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1.
Virulence ; 12(1): 1754-1770, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34233588

RESUMO

In our previous study, a gut microbiota-targeted dietary intervention with a high-fiber diet improved the immune status of both genetically obese (Prader-Willi Syndrome, PWS) and simple obese (SO) children. However, PWS children had higher inflammation levels than SO children throughout the trial, the gut microbiota of the two cohorts was similar. As some virulence factors (VFs) produced by the gut microbiota play a role in triggering host inflammation, this study compared the characteristics and changes of gut microbial VF genes of the two cohorts before and after the intervention using a fecal metagenomic dataset. We found that in both cohorts, the high-fiber diet reduced the abundance of VF, and particularly pathogen-specific, genes. The composition of VF genes was also modulated, especially for offensive and defensive VF genes. Furthermore, genes belonging to invasion, T3SS (type III secretion system), and adherence classes were suppressed. Co-occurrence network analysis detected VF gene clusters closely related to host inflammation in each cohort. Though these cohort-specific clusters varied in VF gene combinations and cascade reactions affecting inflammation, they mainly contained VFs belonging to iron uptake, T3SS, and invasion classes. The PWS group had a lower abundance of VF genes before the trial, which suggested that other factors could also be responsible for the increased inflammation in this cohort. This study provides insight into the modulation of VF gene structure in the gut microbiota by a high-fiber diet, with respect to reduced inflammation in obese children, and differences in VF genes between these two cohorts.

2.
J Chem Phys ; 154(20): 204302, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34241172

RESUMO

A systematic structure and property investigation of MnGen - (n = 3-14) was conducted by means of density functional theory coupled with mass-selected anion photoelectron spectroscopy. This combined theoretical and experimental study allows global minimum and coexistence structures to be identified. It is found that the pentagonal bipyramid shape is the basic framework for the nascent growth process of MnGen - (n = 3-10), and from n = 10, the endohedral structures can be found. For n = 12, the anion MnGe12 - cluster probably includes two isomers: a major isomer with a puckered hexagonal prism geometry and a minor isomer with a distorted icosahedron geometry. Specifically, the puckered hexagonal prism isomer follows the Wade-Mingos rules and can be suggested as a new kind of superatom with the magnetic property. Furthermore, the results of adaptive natural density partitioning and deformation density analyses suggest a polar covalent interaction between Ge and Mn for endohedral clusters of MnGe12 -. The spin density and natural population analysis indicate that MnGen - clusters have high magnetic moments localized on Mn. The density of states diagram visually shows the significant spin polarization for endohedral structures and reveals the weak interaction between the Ge 4p orbital and the 4s, 3d orbitals of Mn.

3.
Cancer ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231883

RESUMO

BACKGROUND: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood. METHODS: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated. RESULTS: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; Pdifference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess. CONCLUSIONS: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.

5.
Acta Pharmacol Sin ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234269

RESUMO

Phage display technology allows for rapid selection of antibodies from the large repertoire of human antibody fragments displayed on phages. However, antibody fragments should be converted to IgG for biological characterizations and affinity of antibodies obtained from phage display library is frequently not sufficient for efficient use in clinical settings. Here, we describe a new approach that combines phage and mammalian cell display, enabling simultaneous affinity screening of full-length IgG antibodies. Using this strategy, we successfully obtained a novel germline-like anti-TIM-3 monoclonal antibody named m101, which was revealed to be a potent anti-TIM-3 therapeutic monoclonal antibody via in vitro and in vivo experiments, indicating its effectiveness and power. Thus, this platform can help develop new monoclonal antibody therapeutics with high affinity and low immunogenicity.

6.
Respir Res ; 22(1): 193, 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217286

RESUMO

BACKGROUND: Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. METHODS: PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. RESULTS: In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1ß. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. CONCLUSION: PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

7.
Clin Biochem ; 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256051

RESUMO

OBJECTIVE: By measuring serum insulin-like growth factor-1 (IGF-1) levels in children aged 2 - 16, we aimed to analyze the changes in IGF-1 levels in different sex and age groups, and compare the consistency of IGF-1 results evaluated by chronological age (CA) and bone age (BA) in children. METHODS: A cross-sectional study was conducted between January 2017 and December 2020 among 2979 relativelyhealthy children who attended the Department of Growth and Development outpatient clinic and health care center of the Affiliated Children's Hospitalof theCapitalInstituteof Pediatrics and underwent health examination and development assessment. Height, weight, and Tanner pubertal stage were measured by pediatricians. The CHN method was used to estimate BA. Venous blood samples were collected from the children, and IGF-1 levels were determined via chemiluminescence. RESULTS: IGF-1 levels in childhood increased slowly with age, dramatically during puberty,and continuously withgrowth until to 15 years for boys and reached a peak value at 13 years for girls based on CA. IGF-1 levels reached peak values at 14 and 13 years for boys and girls, respectively, based on BA. There were differences in IGF-1 values between the CA and BA groups at the age of 10-11 years for boys and 7-11 years for girls. A total of 103 boys (7.7%) and 17 girls (1.0%) had IGF-1 levels below the lower limit of the reference range based on CA; evaluating based on BA, there were 82 boys (6.1%) and 15 girls (0.9%) still had IGF-1 values less than the lower limit of the reference range. Eighteen boys (1.3%) and 173 girls (10.5%) had IGF-1 levels above the upper limit of the reference range based on CA; evaluating based on BA, these numbers reduced to 5 (0.4%) among boys and 41 (2.5%) among girls. CONCLUSIONS: There is a significant difference between BA and CA in evaluating IGF-1 levels in children, which can significantly reduce the proportion of IGF-1 values above the upper limit of the kit reference range in children. This suggests that children with BA advanced in pubertal period, the evaluating results of IGF-1 should be corrected by using BA.

8.
Chem Commun (Camb) ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34259255

RESUMO

An efficient annulation reaction of aurone-derived α,ß-unsaturated imines and activated terminal alkynes mediated by triethylamine is described, which enables the facile synthesis of 1,4-dihydrobenzofuro[3,2-b]pyridines in high yields. When the nucleophile of triethylamine was replaced with triphenylphosphine, another class of 1,4-dihydrobenzofuro[3,2-b]pyridines tethered with an additional acrylate motif were obtained instead. These two types of 1,4-dihydrobenzofuro[3,2-b]pyridines could be aromatized in the presence of DBU to afford benzofuro[3,2-b]pyridines, which could also be accessed via a one-pot procedure.

9.
Mol Cell Endocrinol ; : 111395, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34265344

RESUMO

Three major endothelial cell junctional adhesion molecules (VCAM1, ICAM1 and E-SELECTIN) play important roles in the process of angiogenesis, a progression of extensive physiological vascularization that occurs during the formation of the corpus luteum. Our previous studies demonstrated that TGF-ß1 is a negative regulator of luteinization and progesterone production in luteinized human granulosa (hGL) cells. Whether TGF-ß1 can regulate the expression of these endothelial cell adhesion molecules and subsequent angiogenesis in hGL cells remains to be elucidated. Using dual inhibition approaches (small molecular inhibitors and siRNA-based knockdown), we provided the first data showing that TGF-ß1 significantly upregulates the expression of the SNAIL transcription factor, which in turn suppresses the expression of VCAM1 and ICAM1 in hGL cells. Additionally, we demonstrate that the suppressive effects on the expression of VCAM1 and ICAM1 induced by TGF-ß1 treatment were most likely via an ALK5-mediated SMAD-dependent signaling pathway. Furthermore, functional studies showed that hGL cells cultured on Matrigel exhibited two typical endothelial cell phenotypes, microvascular-like formation and a sprouting microvascular pattern. Notably, these phenotypes were significantly suppressed by either TGF-ß1 treatment or knockdown of VCAM1 and ICAM1. Our findings suggest that TGF-ß1 plays a potential role in the inhibition of granulosa cell angiogenesis by downregulating the expression of VCAM1 and ICAM1 during follicular development and corpus luteum formation.

10.
Plant J ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34252236

RESUMO

Maize is an important crop worldwide, as well as a valuable model with vast genetic diversity. Accurate genome and annotation information for a wide range of inbred lines would provide valuable resources for crop improvement and pan-genome characterization. In this study, we generated a high-quality de novo genome assembly (contig N50 of 15.43 megabases) of the Chinese elite inbred line RP125 using Nanopore long-read sequencing and Hi-C scaffolding, which yield highly contiguous, chromosome-length scaffolds. Global comparison of the RP125 genome with those of B73, W22, and Mo17 revealed a large number of structural variations. To create new germplasm for maize research and crop improvement, we carried out an EMS mutagenesis screen on RP125. We obtained a total of 5,818 independent M2 families, with 946 mutants showing heritable phenotypes. Taking advantage of the high-quality RP125 genome, we successfully cloned 10 mutants from the EMS library, including the novel kernel mutant qk1 (quekou: 'missing a small part' in Chinese), which exhibited partial loss of endosperm and a starch accumulation defect. QK1 encodes a predicted metal tolerance protein that is specifically required for iron transport. Increased accumulation of iron and ROS as well as ferroptosis-like cell death were detected in endosperm of qk1. Our study provides the community with a high-quality genome sequence and a large collection of mutant germplasm.

11.
Dalton Trans ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34254079

RESUMO

This study focuses on uncovering the regioselectivity, directing group, ligand, and solvation effect in B-H activation, which was investigated by DFT calculations. The reaction mechanism was investigated in vacuum, and the advantageous reaction pathway and rate-determining step were determined. Furthermore, the solvation effects and the ligand that coordinated with Pd were studied. The results showed that in neutral and cationic pathways, the anion (OTf)/ligand (1,10-phenanthroline) exerted significant influence on the transition metal catalytic center Pd, thus affecting B-H activation at different sites. The solvation effects also exerted significant influence on the reaction. The greater the polarity of the solvent, the greater the influence on the energies of all stationary points.

12.
Drug Deliv ; 28(1): 1419-1431, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34223777

RESUMO

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

13.
Medicine (Baltimore) ; 100(27): e26401, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232172

RESUMO

BACKGROUND: Nonpharmacological intervention can improve the sleep quality of hemodialysis patients. However, there are many types of nonpharmacological interventions, which makes it difficult to determine the best one. Therefore, this study carried out network meta-analysis to evaluate the effects of nonpharmacological intervention on sleep quality of hemodialysis patients, so as to provide evidence for the selection of the optimal nonpharmacological intervention for the improvement of sleep quality of hemodialysis patients clinically. METHODS: Randomized controlled trials on the effects of nonpharmaceutical interventions on sleep quality in hemodialysis patients were conducted by searching English databases (PubMed, Cochrane Library, EMBASE, and Web of Science) and Chinese databases (Chinese Scientific Journal Database, China National Knowledge Infrastructure Database, Wanfang, and China Biomedical Literature Database) on computer. The retrieval time was from the establishment of the database to May 2021. Literature screening, data extraction, and evaluation of the risk of bias in the included studies were conducted independently by two researchers. Data analysis was performed with STATA14.0 and GEMTC 0.14.3 software. RESULTS: We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals. CONCLUSIONS: This study will provide the best evidence-based evidence to support the effects of non-pharmacological interventions on sleep quality in hemodialysis patients. ETHICS AND DISSEMINATION: Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/4BPKT.


Assuntos
Transtornos Mentais/terapia , Modalidades de Fisioterapia , Qualidade de Vida , Sono/fisiologia , Humanos , Transtornos Mentais/fisiopatologia
14.
Medicine (Baltimore) ; 100(27): e26418, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232174

RESUMO

BACKGROUND: Previous studies have demonstrated that Helicobacter pylori is a critical factor in the development of gastrointestinal diseases. However, only limited studies have reported results on the relationship between H pylori infection and patients with type 2 diabetes mellitus (T2DM). Moreover, the conclusions from these past studies are variable. Because there are contradictory results on this issue, the present study aims to examine the clinical therapeutic impacts of H pylori eradication to treat patients experiencing T2DM. METHODS: The present protocol is drafted according to the provisions of the Preferred Reporting Items for Systematic Review and Meta-analyses Protocols guidelines. PubMed, Cochrane Central Register of Controlled Trials databases, EMBASE, Web of Science, China National Knowledge Infrastructure, and Chinese BioMedical Literature Database will be searched up to May 2021 to obtain randomized controlled trials evaluating the clinical therapeutic effects of H pylori eradication to treat patients experiencing T2DM. We will use 2 investigators independently to carry out study selection, data extraction, and employ the Cochrane Collaboration criteria to evaluate their risks of bias. Furthermore, we will apply Stata 16.0 software to perform data analysis. RESULTS: We intend to evaluate the clinical therapeutic impacts of H pylori eradication to treat patients suffering from T2DM. CONCLUSIONS: Our findings may support existing evidence on the clinical therapeutic impacts of H pylori eradication to treat patients with T2DM. ETHICS AND DISSEMINATION: Since all data will be extracted from the published literature, the study does not require an ethical approval. OSF REGISTRATION NUMBER: May 31, 2021.osf.io/qtexu. (https://osf.io/qtexu/).


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Diabetes Mellitus Tipo 2/complicações , Infecções por Helicobacter/complicações , Humanos
15.
Am J Transplant ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212503

RESUMO

Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.

16.
Chemosphere ; 285: 131525, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34265703

RESUMO

Arsenic (As) is a problematic pollutant that can cause cancer and other chronic diseases due to its potential toxicity. Iron (oxyhydr)oxides can readily sorb As and play important roles in the geochemical cycle of As. Attention has mainly been given to the affinity and mechanism of As sorption by synthetic pure iron (oxyhydr)oxides, and little is known about the relationship between As behavior and multicomponent secondary iron minerals (SIMs) naturally formed in acid mine drainage (AMD). To investigate this relationship, we performed sorption kinetics, isotherm and competitive sorption experiments to investigate As(V) sorption behaviors on naturally formed SIMs harvested from different runoff zones of an abandoned coal mine. Several spectroscopic analyses were used to evaluate the structural and component changes and phase transformation. Three environmental SIMs formed at nascent (n-SIM), transient (t-SIM) and mature (m-SIM) stages were determined to be similar in the element components of Fe, S and O but different in structure. As(V) sorption behaviors on these environmental SIMs followed a pseudo-second-order kinetic model, and the sorption extent followed the sequence of n-SIM > t-SIM > m-SIM. As(V) sorption is not significantly influenced by Na+/Ca2+ concentration or ionic strength except for that of PO43-, and it slightly decreases as the Cr(Ⅲ) concentration increases but increases with increasing Sb(Ⅲ)/(V) concentration. The results of spectral analyses indicate that As(V) immobilization mainly depends on exchange with SO42- and surface complexation, along with the phase transformation of schwertmannite/jarosite to goethite and other phases. These findings are helpful for better understanding the geochemical behaviors of As(V) associated with environmental SIMs.

17.
Int J Food Microbiol ; : 109329, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34275638

RESUMO

Alicyclobacillus species are one of the most significant qualities and safety factors in fruit juice and beverages. The growth of some Alicyclobacillus genus can lead to sour spoilage with the off-odor of medicinal, phenolic or antiseptic, which is mainly caused by the metabolites of guaiacol, dihalophenol and dibromophenol. Especially, guaiacol is regarded as the predominant taint in Alicyclobacillus-spoiled products. In this study, quantitative PCR (qPCR) assays were proposed for the detection of A. acidoterrestris, A. acidiphilus, A. cycloheptanicus and A. herbarius that can produce guaiacol in fruit juice. The 16S rDNA sequences of these four kinds of Alicyclobacillus species were identified and the primers suitable for the qPCR assay were obtained. The sensitivity and specificity of the established methods were evaluated. The results indicated that the developed qPCR approaches were distinctive enough to detect A. acidoterrestris, A. acidiphilus, A. cycloheptanicus and A. herbarius with the sensitivity of 2.6 × 102 CFU/mL, 74 CFU/mL, 2.8 × 102 CFU/mL and 3.1 × 102 CFU/mL, respectively. The correlation coefficients of standard curves were from 0.9807 to 0.9985. Based on the pretreatment of filtration-culture, these bacteria with the initial concentration of 10-1 CFU/mL, 100 CFU/mL and 101 CFU/mL can be effectively detected in 2-20 h, which depended on the target bacteria and their initial concentration. The results displayed that the proposed procedures were effective for the rapid detection of Alicyclobacillus species that can produce guaiacol in apple juice.

18.
Small ; : e2102248, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34278719

RESUMO

Hard carbons are actively developed as a promising anode material for sodium ion batteries (SIBs). However, their sodium storage mechanism is poorly understood, leading to difficulties in design and development of high-performance hard carbon anode materials. In this work, hollow carbon spheres (HCSs) with different shell thickness as a model material to investigate the correlation between the microstructural change and resulting Na+ storage behavior during charge/discharge cycles are designed and synthesized. Ex situ X-ray diffraction and Raman evidences reveal that an interlayer spacing change of the graphitic nanodomains occurs in HCS electrode, leading to a shift of the reversible capacity from the high-potential sloping (HPS) region to the low-potential plateau (LPP) region. This unusual capacity shift suggests a microstructure-dependent Na+ storage reaction on the HCS electrode and can be well explained by "adsorption-intercalation" mechanism for these HCS materials. This work strengthens the understanding of the sodium storage behavior and provides a new perspective for the morphological and structural design of hard carbon anode materials for high-performance SIBs.

19.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199417

RESUMO

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/citologia , Antígeno B7-H1/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Interferon gama/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Cultura Primária de Células , Receptor de Morte Celular Programada 1/química , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
20.
Medicine (Baltimore) ; 100(27): e26610, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232216

RESUMO

RATIONALE: Transjugular intrahepatic portosystemic shunt (TIPS) is well established as an effective treatment tool for portal hypertension. However, the effects of TIPS in patients with liver cirrhosis and portal hypertension have not been adequately verified in clinical trials. PATIENT CONCERNS: To evaluate the effects of TIPS in patients with liver cirrhosis and portal hypertension with or without portal vein thrombosis (PVT). INTERVENTIONS: A total of 55 patients with liver cirrhosis and portal hypertension received TIPS treatment from December 2014 to April 2018 were enrolled. Clinical data, including portal pressure, Child-Pugh score, and relevant complications were recorded. OUTCOMES: TIPS was successfully performed in 54 patients. The overall technical success rate was 98.19% without serious technical complications. After TIPS treatment, portal pressure was significantly reduced from 38.13 ±â€Š4.00 cmH2O to 24.14 ±â€Š3.84 cmH2O (P < 0.05). In addition, symptoms including gastrointestinal bleeding and ascites were improved after TIPS treatment. During the 6 to 21-month follow up, hepatic encephalopathy in 15 patients (27.8%), shunt dysfunction in 5 patients (9.3%), rebleeding in 12 patients (22.2%) and deterioration of liver function in 2 patients (3.7%) were recorded. Moreover, there were no significant differences in the rates of rebleeding and hepatic encephalopathy between patients with PVT and the non-PVT group, whereas the occurrence rate of TIPS dysfunction was higher in the PVT group. LESSONS: TIPS treatment could alleviate the symptoms of liver cirrhosis and portal hypertension in individuals with or without PVT. However, complications during follow-up should be appropriately noted and addressed with corresponding treatments.


Assuntos
Hipertensão Portal/cirurgia , Cirrose Hepática/complicações , Pressão na Veia Porta/fisiologia , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
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