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1.
Anatol J Cardiol ; 25(10): 691-698, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34622783

RESUMO

OBJECTIVE: Presently, an effective model to predict long-term cardiac mortality in patients with hypertrophic obstructive cardiomyopathy (HOCM) is lacking. Therefore, the objective of this study was to evaluate the predictive value of the modified Age, Creatinine clearance, and Ejection Fraction (mACEF) score for long-term cardiac mortality in patients with HOCM. METHODS: Two hundred and ninety two patients with HOCM treated non-invasively were enrolled in this study, all of whom had intact medical information. RESULTS: Over a median follow-up period of 41.9 months, 28 cardiac deaths occurred. In univariate Cox regression analysis, the mACEF score was associated with long-term cardiac death [hazard ratio (HR)=1.795, 95% confidence interval (CI) 1.518-2.124, p<0.001]. Multiple Cox regression analysis identified the mACEF score as an independent risk factor for long-term cardiac death (adjusted HR=1.372, 95% CI 1.076-1.749, p=0.011). Analysis of the receiver operating characteristic (ROC) for long-term cardiac death showed that the mACEF score had a considerable predictive value (area under ROC 0.844, sensitivity 89.29%, specificity 75.00%) with an optimum cut-off value of 0.96. The study population was divided into high-risk (mACEF score ≥0.96, n=91) and low-risk (mACEF score <0.96, n=201) groups according to the optimum cut-off value. Kaplan-Meier survival analysis was performed and showed a dramatic higher rate of long-term cardiac mortality in the high-risk group than in the low-risk group (27.4% vs. 1.7%, p<0.001 by log-rank test). CONCLUSION: The mACEF score has a considerable predictive value for long-term cardiac mortality in patients with HOCM treated non-invasively. A mACEF score ≥0.96 could be considered as a sign of poor prognosis in patients with HOCM.


Assuntos
Cardiomiopatia Hipertrófica , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Creatinina , Humanos , Prognóstico , Estudos Retrospectivos , Volume Sistólico
2.
Front Endocrinol (Lausanne) ; 12: 710240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489866

RESUMO

Background: The triglyceride-glucose index (TyG index) is a valuable marker for predicting adverse cardiovascular events in diabetic patients. However, for nondiabetic patients, whether the TyG index is independently related to poor prognosis remains unclear. This cohort study assessed the association of the TyG index with future cardiovascular risk in nondiabetic subjects who received percutaneous coronary intervention (PCI). Methods: We consecutively enrolled 5,489 nondiabetic patients who underwent PCI. All experimental subjects were divided into three groups based on their TyG index, which was determined by the equation ln (fasting triglyceride (mg/dl) × fasting blood glucose (mg/dl)/2). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and target vessel revascularization (TVR). Results: A total of 386 MACCE were documented during a median 29-month follow-up. The Kaplan-Meier survival results indicated that among the three groups, there was no obvious difference in any endpoints. Further Cox regression analyses suggested that the TyG index was not independently related to adverse cardiovascular outcomes for nondiabetic patients who underwent PCI (HR: 0.77, 95% CI 0.56-1.16, P = 0.210 for MACCE). Subgroup analysis suggested that the TyG index was independently relevant to MACCE for patients with low-density lipoprotein cholesterol (LDL-C) lower than 1.8 mmol/L. Conclusion: The TyG index is not an effective predictive factor for adverse cardiovascular prognosis in nondiabetic patients who underwent PCI. However, in subjects with LDL-C lower than 1.8mmol/L, it may predict future cardiovascular risk.

3.
J Immunother Cancer ; 9(9)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34489334

RESUMO

BACKGROUND: A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies. METHODS: We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15 -/-, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression. RESULTS: GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse. CONCLUSIONS: Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.

4.
J Mater Chem B ; 9(38): 8056-8066, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34491255

RESUMO

Osteoarticular Tuberculosis (TB) is a challenging issue because of its chronicity and recurrence. Many drug delivery systems (DDSs) have been developed for general chemotherapy. Herein, we take advantage of instant hydrogelation to in situ encapsulate drugs onto implants intraoperatively, optimizing the drug release profile against osteoarticular TB. First-line chemodrugs, i.e. rifampicin (RFP) and isoniazid (INH) are firstly loaded on tricalcium phosphate (TCP). Then, the encapsulating hydrogel is fabricated by dipping in chitosan (CS) and ß-glycerophosphate (ß-GP) solution and heating at 80 °C for 40 min. The hydrogel encapsulation inhibits explosive drug release initially, but maintains long-term drug release (INH, 158 days; RFP, 53 days) in vitro. Therefore, this technique could inhibit bone destruction and inflammation from TB effectively in vivo, better than our previous ex situ prepared DDSs. The encapsulating technology, i.e. instant hydrogelation of drug-loaded implants, shows potential for regulating the type and ratio of drugs, elastic and viscous modulus of the hydrogel according to the state of illness intraoperatively for optimal drug release.

5.
Chemosphere ; 287(Pt 1): 131998, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34450373

RESUMO

The sulfur-based autotrophic denitrification (SAD) and the solid organic carbon-based denitrification processes are both efficient techniques to remove nitrate from wastewater, and the hydrogen ions generated by the SAD process would be consumed in the heterotrophic denitrification process. Therefore, it is possible to improve the denitrification capacity when the solid organic carbon was added into a SAD reactor. In this study, corncob powder and sawdust powder were selected as solid organic carbon sources, and the sulfur-based autotrophic denitrification integrated biomass-based heterotrophic denitrification system was formed (SBD). The laboratory and field experiments showed that SBD could shorten the start-up period, decrease the sulfate productivity, and maintain a good denitrification performance when treated wastewater. According to the field experiment results, when the HRT was 1 h, the effluent total nitrogen (TN) concentration was always lower than 15 mg L-1. In addition, nitrite inhibition was observed when the concentration of nitrite in the reactors reached above 30 mg L-1. The mixture of elemental sulfur powder, shell powder, corncob powder, and sawdust powder with a mass ratio of 6:2:1:1 was the optimal filter for the SBD system, with an average nitrate reduction rate (NAR) of 420 mg NO3-N·L-1·d-1 obtained at the end of the study. During the whole operation, the major autotrophs in the SBD systems were Thermomonas, Ferritrophicum, and Thiobacillus, while the major heterotrophs were Saprospiraceae, Ferruginibacter, Dokdonella, and Simplicispira. Overall, the SBD system was a feasible and practically favorable way to remove nitrate from wastewater.

6.
Heart Vessels ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236463

RESUMO

Growing evidences have revealed that a histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA) has anti-fibrotic effect in different diseases. In this study, we first evaluated whether SAHA could suppress cardiac fibrosis. Mice with MI-induced cardiac fibrosis were treated with SAHA by intraperitoneal injection and their cardiac function was improved after SAHA treatment. Results of western blotting and qRT-PCR in heart tissues suggested that TGFß1/P38 pathway was activated in MI mice, and this effect was reversed by SAHA. Cell proliferation assay suggested that SAHA could suppress TGF-ß1-induced cardiac fibroblasts proliferation. Furthermore, results of western blotting and qRT-PCR in cardiac fibroblasts depicted that SAHA may exert its anti-fibrotic effect through inhibiting TGF-ß1-induced P38 phosphorylation by promoting DUSP4 expression. Our findings may substantiate SAHA as a promising treatment for MI-induced cardiac fibrosis.

7.
Nat Commun ; 12(1): 4494, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301935

RESUMO

Self-assembling peptides have shown tremendous potential in the fields of material sciences, nanoscience, and medicine. Because of the vast combinatorial space of even short peptides, identification of self-assembling sequences remains a challenge. Herein, we develop an experimental method to rapidly screen a huge array of peptide sequences for self-assembling property, using the one-bead one-compound (OBOC) combinatorial library method. In this approach, peptides on beads are N-terminally capped with nitro-1,2,3-benzoxadiazole, a hydrophobicity-sensitive fluorescence molecule. Beads displaying self-assembling peptides would fluoresce under aqueous environment. Using this approach, we identify eight pentapeptides, all of which are able to self-assemble into nanoparticles or nanofibers. Some of them are able to interact with and are taken up efficiently by HeLa cells. Intracellular distribution varied among these non-toxic peptidic nanoparticles. This simple screening strategy has enabled rapid identification of self-assembling peptides suitable for the development of nanostructures for various biomedical and material applications.


Assuntos
Nanofibras/química , Nanoestruturas/química , Biblioteca de Peptídeos , Peptídeos/química , Dicroísmo Circular , Técnicas de Química Combinatória/métodos , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Ligação de Hidrogênio , Microscopia Eletrônica de Transmissão , Nanofibras/ultraestrutura , Nanoestruturas/ultraestrutura , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
DNA Cell Biol ; 40(9): 1167-1176, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255539

RESUMO

Skeletal muscle has great plasticity. An increase in protein degradation can cause muscle atrophy. Atrogin-1 and muscle ring finger-1 (MuRF1) are dramatically upregulated in various muscle atrophy. Inhibition of Atrogin-1 and MuRF1 protects against muscle atrophy. MiR-29 plays an important regulatory role in skeletal muscle development. However, the function of miR-29 in skeletal muscle protein metabolism is not clear. To investigate the function of miR-29, we generated miR-29 knockout mice and the miR-29ab1 cluster overexpression mice. The disruption of miR-29 led to severe atrophy of skeletal muscle during puberty, and the muscle-specific overexpression of the miR-29ab1 cluster protected against denervation-induced and fasting-induced muscle atrophy. Furthermore, the overexpression of miR-29a, b mimics in myotubes resisted the muscle atrophy. MuRF1 was the direct target gene of miR-29a, b. These results demonstrate that miR-29ab1 cluster plays a critical role in the maintenance of skeletal muscle. MiR-29ab1 cluster is the excellent inhibitor of MuRF1, ultimately indicating that miR-29ab1 cluster is good therapeutic molecule candidate for adulthood.


Assuntos
MicroRNAs/fisiologia , Desenvolvimento Muscular , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Mioblastos
9.
ACS Nano ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34323463

RESUMO

The overexpression of growth factors and receptors on neovascular endothelial cells (ECs) and their binding may promote the abnormal growth of new blood vessels, leading to corneal neovascularization (CNV). Normally, monoclonal antibodies may bind and block only one growth factor or receptor, such as bevacizumab binding and blocking vascular endothelial growth factor (VEGF). Herein, we develop a monotargeting peptidic network antibody (pepnetibody) that blocks multiple receptors on the membrane of ECs through forming a fibrous network and ultimately achieves high-efficient treatment of CNV. The pepnetibody could bind to integrin αvß3 in particulate formulation and in situ fibrillogenesis on ECs, mimicking the process of fibronectin fibrillogenesis on the cell membrane. The in situ formed peptidic network could firmly block integrin and cover other angiogenesis-related receptors, such as VEGF receptor-2 and neuropilin-1, exhibiting competitive efficacy of antiangiogenesis compared with traditional monoclonal antibody bevacizumab with 97.7 times lower dose.

10.
Endocrine ; 74(1): 128-137, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34081308

RESUMO

PURPOSE: Thyroid dysfunction contributes to adverse events in several types of cardiovascular diseases. The aim of the present study is to determine whether thyroid status is associated with the prognosis of patients with acute myocardial infarction (AMI). METHODS: The present cohort arose from the China PEACE­Prospective AMI study. Based on the evaluation of thyroid status, participants were divided into euthyroid, hypothyroid, and hyperthyroid groups. A total of 2569 AMI patients met the inclusion criteria of our present study. The primary outcomes were the 12-month composite cardiovascular endpoint (CCVE, a composite of all-cause death, myocardial infarction, revascularization, and heart failure) and the composite cardio-cerebral vascular endpoint (CCCVE, comprising CCVE and stroke). RESULTS: Of the entire cohort, 431 patients (16.8%) confirmed hypothyroid status and 102 (4.0%) were at hyperthyroid status. There were total 594 CCVEs (23.1%) and 687 CCCVEs (26.7%) in the general population. After adjusting conventional risk factors, AMI patients from the hypothyroid status group were at increased risk of the two composite endpoints, compared with euthyroid individuals (CCVE, HR:1.337, 95%CI: 1.097-1.630; CCCVE, HR:1.336, 95%CI: 1.111-1.607). However, no significant increased trends of the two composite endpoints could be observed in hyperthyroid group. Furthermore, hypothyroid status was also independently associated with a higher risk of revascularization (HR: 1.648, 95%CI: 1.047-2.595) and heart failure (HR: 1.382, 95%CI: 1.066-1.792). CONCLUSION: Compared with euthyroid status, hypothyroid status has an independent predicting value for adverse cardiovascular events in AMI patients. Further investigations are required to illustrate whether treatment of thyroid dysfunction could improve the prognosis of AMI patients.

11.
Biomaterials ; 275: 120900, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051670

RESUMO

Different from chemical (small molecular inhibitor) and biological (monoclonal antibody) drugs, herein, based on angiogenesis-related neuropilin-1 (NRP-1), we develop a biomimetic superstructure drug, i.e. an antibody-like peptidic network (ALPN) to achieve the high-efficient treatment of choroidal neovascularization (CNV). The ALPN in nanoparticulated formulation (ALPN-NPS) can bind NRP-1 through targeting unit and form fibrous peptidic networks trapping NRP-1 on the surface of endothelial cells (ECs), leading to anti-angiogenesis. The ALPN shows high-efficacy against angiogenesis in CNV rat model ascribed to the superstructure-enhanced binding and blockage of NRP-1. The very low dose of ALPN (0.263 µg/Kg) exhibits similar anti-angiogenesis effect comparing with monoclonal antibody bevacizumab (23.5 µg/Kg), which shows potential advantages over traditional monoclonal antibodies.


Assuntos
Neovascularização de Coroide , Células Endoteliais , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Neovascularização de Coroide/tratamento farmacológico , Neuropilina-1 , Peptídeos/uso terapêutico , Ratos
12.
Chin Med J (Engl) ; 134(9): 1064-1069, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33942801

RESUMO

BACKGROUND: Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS: The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS: The results demonstrated that increased TSH levels were significantly associated with higher TC (ß = 0.052, P = 0.002) and LDL (ß = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (ß = 0.240, P = 0.033) and LDL (ß = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION: Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.


Assuntos
Análise da Randomização Mendeliana , Glândula Tireoide , Metabolismo dos Lipídeos/genética , Testes de Função Tireóidea , Tireotropina , Tiroxina , Tri-Iodotironina
13.
J Ethnopharmacol ; 275: 114102, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831471

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aconiti Lateralis Radix Praeparata (Chinese name: Fuzi), the root of Aconitum carmichaelii Debx., is a representative medicine for restoring yang and rescuing patient from collapse. However, less studies had been reported on the reproductive toxicity and genotoxicity of Fuzi. According to the principle of reducing toxicity and preserving efficiency, only processed products of Fuzi are commonly applied in clinic, including Baifupian, Heishunpian and Danfupian. However, whether processing could alleviate the reproductive toxicity and genotoxicity of Fuzi had not been revealed. AIM OF THE STUDY: To assess the effect and possible mechanism of Fuzi and its processed products on reproductive toxicity and genotoxicity in male mice. MATERIALS AND METHODS: Aqueous extracts of Fuzi and its processed products (Baifupian, Heishunpian and Danfupian, 5.85 g/kg) were administrated by gavage once daily for fourteen consecutive days. The reproductive toxicity was evaluated by testis weight, testis ratio, testis histopathology, sperm count, sperm viability rate and sperm deformity rate. The genotoxicity was evaluated by comet assay and micronucleus test in sperm, peripheral blood cell and bone marrow cell. Possible mechanisms of attenuating toxicity by processing were analyzed by detecting the level of testosterone, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase (CAT). RESULTS: Fuzi significantly caused different degrees of reproductive toxicity and genotoxicity, specifically reducing the weight and testicular coefficient of testis, causing obvious pathological changes in testicular tissue, reducing sperm count and sperm viability rate, increasing sperm deformity rate and DNA damage in sperm/peripheral blood cells/bone marrow cells. Moreover, Fuzi decreased the level of testosterone, SOD, GSH and CAT, while increased the level of MDA in serum. Notably, the reproductive toxicity and genotoxicity induced by the processed products, especially Heishunpian and Danfupian, were significantly lowered compared to Fuzi. Processing could increase the level of testosterone, SOD, GSH, CAT and decrease the level of MDA compared to Fuzi. CONCLUSION: Fuzi and its processed products had reproductive toxicity and genotoxicity, but the toxicity of processed products was significantly weakened compared to Fuzi. The protective mechanism of processing to reduce the toxicity of Fuzi might be related to increasing the level of testosterone and decreasing oxidative stress.


Assuntos
Aconitum/química , Aconitum/toxicidade , Dano ao DNA/efeitos dos fármacos , Extratos Vegetais/toxicidade , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Catalase/sangue , Diterpenos/administração & dosagem , Diterpenos/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/toxicidade , Glutationa/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Camundongos , Extratos Vegetais/administração & dosagem , Espermatozoides/efeitos dos fármacos , Superóxido Dismutase/sangue , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/metabolismo
14.
Acupunct Med ; 39(6): 673-680, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33706560

RESUMO

BACKGROUND: Inflammatory pain is the most common type of pain encountered clinically. The analgesic effect of acupuncture has been well-documented. OBJECTIVE: The aim of this study was to investigate the involvement of chemokine CXCL1 in the serum on manual acupuncture (MA)-induced antinociception. METHODS: Rats with inflammatory pain of the right hind paw were induced by intraplantar (i.pl.) administration of complete Freund's adjuvant (CFA). After wards, the CFA-injected rats were treated daily with MA at ST36 from Day 1 to Day 7, and thermal nociceptive thresholds (paw withdrawal latency; PWL) were analyzed. The concentration of CXCL1 in the serum of the rats was measured by enzyme-linked immunosorbent assay (ELISA) after the first and the last MA treatment. Subsequently, the rats were injected with two doses (5 or 10 µg) of recombinant CXCL1 through the tail vein daily from Day 1 to Day 7 or injected with two doses (6.4 or 16 µg) of anti-CXCL1 antibody using the same methods and course at 30 min before MA, and the PWLs were measured again. Finally, naloxone (500 µg, 0.1 mL) was administered by i.pl. injection into the inflamed paw 5 min before the last MA treatment or last injection of recombinant CXCL1. RESULTS: MA significantly increased the PWLs and upregulated the expression of serum CXCL1 in the CFA-injected rats. Without acupuncture, repeated tail vein injection of recombinant CXCL1 showed an analgesic effect on CFA-induced inflammatory pain. Conversely, the neutralization of serum CXCL1 by anti-CXCL1 antibody decreased MA-induced antinociception in a time-dependent manner. Anti-CXCL1 antibody injected just once before the first MA did not affect MA-induced antinociception. The analgesic effects of MA and recombinant CXCL1 were reversed by an i.pl. injection of naloxone. CONCLUSION: This study indicates MA at ST36 had an analgesic effect on inflammatory pain and found a novel function of CXCL1. Increased serum CXCL1 had an antinociceptive effect on inflammatory pain induced by CFA. CXCL1 in serum appeared to be a key molecule involved in the peripheral mechanism of MA-induced antinociception. The analgesic effect of MA or recombinant CXCL1 on inflammatory pain might be mediated through a peripheral opioid pathway, which needs further investigation.

15.
Cell Host Microbe ; 29(5): 757-764.e3, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33730549

RESUMO

Chikungunya virus (CHIKV) causes a debilitating arthralgic inflammatory disease in humans. The multifunctional CHIKV protein, nsP1, facilitates virus RNA replication and transcription by anchoring the viral replication complex (RC) to plasma membrane vesicles and synthesizing the viral RNA 5' cap-0. Here, we report a cryo-EM structure of CHIKV nsP1 at 2.38 Å resolution. Twelve copies of nsP1 form a crown-shaped ring structure with a 7.5-nm-wide channel for mediating communication and exchange between the viral RC and the host cell. The catalytic site for viral RNA capping is located in a tunnel that is shaped by neighboring nsP1 molecules. Two membrane-association loops target nsP1 to the inner leaflet of the plasma membrane via palmitoylation and hydrophobic and electrostatic interactions. Our study provides the structural basis of viral RNA capping and RC assembly mediated by nsP1 and guides the development of antivirals targeting these essential steps of virus infection.


Assuntos
Membrana Celular/virologia , Febre de Chikungunya/virologia , Vírus Chikungunya/metabolismo , Capuzes de RNA/genética , RNA Viral/genética , Proteínas não Estruturais Virais/metabolismo , Vírus Chikungunya/química , Vírus Chikungunya/genética , Humanos , Capuzes de RNA/química , Capuzes de RNA/metabolismo , RNA Viral/química , RNA Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Replicação Viral
16.
Int J Cardiol ; 333: 60-68, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33744346

RESUMO

BACKGROUND: Debate exists on the prognostic significance of spontaneous myocardial infarction (SMI) and periprocedural myocardial infarction (PMI), which could be diagnosed by various definitions. METHODS AND RESULTS: A total of 10,724 patients undergoing percutaneous coronary intervention (PCI) were consecutively enrolled and followed up for a median of 2.4 years. We evaluated outcomes of all-cause death, cardiac death, and major adverse cardiovascular events (MACE). Patients were stratified into three groups, including the No MI group, PMI group, and SMI group. PMI was defined based on different diagnostic criteria, including the third and fourth universal myocardial infarction (MI) definitions, the society for cardiovascular angiography and interventions (SCAI) definition, and the independent biomarker definition. Regardless of these definitions, the PMI groups were all associated with a significantly increased MACE risk at one year or 1000 days (all P < 0.05), but not all-cause or cardiac death. The SMI group was associated with a markedly elevated risk of death and MACE, but it showed no significant different risk of MACE to PMI using varying definitions. CONCLUSIONS: According to various PMI definitions, PMI and SMI were associated with an increased risk of MACE, but not death for PMI. No significantly different risk of MACE was observed between PMI and SMI.


Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Biomarcadores , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Fatores de Risco , Resultado do Tratamento
17.
Front Endocrinol (Lausanne) ; 12: 571765, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763025

RESUMO

Background: This study aims to investigate the role of free triiodothyronine (fT3) in predicting poor prognosis of adult patients with acute myocarditis. Methods: A total of 173 consecutive adult patients with acute myocarditis completed thyroid function evaluations. They were divided into two groups according to fT3 levels: low fT3 group (n = 54, fT3 < 3.54 pmol/liter) and normal fT3 group (n = 119, fT3 ≥ 3.54 pmol/liter). The primary endpoint was major adverse cardiac events (MACE). Results: During the 3.5 ± 2.8 years follow-up, the rate of MACE was 29.6% versus 3.5% in low fT3 group versus normal fT3 group, respectively (P < 0.0001). Long-term at 8 years MACE-free survival were lower in low fT3 group versus normal fT3 group (52.9% versus 92.3%, log-rank P < 0.0001), respectively. Univariate Cox analysis showed that left ventricular ejection fraction (LVEF) < 50% [hazard ratio (HR) 10.231, 95% confidence interval (CI): 3.418-30.624, P < 0.0001) and low fT3 level (HR 0.360, 95% CI: 0.223-0.582, P < 0.0001) were strongest two predictors of MACE. After adjustment for traditional risk predictors, the prognostic value of fT3 status was still significant (HR 0.540, 95% CI: 0.316-0.922, P = 0.024). Compared with normal fT3 group, those in low fT3 group were at a much higher risk of MACE (HR 5.074, 95% CI: 1.518-16.964, P = 0.008). Conclusions: Low T3 syndrome was a strong predictor of poor prognosis in adult patients with acute myocarditis. These findings suggest that fT3 level could serve as a biomarker for risk stratification in acute myocarditis patients.

18.
Nat Commun ; 12(1): 1142, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602941

RESUMO

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.


Assuntos
Neurônios Colinérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Filtro Sensorial , Comportamento Social , Anedonia/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Disfunção Cognitiva/complicações , Maleato de Dizocilpina/farmacologia , Feminino , Integrases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia
19.
J Ethnopharmacol ; 270: 113792, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33422656

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP), one of the most commonly used antitumor drugs in clinic, could induce reproductive and genetic toxicity. Traditional Chinese medicine believed that this side effect might be caused by the deficiency of both qi and blood. Panax notoginseng (Burk.) F. H. Chen (PN) is a traditional precious Chinese medicine for nourishing blood and hemostasis, which had the synergistic antitumor and reducing toxicity effects. However, the protective effect and mechanism of PN on CP-induced reproductive and genetic toxicity were still unknown. AIM OF THE STUDY: This study was designed to illuminate the possible protective effect and mechanism of PN on CP-induced reproductive and genetic toxicity. MATERIALS AND METHODS: Network pharmacology was first applied to analyze the potential components and targets of PN against CP-induced reproductive and genetic toxicity. Then, the results of network pharmacology were validated in a mouse model of reproductive and genotoxicity induced by CP. Body weight, testis weight, epididymis weight, sperm count, sperm viability and sperm morphology were used to assess protective effects of PN on CP-induced reproductive toxicity. Tail moment in peripheral blood cells and micronucleus in bone marrow cells were used to assess protective effects of PN on CP-induced genetic toxicity. Finally, possible protective targets obtained from network pharmacology, including 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), were experimentally validated by ELISA. RESULTS: One hundred and nineteen components of PN and sixty-eight targets of reproductive/genetic toxicity were acquired and constituted as the component-target network. Network pharmacology analysis showed alleviating oxidative stress might play important role in therapeutic mechanism of PN. In verified experiments, PN significantly improved the decline of body weight, testis weight and epididymis weight, increased sperm count and viability, decreased abnormal sperm morphology rate induced by CP in mice. Moreover, PN also significantly decreased the tail moment in peripheral blood cells and micronucleus formation rate in bone marrow cells in CP-induced mice. Finally, not only the decrease of T-SOD and GSH-Px level but also the increase of 8-OHdG and MDA level in serum were restored under PN treatment. CONCLUSION: Current study found that PN could improve CP-induced reproductive and genetic toxicity, which were probably attributed to alleviating oxidative stress. This finding provided the new perspective for understanding the therapeutic effect of PN on CP-induced reproductive and genetic toxicity and facilitating the clinical use of PN.


Assuntos
Dano ao DNA/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Panax notoginseng/química , Reprodução/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina/sangue , Animais , Células Sanguíneas/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Cisplatino/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Epididimo/efeitos dos fármacos , Glutationa Peroxidase/sangue , Masculino , Malondialdeído/sangue , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Mapas de Interação de Proteínas , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Superóxido Dismutase/sangue , Testículo/efeitos dos fármacos
20.
Adv Mater ; : e2006459, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475199

RESUMO

There is an urgent need to assemble ultrasmall metal chalcogenides (with atomic precision) into functional materials with the required anisotropy and uniformity, on a micro- or even macroscale. Here, a delicate yet simple chemistry is developed to produce a silver-sulfur network microplate with a high monodispersity in size and morphology. Spanning from the atomic, molecular, to nanometer, to micrometer scale, the key structural evolution of the obtained microplates includes 2D confinement growth, edge-sharing growth mode, and thermodynamically driven layer-by-layer stacking, all of which are derived from the [AgS4 ] tetrahedron unit. The key to such a high hierarchical, complex, and accurate assembly is the dense deprotonated ligand layer on the surface of the microplates, forming an infinite surface with high negative charge density. This feature operates at an orderly distance to allow further hierarchical self-assembly on the microscale to generate columnar assemblies composed of microplate components, thereby endowing the feature of the 1D photonic reflector to water (i.e., photonic water). The reflective color of the resulting photonic water is highly dependent on the thickness of the building blocks (i.e., silver-sulfur microplates), and the coexistent order and fluidity help to form robust photonic water.

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