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1.
Expert Opin Drug Saf ; : 1-14, 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33356646

RESUMO

Introduction: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians. Areas covered: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms. Expert opinion: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.

2.
Nanomedicine ; 31: 102302, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32980548

RESUMO

Lupus nephritis (LN) is a major cause of morbidity and mortality among systemic lupus erythematosus patients. Glucocorticoids (GCs) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GC side effects while maintaining their potent therapeutic efficacy, we have developed a macromolecular prodrug nanomedicine based on dexamethasone (ZSJ-0228). The focus of this study was to investigate its long-term efficacy and, most importantly, safety in the lupus-prone NZB/W F1 mouse. Monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. In contrast to treatment with dose equivalent daily free dexamethasone, long-term monthly ZSJ-0228 did not result in any measurable GC-associated side effects. With its outstanding efficacy and exceptional safety, it is anticipated that ZSJ-0228 may be a novel therapy for long-term clinical management of LN.

3.
Int J Artif Organs ; : 391398820953866, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945220

RESUMO

Articular cartilage repair remains a great clinical challenge. Tissue engineering approaches based on decellularized extracellular matrix (dECM) scaffolds show promise for facilitating articular cartilage repair. Traditional regenerative approaches currently used in clinical practice, such as microfracture, mosaicplasty, and autologous chondrocyte implantation, can improve cartilage repair and show therapeutic effect to some degree; however, the long-term curative effect is suboptimal. As dECM prepared by proper decellularization procedures is a biodegradable material, which provides space for regeneration tissue growth, possesses low immunogenicity, and retains most of its bioactive molecules that maintain tissue homeostasis and facilitate tissue repair, dECM scaffolds may provide a biomimetic microenvironment promoting cell attachment, proliferation, and chondrogenic differentiation. Currently, cell-derived dECM scaffolds have become a research hotspot in the field of cartilage tissue engineering, as ECM derived from cells cultured in vitro has many advantages compared with native cartilage ECM. This review describes cell types used to secrete ECM, methods of inducing cells to secrete cartilage-like ECM and decellularization methods to prepare cell-derived dECM. The potential mechanism of dECM scaffolds on cartilage repair, methods for improving the mechanical strength of cell-derived dECM scaffolds, and future perspectives on cell-derived dECM scaffolds are also discussed in this review.

4.
Med Sci Monit ; 26: e922624, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32430492

RESUMO

BACKGROUND Vascularized fibular grafting (VFG) has been successfully employed for treating avascular necrosis of the femoral head (ANFH). In this study, we aimed to evaluate the bone viability of the femoral head and subchondral bone following VFG by using single photon emission computerized tomography and computerized tomography (SPECT/CT). MATERIAL AND METHODS Between March 2011 and June 2014, 14 ANFH patients (17 hips) treated with VFG at Zhongshan Hospital, Fudan University, were prospectively enrolled. The patients included 9 males and 5 females with an average age of 26.6 years (range, 18-34 years). According to the ARCO (Association Research Circulation Osseous) stage criteria, 3 hips corresponded to stage IIA, 4 hips to stage IIB, 2 hips to stage IIC, 5 hips to stage IIIA, and 3 hips to stage IIIB. A novel method based on SPECT/CT was developed to quantitative characterized the bone viability of femoral head and subchondral bone prior to surgery and at 3 months after VFG. All patients were followed for an average duration of 3.8 years (ranging 2.6-5.5 years). RESULTS The bone viability of the femoral head (Vfh) and subchondral bone (Vsb) of patients' hips at ARCO stage III was 58.9±7.6 and 48.9±6.1, respectively, which were significantly lower than the preoperative Vfh (78.1±5.2) and Vsb (69.8±4.3) of hips at stage II (P<0.05). The Vfh of hips at stage II improved to 104.0±9.7 at 3 months post-intervention, and there was no significant difference compared with the Vfh (97.3±7.4) of hips at stage III (P=0.15). The Vsb of hips at stage III improved to 80.4±7.3 at 3 months after VFG; however, this value was significantly lower than that of hips at stage II (92.7±5.5) (P<0.05). CONCLUSIONS The Vfh and Vsb of our patients were associated with their ARCO stages, and could be improved after vascularized fibular grafting procedure as measured by SPECT/CT.

5.
EBioMedicine ; 37: 38-46, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297145

RESUMO

BACKGROUND: Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but the complex immunosuppressive microenvironment confines the therapeutic benefits to a minority of patients with solid tumors. METHODS: A lentivector-based inducible system was established to evaluate the therapeutic effect of cytokines in established tumors. Intratumoral injection of certain cytokine combination in syngeneic tumor models was conducted to assess the therapeutic potentials. FINDINGS: Doxycycline (Dox)-induced local expression of cytokine combinations exhibites a strong synergistic effect, leading to complete regression of tumors. Notably, IL12 + GMCSF+IL2 expression induces eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of ~15 mm in diameter, and generates intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induce tumor elimination in most of mice. Moreover, intratumoral injection of chitosan/IL12 + GMCSF+IL2 solution induces a complete response in all the tested syngeneic tumor models, regardless of various tumor immunograms. INTERPRETATION: Administration of certain cytokine combinations in tumor microenvironment induces a strong synergistic antitumor response, including the recruitment of large amount of immune cells and the generation of systemic antitumor immunity. It provides a versatile method for the immunotherapy of intractable malignant neoplasms. FUND: There is no external funding supporting this study.


Assuntos
Citocinas/imunologia , Doxorrubicina/farmacologia , Neoplasias Experimentais , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
6.
Int J Equity Health ; 17(1): 47, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29685156

RESUMO

BACKGROUND: Children who suffer from parental migration have been manifested to exhibit physical and mental impairments at higher rates. This current study aims to explore unintentional injury disparity among schooling left-behind children, migrant children and residential children in China, and to examine the risk factors of unintentional injury among the three types of children based on a multi-level system framework. This study will fill the gaps of this topic for China and contribute to the world literature in the context of countries with frequent population migration. METHODS: Data for 4479 children aged 6-16 of a representative population sample were obtained from a survey conducted in China in 2017. Child's unintentional injury in this survey was measured based on the definition and classification of ICD-10. Descriptive analysis, multivariable logistic regression and zero-inflated negative binomial regression were employed in this study. RESULTS: Left-behind children showed higher prevalence of total unintentional injury than migrant and residential children, as well as in 14 specific unintentional injuries. There was a statistical difference between left-behind and residential children's unintentional injuries, but no significant difference was found between migrant and residential children. Results also indicated that both individual and environmental factors constructed as a multi-level system were associated with children's unintentional injuries. CONCLUSIONS: Family migration may have contributed to the increased unintentional injury risks among children. Left-behind children were more vulnerable to suffer from unintentional injuries than migrant and residential children, and specific attentions should be paid to unique group of children, especially the left-behind children. Given the importance and serious consequences of children's unintentional injuries, the findings may provide implications for necessary intervention.


Assuntos
Transtornos Mentais/epidemiologia , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Migrantes/estatística & dados numéricos , Ferimentos e Lesões/epidemiologia , Adolescente , Criança , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Fatores de Risco , Inquéritos e Questionários
7.
Artigo em Inglês | MEDLINE | ID: mdl-29614783

RESUMO

This study aims to estimate the prevalence of behavioral problems among left-behind children, migrant children and local children in China, and to compare the risks of behavioral problems among the three types of children. Data on 4479 children aged 6-16 used in this study were from a survey conducted in China in 2017. The school-age version of the Children Behavior Checklist was used to measure children's behavioral problems. Descriptive analysis, correlation analysis, and logistic regressions were conducted. The prevalence of behavioral problems was 18.80% and 13.59% for left-behind children and migrant children, respectively, both of which were higher than that of local children. Logistic regression analysis showed that after adjustments for individual and environmental variables, the likelihood of total, internalizing and externalizing behavior problems for left-behind children and migrant children were higher than those for local children; left-behind children had a higher likelihood of internalizing problems than externalizing problems, while migrant children had a higher prevalence of externalizing problems. Left-behind children had a higher prevalence of each specific syndrome than migrant and local children. Both individual and environmental factors were associated with child behavioral problems, and family migration may contribute to the increased risks. Left-behind and migrant children were more vulnerable than local children to behavioral problems.


Assuntos
Comportamento Problema/psicologia , Migrantes/psicologia , Adolescente , Criança , Saúde da Criança , China , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Modelos Logísticos , Masculino , Psicologia da Criança
8.
Cell Metab ; 26(4): 686-692.e3, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28918935

RESUMO

Efferent signals from the central nervous system represent a key layer of regulation of white adipose tissue (WAT). However, the mechanism by which efferent neural signals control WAT metabolism remains to be better understood. Here, we exploit the volume fluorescence-imaging technique to visualize the neural arborizations in mouse inguinal WAT at single-fiber resolution. The imaging reveals a dense network of sympathetic arborizations that had been previously undetected by conventional methods, with sympathetic fibers being in close apposition to > 90% of adipocytes. We demonstrate that these sympathetic fibers originate from the celiac ganglia, which are activated by cold challenge. Sympathetic-specific deletion of TrkA receptor or pharmacologic ablation by 6-hydroxydopamine abolishes these intra-adipose arborizations and, as a result, cold-induced beiging of inguinal WAT. Furthermore, we find that local sympathetic arborizations function through beta-adrenergic receptors in this beiging process. These findings uncover an essential link connecting efferent neural signals with metabolism of individual adipocytes.


Assuntos
Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/inervação , Tecido Adiposo Branco/metabolismo , Imagem Óptica/métodos , Sistema Nervoso Simpático/ultraestrutura , Tecido Adiposo Branco/ultraestrutura , Animais , Catecolaminas/metabolismo , Temperatura Baixa , Gânglios Simpáticos/metabolismo , Gânglios Simpáticos/ultraestrutura , Imageamento Tridimensional/métodos , Camundongos , Transdução de Sinais , Sistema Nervoso Simpático/metabolismo
9.
Cell Rep ; 19(5): 995-1007, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28467912

RESUMO

Follicular T helper (TFH) cells orchestrate the germinal center (GC) response locally. TFH localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here. we define an antigen-independent, contact-dependent, adhesive guidance system for TFH cells. Unusual for amoeboid cell migration, the system is composed of transmembrane plexin B2 (PlxnB2) molecule, which is highly expressed by GC B cells, and its transmembrane binding partner semaphorin 4C (Sema4C), which is upregulated on TFH cells. Sema4C on TFH cells serves as a receptor to sense the GC-presented PlxnB2 cue and biases TFH migration inwards at the GC edge to promote GC access. The absence of PlxnB2 from the GC or Sema4C from TFH cells causes TFH accumulation along the GC border, impairs T-B cell interactions in the GC, and is associated with defective plasma cell production and affinity maturation. Therefore, Sema4C and PlxnB2 regulate GC TFH recruitment and function and optimize antibody responses.


Assuntos
Movimento Celular , Centro Germinativo/citologia , Proteínas do Tecido Nervoso/metabolismo , Semaforinas/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Linfócitos B/fisiologia , Células Cultivadas , Centro Germinativo/metabolismo , Camundongos , Linfócitos T Auxiliares-Indutores/fisiologia
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