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1.
Immunity ; 55(8): 1448-1465.e6, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35931085

RESUMO

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.


Assuntos
Doença de Alzheimer , Microglia , Envelhecimento , Doença de Alzheimer/genética , Animais , Encéfalo/patologia , Humanos , Macrófagos/patologia , Glicoproteínas de Membrana , Camundongos , Microglia/patologia , Receptores Imunológicos
2.
J Glob Antimicrob Resist ; 17: 312-315, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30682564

RESUMO

OBJECTIVES: Antimicrobial stewardship programmes (ASPs) have often been recommended as a viable solution to minimise the incidence of Clostridium difficile infection (CDI), which can be life-threatening. This study aimed to evaluate whether ASP interventions have contributed to reducing CDI rates. METHODS: A retrospective review of ASP interventions issued from January 2013 to April 2014 was performed using data from the ASP database of Singapore General Hospital, a 1600-bed tertiary-care hospital in Singapore. A total of 283 interventions satisfied the inclusion criteria, of which commonly audited antibiotics were piperacillin/tazobactam (41.3%) and carbapenems (54.8%). Comparisons were made at 30days post-intervention between those with accepted or rejected interventions. The primary outcome was CDI incidence; secondary outcomes included length of hospitalisation post-intervention, 30-day mortality and CDI recurrence rate. RESULTS: Whilst the median duration of antibiotic therapy was reduced by 2days (6days vs. 4 days; P<0.001), acceptance of ASP interventions did not alter primary CDI incidence at 30days (P=0.644) post-intervention. However, reduced CDI recurrence rates were observed for patients positive for CDI in the accepted patient group compared with the rejected group (0% vs. 37.5%; P=0.03), with no difference in CDI 30-day mortality between the two groups. CONCLUSION: Intervention acceptance did not contribute to a significant reduction in CDI incidence but may be associated with lower recurrence rates, although further studies are required.


Assuntos
Gestão de Antimicrobianos/métodos , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/prevenção & controle , Idoso , Antibacterianos/uso terapêutico , Carbapenêmicos , Infecções por Clostridium/mortalidade , Infecção Hospitalar/prevenção & controle , Uso de Medicamentos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Singapura , Centros de Atenção Terciária
3.
ChemMedChem ; 7(9): 1567-79, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22887959

RESUMO

Curcumin arrests the proliferation of acute promyelocytic leukemia (APL) cells by stabilizing the misfolded nuclear receptor co-repressor (N-CoR) protein, thereby sensitizing APL cells to apoptosis induced by the unfolded protein response. This phenomenon was attributed to inhibition of the proteasomal and protease-induced breakdown of misfolded N-CoR by curcumin. Curcumin is, however, a modest inhibitor and affected the viability of APL cells at micromolar concentrations. Modifying curcumin at its conjugated ß-diketone linker and terminal phenyl rings yielded potent congeners with sub-micromolar growth inhibitory activities which selectively kill APL cells over non-APL leukemic and nonmalignant cells. Analogues with pronounced APL-selective anti-proliferative activities, as observed in representative dibenzylidenecyclohexanones and dibenzylidenecyclopentanones, strongly promoted the accumulation of misfolded and nonfunctional N-CoR at significantly lower concentrations than their growth inhibitory IC(50) values. These compounds also inhibited the human 20S proteasome in an enzyme-based assay, thus providing convincing support for the prevailing hypothesis that impeding the degradation of N-CoR is a key mechanistic event contributing to APL cell death.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteínas Correpressoras/metabolismo , Curcumina/análogos & derivados , Curcumina/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proteínas Correpressoras/análise , Humanos , Leucemia Promielocítica Aguda/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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