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ChemMedChem ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32154637


This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides demonstrated cytotoxic activity against cancer cells, besides a mechanism of cytotoxic action was proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted on liver cancer cells (SI for compounds 11b and 12a is 8 and 5 respectively). Tetraoxanes and ozonides in some cases were more specific than that of paclitaxel, artemisinin, and artesunic acid. Annexin V flow cytometry analysis revealed that the active ozonides 22a and 23a induced cell death of HepG2 via apoptosis. Further study showed that compounds 22a and 23a exhibited the strong inhibitory effect on P-glycoprotein (P-gp/ABCB5) overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug-resistant phenotype on liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge for the first time it was found, that peroxide diastereoisomers seem to show stereospecific antimalarial action against the chloroquine sensitive 3D7 strain of P. falciparum . Stereoisomeric ozonide 12b is 11-times more active than stereoisomeric ozonide 12a (IC 50 5.81 µM vs IC 50 65.18 µM). Current findings merit further investigation of ozonides as potential therapeutic agent for drug-resistant hepatocellular carcinoma.

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.

Biomed Res Int ; 2016: 5717108, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27525272


Over the recent decades, China experienced several emerging virus outbreaks including those caused by the severe acute respiratory syndrome- (SARS-) coronavirus (Cov), H5N1 virus, and H7N9 virus. The SARS tragedy revealed faults in China's infectious disease prevention system, propelling the Chinese government to enact reforms that enabled better combating of the subsequent H1N1 and H7N9 avian flu epidemics. The system is buttressed by three fundamental, mutually reinforcing components: (1) enduring government administration reforms, including legislation establishing a unified public health emergency management system; (2) prioritized funding for biotechnology and biomedicine industrialization, especially in the areas of pathogen identification, drug production, and the development of vaccines and diagnostics; and (3) increasing investment for public health and establishment of a rapid-response infectious diseases prevention and control system. China is now using its hard-gained experience to support the fight against Ebola in Africa and the Middle East Respiratory Syndrome in its own country.

Doenças Transmissíveis Emergentes/mortalidade , Doenças Transmissíveis Emergentes/prevenção & controle , Influenza Humana/mortalidade , Influenza Humana/prevenção & controle , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Controle de Doenças Transmissíveis/métodos , Controle de Doenças Transmissíveis/normas , Epidemias/prevenção & controle , Epidemias/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Prevalência , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem