. Whole-exome sequencing (WES) analysis of the remaining 17 cases revealed diagnostic genetic variants in five (29%) cases, indicating that the diagnostic yield of WES for the entire cohort was 17% (5/30). Our findings reveal the high burden of genetic abnormalities in fetal CHD with ARSA. Single-gene disorders contribute substantially to the genetic etiology of fetal CHD with ARSA.

3.
Cell Res ; 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36151216

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts. Allogeneic CAR-T cells, generated from healthy donor T cells, can provide ready-to-use, blast-free therapeutic products, but their application could be complicated by graft-versus-host disease (GvHD) and host rejection. Here we developed healthy donor-derived, CD7-targeting CAR-T cells (RD13-01) with genetic modifications to resist fratricide, GvHD and allogeneic rejection, as well as to potentiate antitumor function. A phase I clinical trial (NCT04538599) was conducted with twelve patients recruited (eleven with T cell leukemia/lymphoma, and one with CD7-expressing acute myeloid leukemia). All patients achieved pre-set end points and eleven proceeded to efficacy evaluation. No dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade ≥ 3) were observed. 28 days post infusion, 81.8% of patients (9/11) showed objective responses and the complete response rate was 63.6% (7/11, including the patient with AML). 3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation. With a median follow-up of 10.5 months, 4 patients remained in complete remission. Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation was observed in several patients, and one died from EBV-associated diffuse large B-cell lymphoma (DLBCL). Expansion of CD7-negative normal T cells was detected post infusion. In summary, we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7+ hematological malignancies. Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7+ tumors.

4.
Brief Bioinform ; 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36151714

RESUMO

The three-dimensional genome structure plays a key role in cellular function and gene regulation. Single-cell Hi-C (high-resolution chromosome conformation capture) technology can capture genome structure information at the cell level, which provides the opportunity to study how genome structure varies among different cell types. Recently, a few methods are well designed for single-cell Hi-C clustering. In this manuscript, we perform an in-depth benchmark study of available single-cell Hi-C data clustering methods to implement an evaluation system for multiple clustering frameworks based on both human and mouse datasets. We compare eight methods in terms of visualization and clustering performance. Performance is evaluated using four benchmark metrics including adjusted rand index, normalized mutual information, homogeneity and Fowlkes-Mallows index. Furthermore, we also evaluate the eight methods for the task of separating cells at different stages of the cell cycle based on single-cell Hi-C data.

5.
Front Immunol ; 13: 949356, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105822

RESUMO

Background: Behçet's disease (BD) is a unique autoimmune chronic systemic vasculitis that affects veins and arteries of all sizes. BD can lead to recurrent vascular events, especially venous thrombosis, with an incidence rate of 40%, or pseudoaneurysms formed under long-term inflammatory reaction or iatrogenic stimulation. BD-related risk factors promote endothelial dysfunction, platelet activation and overactivation of tissue factors leading to mural inflammatory thrombi. Thrombosis may be the first clinical manifestation of BD. Case presentation: A 32-year-old man complaining of progressive swelling and pain in the right lower extremity for 30 days was initially diagnosed with "venous thrombosis of the right lower extremity," using color Doppler ultrasonography. Patient underwent inferior vena cava filter placement combined with deep vein angioplasty of the right lower extremity and catheter-directed urokinase thrombolysis. Postoperative oral anticoagulant therapy was administered. However, the patient was readmitted 20 days later for pulsatile pain in the right groin. Prior medical history included 4 years of repeated oral and perineal ulcers, and 2 months of blurred vision. Abdominal computed tomography angiography (CTA) revealed rupture of the right common iliac artery (CIA) and left internal iliac artery (IIA), complicated by a pseudoaneurysm. Based on the clinical manifestations and other auxiliary examination results, the patient was re-diagnosed with "BD combined with deep venous thrombosis of the right lower extremity and an iliac artery pseudoaneurysm." Stent implantation was performed for iliac artery pseudoaneurysm after symptoms were controlled with timely immunosuppressive therapy. After endovascular treatment, the patient underwent continued immunosuppressive therapy and dynamic reexaminations of abdominal CTA, which revealed that a small amount of contrast agent at the stent in the right CIA continued to flow into the cavity of the pseudoaneurysm; in addition, the size of the pseudoaneurysm was gradually increasing. Therefore, the patient underwent a second stent implantation for iliac artery pseudoaneurysm, and the condition improved further. Conclusion: The importance of early diagnosis of BD should be recognized, and the choice of interventional and surgical procedures should be carefully evaluated, as this may trigger further damage to vascular access in BD patients with aneurysm.


Assuntos
Falso Aneurisma , Síndrome de Behçet , Trombose Venosa , Adulto , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/terapia , Anticoagulantes , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Humanos , Extremidade Inferior , Masculino , Dor , Trombose Venosa/etiologia , Trombose Venosa/terapia
6.
Front Oncol ; 12: 965255, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119475

RESUMO

Background: The aim of this study was to investigate whether circumferential resection margin (CRM) status has an impact on survival and recurrence in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy. Methods: We screened patients with esophageal squamous cell carcinoma who underwent esophagectomy from January 2017 to December 2019. The CRM was reassessed. Patients were grouped into a CRM of 1 mm or less (0 < CRM ≤ 1 mm) and a CRM greater than 1 mm (CRM>1 mm). The impact of CRM on survival was investigated using Kaplan-Meier analysis and Cox regression modeling. The optimal CRM cut point was evaluated using restricted cubic spline curve. Results: A total of 89 patients were enrolled in this study. The CRM status was an independent risk factor for the prognosis (HR: 0.35, 95% CI: 0.16-0.73). Compared with a CRM of 1 mm or less, a CRM greater than 1 mm had better overall survival (HR: 0.35, 95% CI: 0.16-0.73, log-rank P = 0.011), longer disease-free survival (HR: 0.51, 95% CI: 0.27-0.95, log-rank P = 0.040), and less recurrence (HR: 0.44, 95% CI: 0.23-0.85, log-rank P = 0.015). We visualized the association between CRM and the hazard ratio of survival and identified the optimal cut point at 1 mm. Conclusions: A CRM greater than 1 mm had better survival and less recurrence compared to a CRM of 1 mm or less. A more radical resection with adequate CRM could benefit survival in patients with esophageal squamous cell carcinoma after neoadjuvant therapy.

7.
Food Res Int ; 160: 111747, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36076469

RESUMO

Although ß-carotene (BC) exerts beneficial effects on human health, the direct use of this compound as a nutritional supplement is hindered by its low water solubility and oxidation stability. Herein, we develop an oil-in-water emulsion stabilized by whey protein isolate (WPI)-phytosterols (PS) complexes as a delivery system for BC to overcome the above limitations. The rheology and stability of the emulsion were characterized, and the influence of the emulsion on the chemical stability and bioaccessibility of BC was discussed. The results showed that the PSs promoted the adsorption of WPI at the oil-water interface and improved the viscosity and viscoelasticity of the emulsion. The emulsion with a WPI:PS mass ratio of 25:2 (EWPI-PS) featured the highest fraction of interfacial adsorbed protein (88.73 %), excellent stability during 21-day storage at 25 °C. The BC retention rate of EWPI-PS (61.48 %) was significantly higher than that of the emulsion stabilized by WPI only (EWPI, 31.90 %) after 21-day storage at 50 °C. In addition, BC-loaded EWPI-PS showed higher freeze-thaw and thermal stability than BC-loaded EWPI, and a lower free fatty acid release rate and BC bioaccessibility than BC-loaded EWPI in simulated gastrointestinal digestion experiments. These results provide a theoretical basis for the WPI-PS complexes-stabilized emulsion as BC delivery system.


Assuntos
Fitosteróis , beta Caroteno , Emulsões/química , Humanos , Água/química , Proteínas do Soro do Leite/química , beta Caroteno/química
8.
Front Pharmacol ; 13: 941854, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059985

RESUMO

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

9.
Materials (Basel) ; 15(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36143685

RESUMO

Hydrogen fuel cells have been used worldwide due to their high energy density and zero emissions. The metallic bipolar plate is the crucial component and has a significant effect on a cell's efficiency. However, the springback behavior of the metallic bipolar plate will greatly influence its forming accuracy in the micro-scale sheet metal forming process. Therefore, accurate calculation of the springback angle of the micro-scale metallic bipolar plate is urgent but difficult given the state of existing elastoplastic theory. In this paper, a constitutive model that simultaneously considers grain size effect and strain gradient is proposed to analyze micro-scale bending behavior and calculate springback angles. The specialized micro-scale four-point bending tool was designed to better calculate the springback angle and simplify the calculation step. A pure micro-bending experiment on a 316LN stainless steel sheet with a thickness of 0.1 mm was conducted to verify the constitutive model's accuracy.

10.
Environ Technol ; : 1-11, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36062994

RESUMO

The magnesium slag (magnesium nitrate hydrate Mg(NO3)2·6H2O) produced in the nitric acid leaching process of laterite nickel ore can be effectively recycled by thermal decomposition. To this end, this study placed great emphasis on disclosing the thermal decomposition mechanism of Mg(NO3)2·6H2O. Firstly, thermal decomposition paths of Mg(NO3)2·6H2O were revealed through Thermogravimetry-Mass Spectrometry, Differential Scanning Calorimetry and powder X-ray diffraction. It was found that the thermal decomposition of Mg(NO3)2·6H2O was a multistep endothermic reaction involving two dehydration stages and one denitration stage. The two dehydration stages were characterized by the evolution of H2O, with the formation of magnesium nitrate dihydrate and anhydrous magnesium nitrate. The denitration stage was characterized by the simultaneous evolution of O2 and NO2, with the formation of MgO. The conventional kinetic analysis was not suitable for describing such complex multistep reaction behaviour. Thus, the kinetic rate data (dα/dt-T) for the overall reaction were separated into those for three contributing stages by mathematical peak deconvolution. Then, the complete kinetic interpretations of the separated reaction stages for Mg(NO3)2·6H2O pyrolysis were achieved by the Friedman method and the master plots method. Finally, the original experimental α-T curves were successfully simulated using the resulting kinetic triplets.

11.
Front Med (Lausanne) ; 9: 960689, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111114

RESUMO

Objective: Hilar and lung lymph node metastases (N1) are defined as ipsilateral bronchial and intrapulmonary lymph nodes. However, the cleaning standards for ipsilateral bronchial lymph nodes in different lobes and segments within the same lobe in segmentectomy are not clearly defined. Materials and methods: Sixty-six patients undergoing pulmonary resection for the treatment of lung cancer were evaluated. Intraoperatively visible non-tumor-bearing lobe (NTBL) and post-operatively non-tumor-bearing segment (NTBS) lymph nodes were removed and analyzed. The associations between the NTBL LNs and clinicopathological characteristics were analyzed. Results: Non-tumor-bearing lobe LNs metastases were found in 8 (12.1%) of the 66 patients, NTBS LNs metastasis were not found (0/13). The presence of NTBL metastases was significantly associated with age (<60 years vs. ≥60 years, P = 0.037), differentiation (Grade 1 well differentiated vs. Grade 2 moderately differentiated vs. Grade 3 poorly differentiated, P = 0.012), CAT-scan-findings of Mediastinal and hilar lymph nodes metastasis (node-positive vs. node-negative, P = 0.022), pN stage (N0 vs. N1 vs. N2, P = 0.003) and p stage (I vs. II vs. III, P = 0.009). Multivariate logistic analysis showed that tumor differentiation (P = 0.048, HR 6.229; 95% CI 1.016-38.181) and pN (P = 0.024, HR 5.099; 95% CI 1.245-20.878) were statistically significant predictors. Conclusions: Lobar lymph node metastasis of NTBL occurs frequently in patients with NSCLC, but lymph node metastases in NTBS LNs are rare. Advanced age, poorly differentiated and N1 and N2 status of CAT-scan-findings were independent risk factors for the involvement of the NTBL lobar lymph nodes. Although lymph node metastases in NTBS are rare, further investigation of the need to dissect is required.

12.
Am J Perinatol ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36113492

RESUMO

OBJECTIVES: This study aimed to assess the applicability of the National Academy of Medicine (NAM) interim guidelines for twin pregnancies to the specific population of gestational diabetes mellitus by exploring the relationship between gestational weight gain and adverse pregnancy outcomes in Chinese twin-pregnant women with gestational diabetes mellitus. STUDY DESIGN: This was a retrospective cohort study of women diagnosed with diabetes in pregnancy between July 2017 and December 2020 at the Maternal and Child Health Hospital in Chongqing, China. The primary variable of interest was maternal total gestational weight gain. The primary outcomes were perinatal outcomes, which included: preeclampsia, small for gestational age, large for gestational age, low birth weight, neonatal pneumonia, neonatal respiratory distress syndrome, and neonatal intensive unit admission, etc. The association between inappropriate gestational weight gain and adverse pregnancy outcomes was estimated using multiple logistic regression analysis. RESULTS: A total of 455 twin-pregnant women who had gestational diabetes mellitus were analyzed. Women with low gestational weight gain had reduced risk of preeclampsia (adjusted odds ratio [aOR], 0.32; 95% CI or confidence interval, 0.17-0.63; p = 0.001) and their infants had higher risks of small for gestational age (aOR, 1.93; 95% CI, 1.04-3.58; p = 0.037), low birth weight (aOR, 2.27; 95% CI, 1.32-3.90; p = 0.003), neonatal intensive unit admission (aOR, 3.29; 95% CI, 1.10-5.78; p = 0.038), pneumonia (aOR, 2.41; 95% CI, 1.08-5.33; p = 0.031), and neonatal respiratory distress syndrome (aOR, 2.29; 95% CI, 1.10-4.78; p = 0.027); the infants of women with excessive gestational weight gain had a higher risk of large for gestational age (aOR, 3.76; 95% CI, 1.42-9.96; p = 0.008). CONCLUSION: Gestational weight gain controlled within the range recommended by the NAM could reduce the risk of perinatal adverse outcomes. The 2009 NAM gestational weight gain recommendations can be used for Chinese twin-pregnant women with gestational diabetes mellitus. KEY POINTS: · Inappropriate gestational weight gain can lead to adverse perinatal outcomes in twin pregnancies.. · Gestational weight gain controlled within recommended range could reduce the risk of poor perinatal outcomes.. · The National Academy of Medicine recommendations are suitable for Chinese twin-pregnant women with GDM..

13.
Int J Mol Sci ; 23(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36077567

RESUMO

Sunflower (Helianthus annuus L.) is an appropriate crop for current new patterns of green agriculture, so it is important to change sunflower receptacles from waste to useful resource. However, there is limited knowledge on the functions of compounds from the essential oils of sunflower receptacles. In this study, a new method was created for chemical space network analysis and classification of small samples, and applied to 104 compounds. Here, t-SNE (t-Distributed Stochastic Neighbor Embedding) dimensions were used to reduce coordinates as node locations and edge connections of chemical space networks, respectively, and molecules were grouped according to whether the edges were connected and the proximity of the node coordinates. Through detailed analysis of the structural characteristics and fingerprints of each classified group, our classification method attained good accuracy. Targets were then identified using reverse docking methods, and the active centers of the same types of compounds were determined by quantum chemical calculation. The results indicated that these compounds can be divided into nine groups, according to their mean within-group similarity (MWGS) values. The three families with the most members, i.e., the d-limonene group (18), α-pinene group (10), and γ-maaliene group (nine members) determined the protein targets, using PharmMapper. Structure fingerprint analysis was employed to predict the binding mode of the ligands of four families of the protein targets. Thence, quantum chemical calculations were applied to the active group of the representative compounds of the four families. This study provides further scientific information to support the use of sunflower receptacles.


Assuntos
Helianthus , Óleos Voláteis , Agricultura , Análise por Conglomerados , Helianthus/química
14.
Cancers (Basel) ; 14(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077646

RESUMO

OBJECTIVES: The soaring demand for endometrial cancer screening has exposed a huge shortage of cytopathologists worldwide. To address this problem, our study set out to establish an artificial intelligence system that automatically recognizes and diagnoses pathological images of endometrial cell clumps (ECCs). METHODS: We used Li Brush to acquire endometrial cells from patients. Liquid-based cytology technology was used to provide slides. The slides were scanned and divided into malignant and benign groups. We proposed two (a U-net segmentation and a DenseNet classification) networks to identify images. Another four classification networks were used for comparison tests. RESULTS: A total of 113 (42 malignant and 71 benign) endometrial samples were collected, and a dataset containing 15,913 images was constructed. A total of 39,000 ECCs patches were obtained by the segmentation network. Then, 26,880 and 11,520 patches were used for training and testing, respectively. On the premise that the training set reached 100%, the testing set gained 93.5% accuracy, 92.2% specificity, and 92.0% sensitivity. The remaining 600 malignant patches were used for verification. CONCLUSIONS: An artificial intelligence system was successfully built to classify malignant and benign ECCs.

15.
Artigo em Inglês | MEDLINE | ID: mdl-36045534

RESUMO

BACKGROUND AND AIM: Major depressive disorder (MDD) is a common affective disorder. GuiPi decoction (GPD) is used to treat depression in China, Japan, and Korea. However, its effective ingredients and antidepressant mechanisms remain unclear. We attempted to reveal the potential mechanisms of GPD in the treatment of MDD by network pharmacology and molecular docking. In addition, we conducted an enzymatic activity assay to validate the results of molecular docking. METHODS: GPD-related compounds and targets, MDD-related targets were retrieved from databases and literature. The herb-compound-target network was constructed by Cytoscape. The protein-protein interaction network was built using STRING database to find key targets of GPD on MDD. Enrichment analysis of shared targets were analyzed by MetaCore database to obtain the potential pathway and biological process of GPD on MDD. The main active compounds treating for MDD were screened by molecular docking. The PDE4s inhibitors were screened and verified by an enzyme activity assay. RESULTS: GPD contained 1222 ingredients and 190 potential targets for anti-MDD. Possible biological processes regulated by GPD were neurophysiological processes, blood vessel morphogenesis, cAMP responsive element modulator (CREM) pathway, and androgen receptor (AR) signaling crosstalk in MDD. Potential pathways in MDD associated with GPD include neurotransmission, cell differentiation, androgen signaling, and estrogen signaling. Fumarine, m-cresol, quercetin, beta-sitosterol, fumarine, taraxasterol, and lupeol in GPD may be the targets of SLC6A4, monoamine oxidase A (MAOA), DRD2, OPRM1, HTR3A, albumin (ALB), and NTRK1, respectively. The IC50 values of trifolin targeting phosphodiesterase (PDE)4A and girinimbine targeting PDE4B1 were 73.79 µM and 31.86 µM, respectively. The IC50 values of girinimbine and benzo[a]carbazole on PDE4B2 were 51.62 µM and 94.61 µM, respectively. CONCLUSION: Different compounds in GPD may target the same protein, and the same component in GPD can target multiple targets. These results suggest that the effects of GPD on MDD are holistic and systematic, unlike the pattern of one drug-one target.

16.
Food Chem Toxicol ; 169: 113392, 2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36044934

RESUMO

This review summarizes the updated knowledge on the toxicity of T-2 on poultry, followed by potential strategies for detoxification of T-2 in poultry diet. The toxic effects of T-2 on poultry include cytotoxicity, genotoxicity, metabolism modulation, immunotoxicity, hepatotoxicity, gastrointestinal toxicity, skeletal toxicity, nephrotoxicity, reproductive toxicity, neurotoxicity, etc. Cytotoxicity is the primary toxicity of T-2, characterized by inhibiting protein and nucleic acid synthesis, altering the cell cycle, inducing oxidative stress, apoptosis and necrosis, which lead to damages of immune organs, liver, digestive tract, bone, kidney, etc., resulting in pathological changes and impaired physiological functions of these organs. Glutathione redox system, superoxide dismutase, catalase and autophagy are protective mechanisms against oxidative stress and apoptosis, and can compensate the pathological changes and physiological functions impaired by T-2 to some degree. T-2 detoxifying agents for poultry feeds include adsorbing agents (e.g., aluminosilicate-based clays and microbial cell wall), biotransforming agents (e.g., Eubacterium sp. BBSH 797 strain), and indirect detoxifying agents (e.g., plant-derived antioxidants). These T-2 detoxifying agents could alleviate different pathological changes to different degrees, and multi-component T-2 detoxifying agents can likely provide more comprehensive protection against the toxicity of T-2.

17.
Acta Pharm Sin B ; 12(8): 3398-3409, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35967281

RESUMO

The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.

18.
An. bras. dermatol ; 97(4): 458-466, July-Aug. 2022. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1383604

RESUMO

Abstract Background: UVB irradiation can cause acute damage such as sunburn, or photoaging and melanoma, all of which are major health threats. Objective: This study was designed to investigate the mechanism of skin photoaging induced by UVB radiation in mice through the analysis of the differential expression of miRNAs. Methods: A UVB irradiation photoaging model was constructed. HE and Masson special stains were used to examine the modifications in the epidermis and dermis of mice. The miRNA expression profiles of the mouse skin model exposed to UVB radiation and the normal skin of mice were analyzed using miRNA-sequence analysis. GO and Pathway analysis were employed for the prediction of miRNA targets. Results: A total of 23 miRNAs were evaluated for significantly different expressions in comparison to normal skin. Among them, 7 miRNAs were up-regulated and 16 were down-regulated in the skin with photoaging of mice exposed to UVB irradiation. The differential expression of miRNA is related to a variety of signal transduction pathways, among which mmu-miR-195a-5p and mitogen-activated protein kinase (MAPK) signal pathways are crucial. There was a significant differential expression of miRNA in the skin of normal mice in comparison with the skin with photoaging induced by UVB irradiation. Study limitations: Due to time and energy constraints, the specific protein level verification, MAPK pathway exploration, and miR-195a-5p downstream molecular mechanism need to be further studied in the future. Conclusions: UVB-induced skin photoaging can be diagnosed and treated using miRNA.

19.
Infect Drug Resist ; 15: 4241-4251, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35959146

RESUMO

Background: This study aimed to identify risk factors for mortality and outcomes in hematological malignancy (HM) patients with bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods: A retrospective study was conducted at a tertiary teaching hospital in Henan Province, China, between January 2018 and December 2021. All BSIs caused by CRKP in hospitalized HM patients were identified. Data on patient demographics, disease, laboratory tests, treatment regimens, outcomes of infection, and the antimicrobial susceptibility of each isolate were collected from medical records. Results: A total of 129 patients with CRKP BSI were included in the study, and the 28-day mortality rate was 80.6% (104/129). In Cox analysis an absolute neutrophil count < 500 at discharge (hazard ratio [HR] 6.386, 95% confidence interval [CI] 3.074-13.266, p < 0.001), intensive care unit admission (HR 1.834, 95% CI 1.065-3.157, p = 0.029), and higher Pitt bacteremia score (HR 1.185, 95% CI 1.118-1.255, p < 0.001) were independent risk factors associated with 28-day mortality. Survival curve analysis indicated that compared with ceftazidime-avibactam-based therapy, both polymyxin b (HR 8.175, 95% CI 1.099-60.804, p = 0.040) and tigecycline (HR 14.527, 95% CI 2.000-105.541, p =0.008) were associated with a higher risk of mortality. Conclusion: In HM patients CRKP BSI resulted in high mortality. Intensive care unit admission, higher Pitt bacteremia score, and absolute neutrophil count < 500 at discharge were independently associated with higher mortality. Early initiation of new agents such as ceftazidime-avibactam may improve outcomes.

20.
J Virol ; : e0123822, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36037479

RESUMO

The H7N9 subtype influenza A viruses pose a serious threat to public health, and there is still a lack of vaccines or drugs for humans against H7N9 influenza viruses. In this study, we screened two monoclonal antibodies (MAbs), 4H1E8 and 7H9A6, that specifically recognize the hemagglutinin (HA) protein of H7N9 influenza virus and display highly neutralizing activity against H7N9 virus. The epitopes recognized by two MAbs are nearly all conserved within all known H7 subtypes. Characteristic identification showed that two MAbs have high avidity for the HA protein but no hemagglutinin inhibition activity or antibody-dependent cellular cytotoxicity. Mechanistically, the 4H1E8 and 7H9A6 antibodies inhibit the pH-dependent conformational change of HA and block the HA-mediated membrane fusion. More importantly, 4H1E8 and 7H9A6 exhibit promising prophylactic and therapeutic effects against lethal challenge with H7N9 virus. Moreover, 4H1E8- and 7H9A6-treated mice displayed inhibition of pulmonary viral replication and reduced lung lesions after viral challenge. Together, these findings indicate that antibodies 4H1E8 and 7H9A6 recognize unique epitopes in the HA protein and possess the neutralizing activity and protective efficacy against the H7N9 influenza A viruses. IMPORTANCE In 2013, H7N9 influenza viruses appeared in China and other countries resulting in more than 1,500 individual infections or death. There are still limited studies on vaccines or drugs for humans against H7N9 influenza viruses. Alternative approaches against H7N9 virus infection need to be developed. Here, we identified two monoclonal antibodies (4H1E8 and 7H9A6) that possess neutralizing activity by blocking the pH-dependent HA-mediated membrane fusion. Additionally, the two monoclonal antibodies protect mice against the H7N9 virus challenge prophylactically or therapeutically. Therefore, our study demonstrates that 4H1E8 and 7H9A6 could be used for the prevention and treatment of the H7N9 influenza virus, and the conserved epitopes we identified may contribute to the development of a broad H7N9 vaccine and provide insights into unique antiviral approaches.

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