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1.
FASEB J ; 36(1): e22073, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34847253

RESUMO

Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) are important immune checkpoint receptors that prevent an overreacted maternal immune response to fetal antigens during pregnancy. Disruption of complex immune regulation mechanisms is associated with adverse pregnancy outcomes, including preeclampsia (PE). Our recent study showed that the Tim-3 pathway was involved in the regulation of decidual macrophage polarization. Decidual macrophages polarized to the M1 phenotype may impair uterine vessel remodeling during placentation, accounting for the occurrence of PE. Co-blockade of the PD-1/Tim-3 pathway was shown to successfully control tumor growth in preclinical cancer models. However, the effects of activating both PD-1 and Tim-3 pathways as a combined intervention strategy in PE are never reported. Herein, we observed the skew of decidual macrophage polarization toward the M1 phenotype in patients with PE and lipopolysaccharide (LPS)-induced PE-like rat model. Moreover, we found that the activation of PD-1/Tim-3 pathway by using PD-L1 and Gal-9 fusion proteins could alleviate the manifestation of the LPS-induced PE-like rats and protect their offspring. Compared with the single intervention, the combination of PD-L1and Gal-9 fusion proteins exhibited obvious advantages in the relief of PE-like symptoms, trophoblast invasion, and fetal vascular development, indicating a synergistic effect of the activated PD-1/Tim-3 pathway. The in vitro study also revealed that the combined intervention using PD-L1 and Gal-9 fusion proteins inhibited the LPS-induced M1 macrophage polarization via the synergic activation of the ERK/GSK3ß/ß-catenin signaling pathway. Together, our findings provide the first evidence that simultaneous activation of PD-1/Tim-3 signaling pathways may have an optimal protective effect and serve as a new potential target for PE intervention.

2.
Food Chem ; 372: 131255, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34627084

RESUMO

Tibet's native fruit resources have not been explored and remain underutilized due to geographical isolation. "Medog lemon" (ML), an ethno-species of wild citron, is an important functional food and dietary resource for the local people in southeastern Tibet. Herein comprehensive characterization of components of ML were firstly performed with an integrated strategy based on UHPLC-QE Orbitrap MS. A total of 196 components were characterized, among which 33 were detected from Citrus genus for the first time, and 55 were identified as potential new phytochemicals. The chemical comparison of ML with cultivated citron and fingered citron based on partial least squares-discriminant analysis model and univariate analysis revealed the distinct chemical composition of ML and in which more than 30 differentiated components were identified. The distinct morphological and chemical characters, as well as its good antioxidant properties, indicated ML as a potential new food resource that can be beneficial for human health.


Assuntos
Citrus , Frutas , China , Frutas/química , Humanos , Compostos Fitoquímicos , Extratos Vegetais/análise , Tibet
3.
Pharm Biol ; 60(1): 38-45, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34860639

RESUMO

CONTEXT: Ferroptosis was described as an important contributor to the myocardial ischaemia/reperfusion (MIR) injury, and britanin (Bri) was reported to exert antitumor and anti-inflammatory activities. OBJECTIVE: Our study explores the effect and mechanism of Bri on MIR damage. MATERIALS AND METHODS: The rat model of MIR was established by ligation of the left anterior descending coronary artery. Male Sprague-Dawley (SD) rats were divided into three groups: sham group (n = 6), MIR group (n = 6) and MIR + Bri group (n = 6; 50 mg/kg). Rats were intragastrically pre-treated with Bri or normal saline once daily for 3 days. To further verify the role and mechanism of Bri, H9C2 cells were subjected to hypoxia plus reoxygenation (H/R) to induce the in vitro model of MIR. RESULTS: Compared with MIR rats, Bri significantly decreased infarct area (22.50% vs. 38.67%), myocardial apoptosis (23.00% vs. 41.5%), creatine phosphokinase (0.57 U/mL vs. 0.76 U/mL), and lactate dehydrogenase levels (3.18 U/mL vs. 5.17 U/mL), concomitant with alleviation of ferroptosis. Mechanistically, Bri treatment induced the activation of the adenosine monophosphate activated protein kinase (AMPK)/glycogen synthase kinase 3ß (GSK3ß)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in vivo. In addition, the AMPK/GSK3ß/Nrf2 pathway participated in the regulation of glutathione peroxidase 4 (GPX4) expression, and silencing of Nrf2 attenuated the effect of Bri on H/R-induced cell injury. DISCUSSION AND CONCLUSIONS: Bri protected against ferroptosis-mediated MIR damage by upregulating GPX4 through activation of the AMPK/GSK3ß/Nrf2 signalling, suggesting that Bri might become a novel therapeutic agent for MIR.

4.
J Hazard Mater ; 423(Pt A): 127062, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482080

RESUMO

Polyethylene film is the most widely used plastic film in agricultural production activities, and its depolymerization products are mainly polyethylene-particles (PE-particles) of different molecular weights. However, the impact of the molecular weights of the PE-particles on soil-crop microenvironment has not been elucidated. In this study, a potted microcosmic simulation system was used to evaluate the impact of low, medium and high molecular weight PE-particles on soil metabolism, microbial community structure, and crop growth. There were obvious differences in the shape and surface microstructure of PE-particles with different molecular weights. Soil sucrase and peroxidase had significant responses to PE-particles of different molecular weights. In the rhizosphere, the number of microorganisms and the microbial alpha diversity index increased with increasing PE-particles molecular weight. Rhizobacter, Nitrospira, and Sphingomonas were the dominant microorganisms induced by PE-particles to regulate the metabolism of elements. Carbohydrate and amino acid contents in rhizosphere soils were the key factors affecting the species abundance of Lysobacter, Polyclovorans, Rhizobacter, and Sphingomonas. In plants, PE-particles treatment reduced the plant biomass and photosynthetic rate and disrupted normal mineral nutrient metabolism. Different molecular weight PE-particles may therefore have adverse effects on the soil-plant system.

5.
Food Chem ; 368: 130902, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34438176

RESUMO

Overcoming harsh gastric environment is still a challenging to bioactive proteins, microencapsulation provides one strategy in designing this protection barrier. In this work, bovine serum albumin and ovalbumin were chosen as model proteins, while polylysine-alginate complex was fabricated for microencapsulation purpose. Both of the protein-loaded microcapsules had regular internal microstructures. The model protein's embedding increased the thermal stability of the microcapsules. Both of the protein-loaded microcapsules had a slow release rate in simulated gastric fluids (pH 3.0), while a sustained release profile in simulated intestinal fluids (pH 6.4), indicating an excellent tolerance to the acidic gastric environment. The microencapsulation process was mild and had no influence on the protein's molecular weight, while a slight peak shifting occurred in the secondary structure of the released proteins. The developed microcapsules could be explored as a kind of vehicle for bioactive proteins applied in functional foods, health care products and medical formulations.


Assuntos
Polilisina , Soroalbumina Bovina , Alginatos , Cápsulas , Ovalbumina
6.
J Hazard Mater ; 422: 126869, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34399216

RESUMO

In this paper, photocatalysts based on TiO2 nanotubes (TNTs) and TiO2 nanotube arrays (TNTAs) sensitized by Cu(II) meso-tetrakis(N-ethylpyridinium-4-yl) porphyrin (CuTEPyP) were synthesized and their structures were characterized by various analytical methods. The photocatalytic activities of both composites were then investigated through degradation of 4-nitrophenol (4-NP) in aqueous solutions under visible light irradiation. It was found that CuTEPyP/TNTAs could eliminate 95% 4-NP within 4 h, which was considerably higher than the yield obtained with CuTEPyP/TNTs (56%) under the same conditions. Compared to CuTEPyP/TNTs, the improved photocatalytic activity of CuTEPyP/TNTAs can be ascribed to increased light absorption, high separation rate of photo-generated charge pairs, and efficient charge transfer. A plausible photocatalytic degradation mechanism involving hydroxyl radicals, superoxide radical anions and singlet oxygen species was also proposed. This work presents an efficient paradigm for eliminating 4-NP under visible light irradiation.

7.
PLoS Genet ; 17(12): e1009947, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34860835

RESUMO

Efferocytosis is the process by which phagocytes recognize, engulf, and digest (or clear) apoptotic cells during development. Impaired efferocytosis is associated with developmental defects and autoimmune diseases. In Drosophila melanogaster, recognition of apoptotic cells requires phagocyte surface receptors, including the scavenger receptor CD36-related protein, Croquemort (Crq, encoded by crq). In fact, Crq expression is upregulated in the presence of apoptotic cells, as well as in response to excessive apoptosis. Here, we identified a novel gene bfc (booster for croquemort), which plays a role in efferocytosis, specifically the regulation of the crq expression. We found that Bfc protein interacts with the zinc finger domain of the GATA transcription factor Serpent (Srp), to enhance its direct binding to the crq promoter; thus, they function together in regulating crq expression and efferocytosis. Overall, we show that Bfc serves as a Srp co-factor to upregulate the transcription of the crq encoded receptor, and consequently boosts macrophage efferocytosis in response to excessive apoptosis. Therefore, this study clarifies how phagocytes integrate apoptotic cell signals to mediate efferocytosis.

8.
Int J Ophthalmol ; 14(11): 1674-1682, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804856

RESUMO

AIM: To explore the regulatory mechanism of nuclear paraspeckle assembly transcript 1 (NEAT1) in the pathogenesis of posterior capsule opacification (PCO). METHODS: Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was executed to analyze NEAT1 and microRNA (miR)-26a-5p expression in transforming growth factor-beta 2 (TGF-ß2)-disposed lens epithelial cells (LECs). The proliferation, cell cycle progression, apoptosis, and migration of TGF-ß2-disposed LECs were evaluated. The relationship between NEAT1 or fanconi anemia (FA) complementation group E (FANCE) and miR-26a-5p was verified by dual-luciferase reporter assay. RESULTS: TGF-ß2 induced NEAT1 expression in LECs. NEAT1 inhibition accelerated apoptosis, cell cycle arrest, decreased proliferation, epithelial-mesenchymal transition (EMT), and migration of TGF-ß2-disposed LECs. NEAT1 sponged miR-26a-5p to further regulate FANCE expression. Rescue experiments presented that miR-26a-5p downregulation overturned NEAT1 silencing-mediated impacts on TGF-ß2-disposed LEC biological behaviors. Additionally, FANCE overexpression reversed miR-26a-5p mimic-mediated impacts on TGF-ß2-disposed LEC biological behaviors. CONCLUSION: TGF-ß2-induced NEAT1 facilitates LEC proliferation, migration, and EMT by upregulating FANCE via sequestering miR-26a-5p.

9.
Front Med (Lausanne) ; 8: 772578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805232

RESUMO

Background: The purpose of this study was to analyze the ocular biometric parameters of primary angle-closure disease (PACD) in younger patients and compare them with those of elderly patients. Methods: This clinic-based, cross-sectional study included 154 eyes of 154 patients with PACD, consisting of 77 eyes of patients aged 40 years or younger and 77 eyes of patients older than 40. The PACD case definition was compatible with the ISGEO definition. Anterior segment parameters were measured by ultrasound biomicroscopy, axial length (AL) and lens thickness (LT) were measured by A-scan ultrasonography measurements, and the thickness of the retina and choroid were measured by optical coherence tomography. The differences in ocular biometric parameters between different age groups were compared by independent sample t-tests or Mann-Whitney U tests, and the correlation between the parameters and age was analyzed. Results: Compared to older PACD patients, the lens vault(LV),LV/LT and subfoveal choroidal thickness (SFCT) of younger patients were larger, while the peripheral and mean iris thickness (IT), trabecular-ciliary angle (TCA), ciliary body thickness (CBT), AL and LT were smaller (all P < 0.01). There was no significant difference in anterior chamber depth, anterior chamber width, pupil diameter, angle opening distance at 500 µm from the scleral spur, anterior chamber angle and iris convexity between the two groups (all P > 0.05). AL, LT, IT, TCA and CBT were positively associated with age (all P < 0.001), while LV and SFCT were negatively associated with age (P = 0.027 and P < 0.001, respectively). Conclusions: Compared with elderly patients, younger PACD patients had more anteriorly positioned lenses, thinner and more anteriorly rotated ciliary bodies, thicker choroids, and shorter axial length. These characteristics might be important anatomical bases for the earlier onset of PACD and the higher risk of malignant glaucoma after filtering surgery.

10.
Proc Natl Acad Sci U S A ; 118(48)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34810257

RESUMO

Kinetochores, a protein complex assembled on centromeres, mediate chromosome segregation. In most eukaryotes, centromeres are epigenetically specified by the histone H3 variant CENP-A. CENP-T, an inner kinetochore protein, serves as a platform for the assembly of the outer kinetochore Ndc80 complex during mitosis. How CENP-T is regulated through the cell cycle remains unclear. Ccp1 (counteracter of CENP-A loading protein 1) associates with centromeres during interphase but delocalizes from centromeres during mitosis. Here, we demonstrated that Ccp1 directly interacts with CENP-T. CENP-T is important for the association of Ccp1 with centromeres, whereas CENP-T centromeric localization depends on Mis16, a homolog of human RbAp48/46. We identified a Ccp1-interaction motif (CIM) at the N terminus of CENP-T, which is adjacent to the Ndc80 receptor motif. The CIM domain is required for Ccp1 centromeric localization, and the CIM domain-deleted mutant phenocopies ccp1Δ. The CIM domain can be phosphorylated by CDK1 (cyclin-dependent kinase 1). Phosphorylation of CIM weakens its interaction with Ccp1. Consistent with this, Ccp1 dissociates from centromeres through all stages of the cell cycle in the phosphomimetic mutant of the CIM domain, whereas in the phospho-null mutant of the domain, Ccp1 associates with centromeres during mitosis. We further show that the phospho-null mutant disrupts the positioning of the Ndc80 complex during mitosis, resulting in chromosome missegregation. This work suggests that competitive exclusion between Ccp1 and Ndc80 at the N terminus of CENP-T via phosphorylation ensures precise kinetochore assembly during mitosis and uncovers a previously unrecognized mechanism underlying kinetochore assembly through the cell cycle.

11.
J Hazard Mater ; : 127718, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34815127

RESUMO

Elucidation of the phytotoxic mechanisms of thorium (Th) is important for controlling Th accumulation in crops and improving the efficiency of phytoremediation. Here, we analyzed the subcellular distribution of Th in Vicia faba seedlings and the toxic reaction of seedlings to Th (5-40 µmol·L-1) at the subcellular and cellular levels. Increasing the phosphate level in the culture medium from 0.01 to 0.1 mmol·L-1 decreased the Th accumulation by the roots by 47-57%. Th was mainly distributed in the root cell walls (94-96%) and existed mainly in the form of residue (92-94%). Th accumulation in the root was similar to the changes observed for P, Ni, Cu, and Fe. High concentrations of Th (40 µmol·L-1) induced abnormal root growth and leaf photosynthetic metabolism. At the cellular level, Th (40 µmol·L-1) induced root edge cell death and inhibited root respiration and cell mitosis. SOD, POD and CAT activities were involved in the regulation of reactive oxygen species accumulation in the roots. Untargeted metabolomics identified 580 and 262 differentially expressed metabolites in roots and leaves. At the metabolic level, its toxicological mechanism involved a severe inhibition of the expression of nucleotides in roots and leaves.

12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(6): 992-1000, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34841767

RESUMO

Objective: To analyze the impact of the social environment of a community on the self-rated health of middle-aged and older adults living in the community, and to provide a basis for building favorable community social environment that promotes the health of middle-aged and older adults. Methods: Using the community and individual survey data from China Health and Retirement Longitudinal Study (CHARLS) done in 2011, 7822 middle-aged and older adults living in 397 communities were selected as the subjects of the study. Community social environment under study included community socioeconomic status, community social security and community services. Self-rated health was measured with a five-level score. A three-level hierarchical generalized linear model (HGLM) was used to analyze the impact of community social environment on the self-rated health of middle-aged and older adults. Results: The proportion of subjects who reported self-rated poor health was 28.8%. According to the results of the three-level HGLM, the self-rated health of middle-aged and older adults showed differences at both the city and the community levels, and the variance reduction ratio reached 35.71% at the community level. The self-rated health status of residents in the communities with medium and high net per capita income was better than that in the communities with low net per capita income ( OR=0.84, P<0.05; OR=0.70, P<0.05). The self-rated health status of residents in the communities with secondary and higher education levels was better than that in the communities with low education level ( OR=0.78, P<0.05; OR=0.73, P<0.05). The self-rated health of middle-aged and older adults in the communities with unemployment subsidies was much better ( OR=0.77, P<0.05). The self-rated health status of middle-aged and older adults with chronic diseases was worse ( OR=4.46, P<0.05). Middle-aged and older adults living in cities had better self-rated health status ( OR=0.67, P<0.05). Conclusion: Community socioeconomic status and community unemployment subsidy are positively correlated with the self-rated health of middle-aged and older adults living in the community. It is necessary to pay special attention to the health status of middle-aged and older adults in communities of low socioeconomic status, improve unemployment insurance policies, and promote the health of middle-aged and older adults.


Assuntos
Nível de Saúde , Meio Social , Idoso , Correlação de Dados , Humanos , Renda , Estudos Longitudinais , Pessoa de Meia-Idade
13.
Zhongguo Gu Shang ; 34(11): 1044-52, 2021 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-34812023

RESUMO

OBJECTIVE: To explore the efficacy of Yishen Huoxue Tongluo() decoction containing serum on the apoptosis of human disc nucleus pulposus cells under the overload static pressure stress and its related mechanism. METHODS: Human nucleus pulposus cells were divided into three groups. The blank group had no intervention. The model group and traditional Chinese medicine serum intervention group were treated with 3 MPa compressive stress in vitro for 2, 4 and 6 hours. The changes and differences of morphology, growth status and ultrastructure of intervertebral disc nucleus pulposus cells were observed. The apoptosis rate of nucleus pulposus cells and nuclear factor kappa-B p65 (NF-κB p65), SRY-related high mobility group box 9 (SOX9), C/EBP-homologous protein (CHOP), matrix metalloprotein-13 (MMP-13) and corresponding gene expression were detected. RESULTS: At the same time, compared with the blank group, the nucleus pulposus cells in the model group were smaller in volume, less in cytoplasm and worse in growth; the nucleus pulposus cells in the traditional Chinese medicine serum intervention group were slightly larger in volume, more complete in morphology, richer in cytoplasm and better in growth. Under the same action time, the ultrastructure of nucleus pulposus cells in blank group was complete, and the structures of primary and secondary processes were not broken;and the ultrastructure of model group and traditional Chinese medicine serum intervention group were damaged, the main and secondary processes were broken to varying degrees, and there was no significant difference between the two groups. At the same time, the apoptosis rate of nucleus pulposus cells in model group was higher than that in blank group, while the apoptosis rate of nucleus pulposus cells in the traditional Chinese medicine serum intervention group was lower than that inmodel group, the difference was statistically significant (P<0.05); with the increase of action time, there was no significant difference in the apoptosis rate of nucleus pulposus cells between blank group and traditional Chinese medicine serum intervention group, and the apoptosis rate of nucleus pulposus cells in model group was increased. Compared with model group, the expression of NF-κB p65, CHOP, MMP-13 were decreased and SOX9 was increased in traditional Chinese medicine serum intervention group at the same time (P<0.05);with the increase of action time, the expression of NF-κB p65, CHOP and MMP-13 were increased, and the expression of SOX9 was decreased in blank group and model group(P<0.05), and the expression level of model group was higher than that of blank group(P<0.05). Overall observation by gene expression, under the same action time, the relative quantifications of NF-κB p65, CHOP and MMP-13 in traditional Chinese medicine serum intervention group were lower than that in model group, while SOX9 was increased (P<0.05);compared with model group, the relative quantifications of NF-κB p65, CHOP and MMP-13 in blank group were decreased(P<0.05), and the relative quantification of SOX9 was increased(P<0.05);with the increase of action time, the relative quantifications of NF-κB p65, CHOP and MMP-13 of nucleus pulposus cells in blank group and model group were increased and SOX9 was decreased(P<0.05). CONCLUSION: Yishen Huoxue Tongluo() decoction can reduce the apoptosis of nucleus pulposus cells under overload and static pressure, and has the effect of delaying the degeneration of nucleus pulposus cells. Its mechanism may be related to the decrease of CHOP, MMP-13 expression and the increase of SOX9 expression by inhibiting NF-κB p65 signal pathway of nucleus pulposus cells.


Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Apoptose , Medicamentos de Ervas Chinesas , Humanos
14.
Curr Neurovasc Res ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758715

RESUMO

OBJECTIVE: To determine whether the administration of intravenous alteplase would be beneficial or futile to patients with acute ischemic stroke caused by large vessel occlusion (LVO) before endovascular treatment (EVT), we conducted this study to determine the relationship between Hounsfield units (HU) in non-contrast computed tomography (NCCT) and recanalization by alteplase. METHODS: We performed a retrospective analysis of patients with acute ischemic stroke caused by LVO received intravenous thrombolysis (IVT) or followed by EVT at our center during November 2016 and October 2020. The clinical characteristics and imaging features of patients who achieved recanalization after IVT, and those who did not, were compared. RESULTS: Forty-three eligible patients were enrolled; 12 achieved recanalization by IVT. Baseline clinical characteristics did not differ between patients of the recanalization and non-recanalization groups. HU in the NCCT were estimated and statistically significant maximum and mean values of the ipsilateral middle cerebral artery (MCA) were found between the groups (P< 0.05). The results hint that patients in the non-recanalization group have a higher rHU and δHU value of the ipsilateral MCA compared with recanalization group (P< 0.05). With regards the receiver operator characteristic (ROC) curve, we demonstrated that a high HU value of the ipsilateral MCA could be a predictor for non-recanalization by IVT. CONCLUSION: Patients suffering LVO stroke are less likely to obtain recanalization by IVT with a high HU value of the ipsilateral MCA. It is feasible to screen patients with LVO using HU for direct EVT.

16.
Br J Haematol ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741461

RESUMO

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

17.
Anal Biochem ; 637: 114472, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34801481

RESUMO

Polysorbates (PSs) are surfactants commonly added to therapeutic protein drug product formulations to protect proteins from denaturation and aggregation during storage, transportation, and delivery. However, enzymatic hydrolysis of PSs has been recognized as the primary route of PS degradation in monoclonal antibody formulations, resulting in the release of free fatty acids that drive undesired particulate formation. Here, we present a rapid lipase activity assay with optimized incubation conditions for accurate quantitation of free fatty acids without a fatty acid extraction step. This assay can detect low levels of PS degradation (0.000024% PS20 degradation) within 1 day with minimal sample preparation. The levels of released free fatty acids were found to strongly correlate with the degree of PS20 degradation. The case study described herein suggests that this approach can detect low levels of PS20 degradation caused by sub-ppm lipase levels within 1 day, compared with the duration of 14 days needed for PS degradation assays based on two-dimensional liquid chromatography-charge aerosol detection.

18.
Biomedicines ; 9(11)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34829869

RESUMO

The network module-based method has been used for drug repositioning. The traditional drug repositioning method only uses the gene characteristics of the drug but ignores the drug-triggered metabolic changes. The metabolic network systematically characterizes the connection between genes, proteins, and metabolic reactions. The differential metabolic flux distribution, as drug metabolism characteristics, was employed to cluster the agents with similar MoAs (mechanism of action). In this study, agents with the same pharmacology were clustered into one group, and a total of 1309 agents from the CMap database were clustered into 98 groups based on differential metabolic flux distribution. Transcription factor (TF) enrichment analysis revealed the agents in the same group (such as group 7 and group 26) were confirmed to have similar MoAs. Through this agent clustering strategy, the candidate drugs which can inhibit (Japanese encephalitis virus) JEV infection were identified. This study provides new insights into drug repositioning and their MoAs.

19.
Insects ; 12(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34821783

RESUMO

Insect galls are the abnormal growth of plant tissues induced by a wide variety of galling insects and characterized by high concentrations of auxins and cytokinins. It remains unclear whether the auxins and cytokinins affect the bacterial community structure of insect galls. We determined the concentrations of indoleacetic acid (IAA) as an example of auxin, trans-zeatin riboside (tZR) and isopentenyladenine (iP) as cytokinins in Lithosaphonecrus arcoverticus (Hymenoptera: Cynipidae) galls and the galled twigs of Lithocarpus glaber (Fagaceae) using liquid chromatography-tandem mass spectrometry. Moreover, for the first time, we compared the bacterial community structure of L. arcoverticus galls and galled twigs by high-throughput sequencing, and calculated the Spearman correlation and associated degree of significance between the IAA, tZR and iP concentrations and the bacterial community structure. Our results indicated the concentrations of IAA, tZR and iP were higher in L. arcoverticus galls than in galled twigs, and positively correlated with the bacterial community structure of L. arcoverticus galls. We suggest the high concentrations of IAA, tZR and iP may affect the bacterial community structure of L. arcoverticus galls.

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