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1.
Front Immunol ; 12: 746017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621277

RESUMO

Vibrio species are ubiquitously distributed in marine environments, with important implications for emerging infectious diseases. However, relatively little is known about defensive strategies deployed by hosts against Vibrio pathogens of distinct virulence traits. Being an ecologically relevant host, the oyster Crassostrea hongkongensis can serve as an excellent model for elucidating mechanisms underlying host-Vibrio interactions. We generated a Vibrio alginolyticus mutant strain (V. alginolyticus △ vscC ) with attenuated virulence by knocking out the vscC encoding gene, a core component of type III secretion system (T3SS), which led to starkly reduced apoptotic rates in hemocyte hosts compared to the V. alginolyticus WT control. In comparative proteomics, it was revealed that distinct immune responses arose upon encounter with V. alginolyticus strains of different virulence. Quite strikingly, the peroxisomal and apoptotic pathways are activated by V. alginolyticus WT infection, whereas phagocytosis and cell adhesion were enhanced in V. alginolyticus △ vscC infection. Results for functional studies further show that V. alginolyticus WT strain stimulated respiratory bursts to produce excess superoxide (O2•-) and hydrogen peroxide (H2O2) in oysters, which induced apoptosis regulated by p53 target protein (p53tp). Simultaneously, a drop in sGC content balanced off cGMP accumulation in hemocytes and repressed the occurrence of apoptosis to a certain extent during V. alginolyticus △ vscC infection. We have thus provided the first direct evidence for a mechanistic link between virulence of Vibrio spp. and its immunomodulation effects on apoptosis in the oyster. Collectively, we conclude that adaptive responses in host defenses are partially determined by pathogen virulence, in order to safeguard efficiency and timeliness in bacterial clearance.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34609683

RESUMO

Environmental factors could influence the epidemic of virus in human; however, the association remains intricate, and the evidence is still not clear in human coronaviruses (HCoVs). We aimed to explore and compare the associations between HCoVs' epidemic and environmental factors globally. Four common HCoVs' data were collected by a systematic literature review, and data of MERS, SARS, and COVID-19 were collected from the World Health Organization's reports. Monthly positive rates of common HCoVs and incidence rates of MERS, SARS, and COVID-19 were calculated. Geographical coordinates were used to link virus data and environmental data. Generalized additive models (GAMs) were used to quantitatively estimate the association of environmental factors with HCoVs' epidemic. We found that there are wide associations between HCoVs and environmental factors on a global scale, and some of the associations were nonlinear. In addition, COVID-19 has the most similarities in associations' direction with common HCoVs, especially for HCoV-HKU1 in four environmental factors including the significantly negative associations with average temperature, precipitation, vegetation coverage (p<0.05), and the U-shaped association with temperature range. This study strengthened the relevant research evidences and provided significant insights into the epidemic rules of HCoVs in general. The similarities between COVID-19 and common HCoVs indicated that it is critically important to strengthen surveillance on common HCoVs and pay more attention to environmental factors' role in surveillance and early warning of HCoVs' epidemic.

3.
FASEB J ; 35(11): e21977, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34613640

RESUMO

Xylo-oligosaccharide (XOS), which is considered as a potential prebiotic, exhibits multiple beneficial effects on modulation of gut microbiota, strength of intestinal barrier, and inhibition of intestinal inflammation. The objective of this study is to investigate whether XOS protects against Salmonella infection by modulating gut microbiota, enhancing the intestinal barrier, and resisting colonization. C57BL/6 male mice received water supplementation with 5% XOS for 14 days before Salmonella Typhimurium infection. The results showed that XOS suppressed the Salmonella-induced inflammation, but had limited effects on tight junction molecules and mRNA expression of mucus proteins, except for claudin-1 in the colon. Data of 16S rDNA sequencing indicated that XOS modulated gut microbiota composition by significantly stimulating Bifidobacterium animalis (B. animalis), and reducing Salmonella counts. Therefore, the potential protective effects of B. animalis against Salmonella challenge were investigated as well. Bifidobacterium animalis subsp lactis BB-12 (BB12), which could markedly increase in XOS, was selected to treat mice. Similarly, Salmonella-induced inflammatory reactions were alleviated by BB12 but tight junction molecules and mucin proteins in the colonic tissues were not affected. Administration of BB12 remarkably decreased the copies of Salmonella in cecal digesta post Salmonella infection. Additionally, the decrease concentrations of cecal propionate and total short-chain fatty acids (SCFAs) in Salmonella-infected mice were reversed by BB12 treatment, and propionate performed a strong inhibitory effect on Salmonella growth in vitro. Besides that, BB12 could directly restrict Salmonella proliferation in vitro. Moreover, BB12 reduced the adhesion ability of Salmonella on the Caco-2 cells model. Our results suggest that XOS could be considered as a candidate of functional food to protect against Salmonella infection by stimulating Bifidobacterium, which then resists Salmonella colonization by maintaining the intestinal SCFAs levels and suppressing adhesibility.

4.
BMC Med ; 19(1): 245, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34663309

RESUMO

BACKGROUND: The combination of bevacizumab and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could prolong progression-free survival (PFS) in patients with EGFR-mutant advanced non-small-cell lung cancer (NSCLC). Our study investigated the clinical and molecular factors that affect the efficacy of first-generation EGFR-TKI with or without bevacizumab and identify the subset of patients who can benefit from combination therapy. METHODS: Our study included 318 patients with EGFR-mutant locally advanced/advanced NSCLC treated with either first-generation EGFR-TKI combined with bevacizumab (A+T; n = 159) or EGFR-TKI monotherapy (T; n = 159). Two nomogram models to predict PFS and overall survival (OS), respectively, were constructed using two factors that impact EGFR-TKI efficacy: metastatic site and presence of concurrent mutations. The study cohort was stratified into 2 cohorts for training (n = 176) and validation (n = 142) of the nomogram model. Using the median score from the nomogram, the patients were stratified into two groups to analyze their survival outcome. RESULTS: The A+T group had significantly longer PFS (14.0 vs. 10.5 months; p < 0.001) and OS (37.0 vs. 26.0 months; p = 0.042) than the T group. Among the patients with concurrent mutations in tumor suppressor genes, those in the A+T group had significantly longer PFS and OS than the T group (PFS 14.5 vs. 8.0 months, p < 0.001; OS 39.0 vs. 20.0 months, p = 0.003). The higher scores from the nomograms were associated with the presence of brain/liver/pleural metastasis or concomitant gene mutations, which indicated a higher likelihood of shorter PFS and OS. The validation of the nomogram revealed that patients with lower scores had significantly longer PFS for the T group than those with higher scores (15.0 vs. 9.0 months, p = 0.002), but not for the A+T group (15.9 vs. 13.9 months, p = 0.256). CONCLUSIONS: Using a nomogram, our study demonstrated that the addition of bevacizumab may enhance the therapeutic effectiveness of EGFR-TKI by overcoming the negative impact of certain clinical and molecular factors on the efficacy of EGFR-TKI.

5.
Spectrochim Acta A Mol Biomol Spectrosc ; 266: 120458, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34619508

RESUMO

Near-infrared (NIR) photothermal therapy is an effective partner to the chemotherapy of tumors with the merits of high therapeutic ability and slight side effect on normal tissues. Herein, we synthesized gold nanorods and assembled them with L-cysteine reduced graphene oxide (AuNR@Lcyst-rGO) for efficient photothermal therapy. The high therapeutic efficacy of AuNR@Lcyst-rGO can be due to the high photothermal effect of gold nanorods and reduced graphene oxide, and the synergistic effect of them. The nontoxicity of L-cysteine also guarantees the comfortable biocompatibility of reduced graphene oxide, which is essential for the photothermal absorber used in human tissue. The results demonstrate that assembly of gold nanorods with reduced graphene oxide (AuNR@Lcyst-rGO) is a promising photothermal agent with high efficient NIR-triggered photothermal therapy efficiency, excellent stability, superior biocompatibility.

6.
Front Immunol ; 12: 693775, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484190

RESUMO

Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/imunologia , Mutação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Anticorpos Neutralizantes/imunologia , Convalescença , Humanos , Evasão da Resposta Imune , Imunidade Humoral , Testes de Neutralização , Ligação Proteica
7.
BMC Med ; 19(1): 206, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34511132

RESUMO

BACKGROUND: ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. METHODS: Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). RESULTS: The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p < 0.001). Patients harboring single CD74-ROS1 (n = 90) had significantly shorter median PFS with crizotinib than those harboring non-CD74 ROS1 fusions (n = 69) (17.0 months vs. 21.0 months; p = 0.008). Patients with baseline brain metastasis (n = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis (n = 123) (16.0 months vs. 22.0 months; p = 0.03). At progression, intracranial-only progression (n = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression (n = 64) (19.0 months vs. 13.0 months, p < 0.001). TP53 mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with CD74-ROS1 fusions, and 18.8% (6/32) with non-CD74 ROS1 fusions. Patients with concomitant TP53 mutations (n=13) had significantly shorter PFS than those who had wild-type TP53 (n = 81) (6.5 months vs. 21.0 months; p < 0.001). PFS was significantly shorter for the patients who harbored concomitant driver mutations (n = 9) (11.0 months vs 24.0 months; p = 0.0167) or concomitant tumor suppressor genes (i.e., TP53, RB1, or PTEN) (n = 25) (9.5 months vs 24.0 months; p < 0.001) as compared to patients without concomitant mutations (n = 58). CONCLUSION: Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with ROS1-rearranged lung cancer. CLINICAL TRIALS REGISTRATION: CORE, NCT03646994.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34519395

RESUMO

In catalysis science, the electronic structure of the active site determines the structure-activity relationship of the catalyst to a large extent. Therefore, modulating the electronic structure has become a main route for the rational design of metal-based catalyst materials. In this work, we prepared a LaCoSiH x material that has more electronegativity and a lower workfunction than traditional supported Co-based catalysts. Using CO 2 methanation as a model catalytic reaction, the facile dissociation of CO 2 and CO (a key reaction intermediate) on the surface of the LaCoSiH x catalyst is observed by various experimental methods (e.g., in situ Raman and FTIR) at room temperature. Moreover, theoretical calculation results further show that LaCoSiH x has a much stronger capacity for carbon-oxygen bond activation than does the Co surface. The intrinsic mechanism is attributed to the marked electron transferring from catalysts into the antibonding orbital of CO 2 and CO.

9.
Artigo em Inglês | MEDLINE | ID: mdl-34546921

RESUMO

We present joint multi-dimension pruning (abbreviated as JointPruning), an effective method of pruning a network on three crucial aspects: spatial, depth and channel simultaneously. To tackle these three naturally different dimensions, we proposed a general framework by defining pruning as seeking the best pruning vector (i.e., the numerical value of layer-wise channel number, spacial size, depth) and construct a unique mapping from the pruning vector to the pruned network structures. Then we optimize the pruning vector with gradient update and model joint pruning as a numerical gradient optimization process. To overcome the challenge that there is no explicit function between the loss and the pruning vectors, we proposed self-adapted stochastic gradient estimation to construct a gradient path through network loss to pruning vectors and enable efficient gradient update. We show that the joint strategy discovers a better status than previous studies that focused on individual dimensions solely, as our method is optimized collaboratively across the three dimensions in a single end-to-end training and it is more efficient than the previous exhaustive methods. Extensive experiments on large-scale ImageNet dataset across a variety of network architectures MobileNet V1&V2&V3 and ResNet demonstrate the effectiveness of our proposed method. For instance, we achieve significant margins of 2.5% and 2.6% improvement over the state-of-the-art approach on the already compact MobileNet V1&V2 under an extremely large compression ratio.

10.
Mater Sci Eng C Mater Biol Appl ; 129: 112416, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34579925

RESUMO

Infection and inflammation are the main causes resulting in the failure of dental implants. In this work, molybdenum diselenide (MoSe2) was synthesized hydrothermally on the surface of porous TiO2 coating prepared by micro-arc oxidation on titanium (Ti) implants to render the coating excellent in situ antibacterial activity under the irradiation of near-infrared (NIR) light. Chitosan (CHI) was adsorbed on the surface of MoSe2 nanosheets by electrostatic bonding to improve the biocompatibility. The introduction of MoSe2 significantly improved the photothermal and photodynamic ability of TiO2 coating and made the implants possess excellent in vitro and in vivo antibacterial property against Streptococcus mutans (S. mutans) under the irradiation of 808 nm NIR light for 15 min because of the synergistic of hyperthermia and reactive oxygen species (ROS). The immobilization of CHI improved the hydrophilicity and biocompatibility of MoSe2, and the hybrid coating (TiO2/MoSe2/CHI) promoted osseointegration even in the presence of infection in vivo under 808 nm light irradiation. The light - assisted antibacterial coating described here has large clinical potential in dental implants applications.


Assuntos
Quitosana , Implantes Dentários , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Streptococcus mutans , Propriedades de Superfície , Titânio/farmacologia
11.
Chem Phys Lipids ; 240: 105135, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34499882

RESUMO

Ceramide-1-phosphate (C1P) is a bioactive phosphorylated sphingolipid (SL), produced through the direct phosphorylation of ceramide by ceramide kinase. It plays important roles in regulating cell survival, migration, apoptosis and autophagy and is involved in inflammasome assembly/activation, which can stimulate group IVA cytosolic phospholipase A2α and subsequently increase the levels of arachidonic acid and pro-inflammatory cytokines. Human C1P transfer protein (CPTP) can selectively transport C1P from the Golgi apparatus to specific cellular sites through a non-vesicular mechanism. Human CPTP also affects specific SL levels, thus regulating cell SL homeostasis. In addition, human CPTP plays a crucial role in the regulation of autophagy, inflammation and cell death; thus, human CPTP is closely associated with autophagy and inflammation-related diseases such as cardiovascular and neurodegenerative diseases, and cancers. Therefore, illustrating the functions and mechanisms of human CPTP is important for providing the research foundations for targeted therapy. The key human CPTP residues for C1P recognition and binding are highly conserved in eukaryotic orthologs, while the human CPTP homolog in Arabidopsis (accelerated cell death 11) also exhibits selective inter-membrane transfer of phyto-C1P. These results demonstrate that C1P transporters play fundamental roles in SL metabolism in cells. The present review summarized novel findings of C1P and its TPs in eukaryotes.

12.
Front Immunol ; 12: 715464, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539645

RESUMO

The mutants resulted from the ongoing SARS-CoV-2 epidemic have showed resistance to antibody neutralization and vaccine-induced immune response. The present study isolated and identified two novel SARS-CoV-2 neutralizing antibodies (nAbs) from convalescent COVID-19 patients. These two nAbs (XG81 and XG83) were then systemically compared with nine nAbs that were reconstructed by using published data, and revealed that, even though these two nAbs shared targeting epitopes on spike protein, they were different from any of the nine nAbs. Compared with XG81, XG83 exhibited a higher RBD binding affinity and neutralization potency against wild-typed pseudovirus, variant pseudoviruses with mutated spike proteins, such as D614G, E484Q, and A475V, as well as the authentic SARS-CoV-2 virus. To explore potential broadly neutralizing antibodies, heavy and light chains from all 18 nAbs (16 published nAbs, XG81 and XG83) were cross-recombined, and some of the functional antibodies were screened and studied for RBD binding affinity, and neutralizing activity against pseudovirus and the authentic SARS-CoV-2 virus. The results demonstrated that several recombined antibodies had a more potent neutralization activity against variant pseudoviruses compared with the originally paired Abs. Taken together, the novel neutralizing antibodies identified in this study are a likely valuable addition to candidate antibody drugs for the development of clinical therapeutic agents against SARS-CoV-2 to minimize mutational escape.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/genética , Anticorpos Antivirais/uso terapêutico , Afinidade de Anticorpos/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/genética , COVID-19/imunologia , COVID-19/terapia , Linhagem Celular , Epitopos/imunologia , Humanos , Imunoterapia/métodos , Testes de Neutralização , SARS-CoV-2/efeitos dos fármacos
13.
Sci Total Environ ; 802: 149729, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34454135

RESUMO

Atmospheric heavy metal deposition in agroecosystems has increased recently, especially in northern China, which poses serious risks to crop safety and human health via food chain. Wheat grains can accumulate high levels of Pb even when wheat is planted in soils with low levels of Pb. However, the influence of atmospheric deposition on the accumulation and distribution of Pb in wheat grain is still unclear. A field survey was conducted in three districts (A: a district with industrial and traffic pollution; B: a district with traffic pollution; and C: an unpolluted district) in Hebei Province, North China. The grain of wheat cultivated in district A accumulated more Pb from soil and atmospheric deposition than those in other districts, and the bran from district A contained 3.50 and 2.04 times more Pb than those from districts B and C, respectively. The Pb distribution pattern in wheat grain detected by laser ablation inductively coupled mass spectrometry (LA-ICP-MS) was characterized by accumulation mostly in the pericarp and seed coat rather than in the crease, embryo and endosperm. Furthermore, Pb isotopic data showed that airborne Pb was the major source (>50%) of Pb in wheat grain. Interestingly, average contributions of Pb from atmospheric deposition to white flour (78.22%) were higher than its contributions to bran (56.27%). In addition, wheat flag leaves were exposed to PbSO4 at the booting stage, and much greater Pb accumulation (0.33-0.48 mg/kg) was observed in exposed wheat grain than in the control (P < 0.05), PbSO4 constituted most (82.80-100%) of the Pb in the wheat grain. In summary, the results confirmed the efficient foliar Pb uptake and transfer from atmospheric deposition into wheat grain. It would be a new sight for understanding the contribution of airborne Pb to Pb accumulation in wheat grains.

14.
Mar Drugs ; 19(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34436258

RESUMO

Antimicrobial peptides are a fundamental component of mollusks' defense systems, though they remain a thinly investigated subject. Here, infection by Vibrio parahemolyticus triggered a significant increase in antimicrobial activity in oyster plasma. By using PBS-challenged oysters as a control, plasma peptides from immunologically challenged oysters were subjected to peptidomic profiling and in silico data mining to identify bioactive peptides. Thirty-five identified plasma peptides were up-regulated post infection, among which, six up-regulated peptides (URPs) showed a relatively high positive charge. URP20 was validated with significant antibacterial activity. Virtually, URP20 triggered aggregation of bacterial cells, accompanied by their membrane permeabilization. Interestingly, URP20 was found to be active against Gram-positive and Gram-negative foodborne pathogens as well as Candida albicans, with no cytotoxicity to mammalian cells and mice. Our study provides the first large-scale plasma peptidomic dataset that identifies novel bioactive peptides in marine mollusks. Further exploration of peptide diversity in marine invertebrates should prove a fruitful pursuit for designing novel AMPs with broad applications.

15.
J Fungi (Basel) ; 7(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34436210

RESUMO

The simultaneous effects of arbuscular mycorrhizal (AM) fungi and abscisic acid (ABA) on the tolerance of plants to heavy metal (HM) remain unclear. A pot experiment was carried out to clarify the effects of simultaneous applications of AM fungi and ABA on plant growth, Zn accumulation, endogenous ABA contents, proline metabolism, and the oxidative injury of black locust (Robinia pseudoacacia L.) exposed to excess Zn stress. The results suggested that exogenously applied ABA positively enhanced AM colonization, and that the growth of plants only with AM fungi was improved by ABA application. Under Zn stress, AM inoculation and ABA application increased the ABA content in the root/leaf (increased by 48-172% and 92%, respectively) and Zn content in the root/shoot (increased by 63-152% and 61%, respectively) in AM plants, but no similar trends were observed in NM plants. Additionally, exogenous ABA addition increased the proline contents of NM roots concomitantly with the activities of the related synthases, whereas it reduced the proline contents and the activity of Δ1-pyrroline-5-carboxylate synthetase in AM roots. Under Zn stress, AM inoculation and ABA application decreased H2O2 contents and the production rate of O2, to varying degrees. Furthermore, in the roots exposed to Zn stress, AM inoculation augmented the activities of SOD, CAT, POD and APX, and exogenously applied ABA increased the activities of SOD and POD. Overall, AM inoculation combined with ABA application might be beneficial to the survival of black locust under Zn stress by improving AM symbiosis, inhibiting the transport of Zn from the roots to the shoots, increasing the distribution of ABA in roots, and stimulating antioxidant defense systems.

16.
Biochim Biophys Acta Gen Subj ; 1865(11): 129990, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34390793

RESUMO

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet. METHODS: The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis. RESULTS: The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1. CONCLUSION: The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance. GENERAL SIGNIFICANCE: Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.

17.
Neurochem Res ; 46(9): 2495-2504, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34231112

RESUMO

Paired associated stimulation (PAS) has been confirmed to play a role in motor recovery after stroke, but the underlying mechanism has not been fully elucidated. In this study, we employed a comprehensive battery of measurements, including behavioral test, electrophysiology and 1H-NMR approaches, to investigate the therapeutic effects of PAS in rat model of cerebral ischemia and its underlying mechanism. Rats were randomly divided into a transient middle cerebral artery occlusion group (tMCAO group), a tMCAO + PAS group (PAS group), and a sham group. PAS was applied over 7 consecutive days in PAS group. The behavioral function of rats was evaluated by modified Garcia Scores and Rota-rod test. Electrophysiological changes were measured by motor evoked potentials (MEP). Metabolic changes of ischemic penumbra were detected by 1H-NMR. After PAS intervention, the performances on Rota-rod test and Garcia test improved and the amplitude of MEP increased significantly. The gamma-aminobutyric acid (GABA) in penumbra cortex was decreased significantly, whereas the glutamate showed the opposite changes. The results suggested that post-stroke recovery promoted by PAS may be related to the metabolites alteration in ischemic penumbra and also regulate the excitability of motor cortex.

18.
Orphanet J Rare Dis ; 16(1): 327, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294091

RESUMO

BACKGROUND: There are over 16.8 million rare disease patients in China, representing a large community that should not be neglected. While the public lack the awareness of their existence and difficult status quo, for one reason that they exist as a rare and special group in our society, for another reason that all sectors of the community haven't introduced and propagandized them suitably. However, as a special group with more difficulties in all aspects than normal healthy persons, they need enough care and love from us. To provide a basis for policy-makers to better understand the status quo of rare disease patients and care-givers in China and to devise some new policies to improve their quality of life, a comprehensive analysis of the status quo, unmet needs, difficulty caused by the rare disease is essential. METHODS: A questionnaire-based online study of patients and care-givers (usually family members) was performed. The questionnaire was composed of 116 questions, such as the diagnosis process, treatment access, financial burden, views on patients' organizations, and a series of standardized tests to assess the quality of their life, including the SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI. To examine the influence of age, disease type, and relationship to patients on the scores in these tests, statistical analysis with a general linear model was conducted. FINDINGS: A total of 1959 patients and care-givers participated in the survey, representing 104 rare diseases, such as lysosomal storage diseases, hemophilia, and muscular dystrophy diseases. The diagnosis was delayed for 1.4 ± 3.0 years, and patients experienced 1.6 ± 3.8 misdiagnoses between 3.2 ± 2.4 hospitals. The hospitals where diagnoses were made were highly concentrated in 10 large hospitals (43.8%) and 5 big cities (42.1%), indicating a significant inequality of medical resources. The disease often led to difficulty in social life, education, and employment, as well as financial burden that was seldom covered by medical insurance. A battery of standardized tests demonstrated poor health status, depression, somatization, anxiety, and sleeping issues among both patients and care-givers (p < 0.05). Statistical analysis of the questionnaire also showed that poor health, anxiety, depression, somatization, and sleeping problems were more prevalent in patients than in care-givers, and more prevalent in more severe diseases (e.g., hemophilia, Dravet) or undiagnosed than in other diseases. INTERPRETATIONS: This study identified the lack of rare disease awareness and legislative support as the major challenge to rare diseases in China, and makes key recommendations for policy-makers, including legislating orphan drug act, raising rare disease awareness, providing sufficient and fair opportunities about education and employment, expanding the medical insurance coverage of treatments, and protecting rights in education and employment.


Assuntos
Qualidade de Vida , Doenças Raras , China , Humanos , Produção de Droga sem Interesse Comercial , Inquéritos e Questionários
19.
J Clin Neurosci ; 90: 363-369, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275577

RESUMO

OBJECTIVE: To investigate the effects of paired associated stimulation (PAS) with different stimulation position on motor cortex excitability and upper limb motor function in patients with cerebral infarction. METHOD: A total of 120 volunteers with cerebral infarction were randomly divided into four groups. Based on conventional rehabilitation treatment, the PAS stimulation group was given the corresponding position of PAS treatment once a day for 28 consecutive days. The MEP amplitude and RMT of both hemispheres were assessed before and after treatment, and a simple upper limb Function Examination Scale (STEF) score, simplified upper limb Fugl-Meyer score (FMA), and improved Barthel Index (MBI) were used to assess upper limb motor function in the four groups. RESULTS: Following PAS, the MEP amplitude decreased, and the RMT of abductor pollicis brevis (APB) increased on the contralesional side, while the MEP amplitude increased and the RMT of APB decreased on the ipsilesional side. After 28 consecutive days the scores of STEF, FMA, and MBI in the bilateral stimulation group were significantly better than those in the ipsilesional stimulation group and the contralesional stimulation group, but there was no significant difference in the scores of STEF, FMA, and MBI between the ipsilesional stimulation group and the contralesional stimulation group. CONCLUSION: The excitability of the motor cortex can be changed when the contralesional side or the ipsilesional side was given the corresponding PAS stimulation, while the bilateral PAS stimulation can more easily cause a change of excitability of the motor cortex, resulting in better recovery of the upper limb function.


Assuntos
Infarto Cerebral/fisiopatologia , Infarto Cerebral/reabilitação , Terapia por Estimulação Elétrica , Córtex Motor/fisiopatologia , Extremidade Superior/fisiopatologia , Adulto , Potencial Evocado Motor , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Estimulação Magnética Transcraniana
20.
Front Cell Infect Microbiol ; 11: 663884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34277466

RESUMO

Background: The pandemic of Coronavirus Disease 2019 (COVID-19) brings new challenges for pediatricians, especially in the differentiation with non-COVID-19 pneumonia in the peak season of pneumonia. We aimed to compare the clinical characteristics of pediatric patients with COVID-19 and other respiratory pathogens infected pneumonias. Methods: We conducted a multi-center, cross-sectional study of pediatric inpatients in China. Based on pathogenic test results, pediatric patients were divided into three groups, including COVID-19 pneumonia group, Non-COVID-19 viral (NCV) pneumonia group and Non-viral (NV) pneumonia group. Their clinical characteristics were compared by Kruskal-Wallis H test or chi-square test. Results: A total of 636 pediatric pneumonia inpatients, among which 87 in COVID-19 group, 194 in NCV group, and 355 in NV group, were included in analysis. Compared with NCV and NV patients, COVID-19 patients were older (median age 6.33, IQR 2.00-12.00 years), and relatively fewer COVID-19 patients presented fever (63.2%), cough (60.9%), shortness of breath (1.1%), and abnormal pulmonary auscultation (18.4%). The results were verified by the comparison of COVID-19, respiratory syncytial virus (RSV) and influenza A (IFA) pneumonia patients. Approximately 42.5%, 44.8%, and 12.6% of the COVID-19 patients presented simply ground-glass opacity (GGO), simply consolidation, and the both changes on computed tomography (CT) scans, respectively; the proportions were similar as those in NCV and NV group (p>0.05). Only 47.1% of COVID-19 patients had both lungs pneumonia, which was significantly lower than that proportion of nearly 80% in the other two groups. COVID-19 patients presented lower proportions of increased white blood cell count (16.5%) and abnormal procalcitonin (PCT) (10.7%), and a higher proportion of decreased lymphocyte count (44.0%) compared with the other two groups. Conclusion: Majority clinical characteristics of pediatric COVID-19 pneumonia patients were milder than non-COVID-19 patients. However, lymphocytopenia remained a prominent feature of COVID-19 pediatric pneumonia.


Assuntos
COVID-19 , Pneumonia , Criança , China/epidemiologia , Estudos Transversais , Humanos , Pulmão/diagnóstico por imagem , Pneumonia/epidemiologia , Estudos Retrospectivos , SARS-CoV-2
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