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Br J Pharmacol ; 176(16): 2922-2944, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124139


BACKGROUND AND PURPOSE: Celastrol exhibits anti-arthritic effects in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol-induced Ca2+ signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. EXPERIMENTAL APPROACH: We used computational docking, Ca2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), mechanisms of Ca2+ -mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti-arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. KEY RESULTS: Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via Ca2+ /calmodulin-dependent kinase kinase-ß-AMP-activated protein kinase-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes down-regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca2+ in celastrol-regulated gene expression. CONCLUSION AND IMPLICATIONS: Celastrol triggered Ca2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca2+ signalling.

Clin Interv Aging ; 9: 283-91, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24550670


BACKGROUND: Stroke survivors may not be receiving optimal rehabilitation as a result of a shortage of hospital resources, and many of them are institutionalized. A rehabilitation program provided in a short-term residential care setting may help to fill the service gap. OBJECTIVES: The primary objectives of this study were, first, to examine whether there were significant differences in terms of rehabilitation outcomes at 1 year after admission to the rehabilitation program (defined as baseline) between those using short-term residential care (intervention group) and those using usual geriatric day hospital care (control group), and, second, to investigate whether lower 1-year institutionalization rates were observed in the intervention group than in the control group. PARTICIPANTS: 155 stroke survivors who completed at least the first follow-up at 4 months after baseline. INTERVENTION: The intervention group was stroke survivors using self-financed short-term residential care for stroke rehabilitation. The control group was stroke survivors using the usual care at a public geriatric day hospital. MEASUREMENTS: Assessments were conducted by trained research assistants using structured questionnaires at baseline, 4 months, and 1 year after baseline. The primary outcome measures included Modified Barthel Index score, Mini-Mental Status Examination score, and the institutionalization rate. RESULTS: Cognitive status (as measured by Mini-Mental Status Examination score) of patients in both groups could be maintained from 4 months to 1 year, whereas functional status (as measured by Modified Barthel Index score) of the patients could be further improved after 4 months up to 1 year. Meanwhile, insignificant between-group difference in rehabilitation outcomes was observed. The intervention participants had a significantly lower 1-year institutionalization rate (15.8%) than the control group (25.8%). CONCLUSION: Short-term residential care for stroke rehabilitation promoted improvements in rehabilitation outcomes comparable with, if not better than, the usual care at geriatric day hospital. Furthermore, it had a significantly lower 1-year institutionalization rate. This type of service could be promoted to prevent institutionalization.

Institucionalização/estatística & dados numéricos , Reabilitação do Acidente Vascular Cerebral , Idoso , Feminino , Humanos , Masculino , Instituições Residenciais/métodos , Sobreviventes , Fatores de Tempo , Resultado do Tratamento
Clin Interv Aging ; 8: 1167-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24039413


We conducted a quasi-experimental study to compare the effectiveness of a new short-term residential care option for stroke rehabilitation with that of usual day hospital care. Primary data were collected from stroke patients and their caregivers from June 2009 to May 2012. New service option users and their caregivers were recruited for the intervention group, while users of usual public geriatric day hospital care and their caregivers were recruited for the control group. The primary outcome measures were Modified Barthel Index (MBI) and Mini-Mental Status Examination (MMSE) scores. Trained research assistants assessed the outcome measures at the beginning of the rehabilitation program (baseline) and at a 4-month follow-up. Sixty and 128 stroke patients were recruited for the intervention and control groups, respectively; 50 and 105 participants, respectively, completed the 4-month follow-up. At 4-month follow-up, the intervention group had an increased MBI score of 15.3 (95% confidence interval [CI] 10.8-19.8) and an MMSE score of 1.3 (95% CI 0.4-2.1). In comparison, the control group had an increased MBI score of 13.3 (95% CI 9.7-16.8) and an MMSE score of 1.1 (95% CI 0.4-1.9). Both groups showed a significant improvement in MBI and MMSE scores after 4 months, and there was no significant between-group difference. To conclude, the new service option and the usual care option showed similar improvement in rehabilitation outcomes at 4 months after baseline. Initiatives to provide alternative care options on a user-pay model should be encouraged to ensure a sustainable health care system.

Instituições Residenciais , Reabilitação do Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Intervalos de Confiança , Hospital Dia , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo