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1.
Transplant Direct ; 8(8): e1347, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37077732

RESUMO

The COVID-19 pandemic has limited liver transplant (LT) candidates access to clinics. Telehealth methods to assess frailty are needed. We developed a method to estimate the step length of LT candidates, which would permit remotely obtaining the 6-min walk test (6MWT) distance with a personal activity tracker (PAT). Methods: 6MWT was performed while candidates wore a PAT. On first 21 subjects (stride cohort), the step length was measured and compared with calculated one (6MWT-distance/6MWT steps). On a second cohort (PAT-6MWT; n = 116), we collected the 6MWT step count and used multivariable models to generate formulas estimating step length. We multiplied the estimated step length times 6MWT steps to estimate the distance and compared it to the measured distance. The liver frailty index (LFI) and 6MWT were used as frailty metrics. Results: Measured/calculated step length were highly correlated (ρ = 0.85; P < 0.001) in the stride cohort. In the PAT-6MWT cohort, LFI was the strongest variable associated with step length, along with height, albumin, and large-volume paracentesis (R 2 = 0.58). On a second model without LFI, age, height, albumin, hemoglobin, and large-volume paracentesis were strongly associated with step length (R 2 = 0.45). There was a robust correlation between observed 6MWT and PAT-6MWT utilizing step length equations with (ρ = 0.80; P < 0.001) or without LFI (ρ = 0.75; P < 0.001). Frailty by 6MWT <250 m did not change significantly using the observed (16%) or the with/without LFI-estimated (14%/12%) methods. Conclusions: We created a method to obtain 6MWT distance remotely with the use of a PAT. This novel approach opens the possibility of performing telemedicine PAT-6MWT to monitor LT candidates' frailty status.

2.
JCI Insight ; 6(14)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34291733

RESUMO

Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.


Assuntos
Proteínas Quinases Ativadas por AMP/deficiência , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T Reguladores/imunologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Transplante de Medula Óssea/efeitos adversos , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Linfócitos T Reguladores/metabolismo , Transplante Homólogo/efeitos adversos
3.
Front Immunol ; 11: 1517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793207

RESUMO

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined by graft-versus-host disease (GVHD), where T cells from the donor attack and destroy recipient tissues. Given the strong interconnection between T cell metabolism and cellular function, determining the metabolic pathways utilized by alloreactive T cells is fundamental to deepening our understanding of GVHD biology, including its initiation, propagation, and potential mitigation. This review summarizes the metabolic pathways available to alloreactive T cells and highlights key metabolic proteins and pathways linking T cell metabolism to effector function. Our current knowledge of alloreactive T cell metabolism is then explored, showing support for glycolysis, fat oxidation, and glutamine metabolism but also offering a potential explanation for how these presumably contradictory metabolic findings might be reconciled. Examples of additional ways in which metabolism impacts aHSCT are addressed, including the influence of butyrate metabolism on GVHD resolution. Finally, the caveats and challenges of assigning causality using our current metabolic toolbox is discussed, as well as likely future directions in immunometabolism, both to highlight the strengths of the current evidence as well as recognize some of its limitations.


Assuntos
Isoantígenos/imunologia , Redes e Vias Metabólicas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Metabolismo Energético , Doença Enxerto-Hospedeiro/etiologia , Efeito Enxerto vs Tumor/imunologia , Humanos , Imunidade Celular , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Acta Neuropathol Commun ; 5(1): 81, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29115989

RESUMO

It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems. We have shown that clusterin directly interacts with TDP-43 in vitro and potently inhibits its aggregation, and observed that in ER stressed neuronal cells, clusterin co-localized with TDP-43 and specifically reduced the numbers of cytoplasmic inclusions. We further showed that the expression of TDP-43 in transgenic Drosophila neurons induced ER stress and that co-expression of clusterin resulted in a dramatic clearance of mislocalized TDP-43 from motor neuron axons, partially rescued locomotor activity and significantly extended lifespan. We also showed that in Drosophila photoreceptor cells, clusterin co-expression gave ER stress-dependent protection against proteotoxicity arising from both Huntingtin-Q128 and mutant (R406W) human tau. We therefore conclude that increased expression of clusterin can provide an important defense against intracellular proteotoxicity under conditions that mimic specific features of neurodegenerative disease.


Assuntos
Clusterina/metabolismo , Clusterina/farmacologia , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Clusterina/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Estresse do Retículo Endoplasmático/genética , Olho/metabolismo , Olho/ultraestrutura , Hemolinfa/citologia , Humanos , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Larva , Atividade Motora/genética , Atividade Motora/fisiologia , Neurônios Motores/ultraestrutura , Neuroblastoma/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/patologia , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção
5.
J Biol Chem ; 292(35): 14425-14437, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28710283

RESUMO

The misfolding of proteins and their accumulation in extracellular tissue compartments as insoluble amyloid or amorphous protein aggregates are a hallmark feature of many debilitating protein deposition diseases such as Alzheimer's disease, prion diseases, and type II diabetes. The plasminogen activation system is best known as an extracellular fibrinolytic system but was previously reported to also be capable of degrading amyloid fibrils. Here we show that amorphous protein aggregates interact with tissue-type plasminogen activator and plasminogen, via an exposed lysine-dependent mechanism, to efficiently generate plasmin. The insoluble aggregate-bound plasmin is shielded from inhibition by α2-antiplasmin and degrades amorphous protein aggregates to release smaller, soluble but relatively hydrophobic fragments of protein (plasmin-generated protein fragments (PGPFs)) that are cytotoxic. In vitro, both endothelial and microglial cells bound and internalized PGPFs before trafficking them to lysosomes. Clusterin and α2-macroglobulin bound to PGPFs to significantly ameliorate their toxicity. On the basis of these findings, we hypothesize that, as part of the in vivo extracellular proteostasis system, the plasminogen activation system may work synergistically with extracellular chaperones to safely clear large and otherwise pathological protein aggregates from the body.


Assuntos
Fibrinolisina/metabolismo , Microglia/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Ativadores de Plasminogênio/toxicidade , Agregados Proteicos , Ativador de Plasminogênio Tecidual/metabolismo , alfa 2-Antiplasmina/metabolismo , Substituição de Aminoácidos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Clusterina/química , Clusterina/metabolismo , Conalbumina/química , Conalbumina/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Fibrinolisina/antagonistas & inibidores , Fibrinolisina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microglia/metabolismo , Microglia/patologia , Microglia/ultraestrutura , Mutação , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Plasminogênio/química , Plasminogênio/metabolismo , Ativadores de Plasminogênio/química , Ativadores de Plasminogênio/genética , Ativadores de Plasminogênio/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Solubilidade , Superóxido Dismutase-1/química , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Ativador de Plasminogênio Tecidual/química
7.
Bioorg Med Chem Lett ; 21(2): 660-3, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21190849

RESUMO

Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Brain Behav Evol ; 71(4): 247-62, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18431052

RESUMO

Growth-associated protein-43 is typically expressed at high levels in the nervous system during development. In adult animals, its expression is lower, but still observable in brain areas showing structural or functional plasticity. We examined patterns of GAP-43 immunoreactivity in the brain of the bullfrog, an animal whose nervous system undergoes considerable reorganization across metamorphic development and retains a strong capacity for plasticity in adulthood. Immunolabeling was mostly diffuse in hatchling tadpoles, but became progressively more discrete as larval development proceeded. In many brain areas, intensity of immunolabel peaked at metamorphic climax, the time of final transition from aquatic to semi-terrestrial life. Changes in intensity of GAP-43 expression in the medial vestibular nucleus, superior olivary nucleus, and torus semicircularis appeared correlated with stage-dependent functional changes in processing auditory stimuli. Immunolabeling in the Purkinje cell layer of the cerebellum and in the cerebellar nucleus was detectable at most developmental time points. Heavy immunolabel was present from early larval stages through the end of climax in the thalamus (ventromedial, anterior, posterior, central nuclei). Immunolabel in the tadpole telencephalon was observed around the lateral ventricles, and in the medial septum and ventral striatum. In postmetamorphic animals, immunoreactivity was confined mainly to the ventricular zones and immediately adjacent cell layers. GAP-43 expression was present in olfactory, auditory and optic cranial nerves throughout larval and postmetamorphic life. The continued expression of GAP-43 in brain nuclei and in cranial nerves throughout development and into adulthood reflects the high regenerative potential of the bullfrog's central nervous system.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteína GAP-43/metabolismo , Metamorfose Biológica/fisiologia , Rana catesbeiana/crescimento & desenvolvimento , Rana catesbeiana/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/citologia , Imuno-Histoquímica , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Larva/metabolismo , Bulbo/citologia , Bulbo/crescimento & desenvolvimento , Bulbo/metabolismo , Mesencéfalo/citologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/metabolismo , Vias Neurais/citologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Rana catesbeiana/anatomia & histologia , Regulação para Cima/fisiologia
9.
Brain Behav Evol ; 71(1): 41-53, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17878717

RESUMO

The distribution of proliferating cells in the midbrain, thalamus, and telencephalon of adult bullfrogs (Rana catesbeiana) was examined using immunohistochemistry for the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) and DNA dot-blotting. At all time points examined (2 to 28 days post-injection), BrdU-labeled cells were located in ventricular zones at all levels of the neuraxis, but with relatively more label around the telencephalic ventricles. Labeled cells, some showing profiles indicative of dividing and migrating cells, were present in brain parenchyma from 7 to 28 days post-injection. These labeled cells were particularly numerous in the dorsal and ventral hypothalamus, preoptic area, optic tectum, and laminar and principal nuclei of the torus semicircularis, with label also present, but at qualitatively reduced levels, in thalamic and telencephalic nuclei. Double-label immunohistochemistry using glial and early neural markers indicated that gliogenesis and neurogenesis both occurred, with new neurons observed particularly in the hypothalamus, optic tectum, and torus semicircularis. In all brain areas, many cells not labeled with BrdU were nonetheless labeled with the early neural marker TOAD-64, indicating that these cells were postmitotic. Incorporation of DNA measured by dot-blotting confirms the presence of DNA synthesis in the forebrain and brainstem at all time points measured. The pattern of BrdU label confirms previous experiments based on labeling with (3)H-thymidine and proliferating cell nuclear antigen showing cell proliferation in the adult ranid brain, particularly in hypothalamic nuclei. The consistent appearance of new cells in the hypothalamus of adult frogs suggests that proliferative activity may be important in mediating reproductive behaviors in these animals.


Assuntos
Proliferação de Células , Mesencéfalo/citologia , Prosencéfalo/citologia , Rana catesbeiana/fisiologia , Animais , Bromodesoxiuridina/metabolismo , Immunoblotting , Imuno-Histoquímica , Mesencéfalo/metabolismo , Prosencéfalo/metabolismo , Fatores de Tempo
10.
Am J Orthod Dentofacial Orthop ; 130(2): 163-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16905059

RESUMO

INTRODUCTION: The objectives of the study were to determine the relative importance of various dental features that contribute to overall dental attractiveness and to test the validity of the concepts of golden proportion and golden percentage as applied to the human dentition. METHODS: Sixty 30-year-old subjects (29 men, 31 women) were selected from the 20-year longitudinal Cardiff Survey. Color photographs of the subjects' dentitions were taken with the lips retracted so that their teeth and gums were clearly exposed. Twelve nondentists, aged 32 to 33 years, equally divided according to sex, rated the subjects' dental appearances on a 5-point Likert attractiveness scale. The maxillary anterior teeth were measured, and relevant ratios were calculated and compared with the golden proportion. Factor analyses and linear regression were used to investigate the hierarchy of dental features, and variance components analysis was used to estimate interrater agreement. RESULTS AND CONCLUSIONS: Overall dental attractiveness did not depend on any particular feature of the dentition. A hierarchy of various features was established, with crown shape ranked highest, and tooth and gum color ranked lowest. The golden proportion and the golden percentage were not decisive factors in determining dental attractiveness.


Assuntos
Estética Dentária/psicologia , Adulto , Cor , Análise Fatorial , Feminino , Gengiva/anatomia & histologia , Humanos , Modelos Lineares , Masculino , Odontometria , Grupo Associado , Fotografia Dentária , Inquéritos e Questionários , Coroa do Dente/anatomia & histologia
11.
J Neurobiol ; 66(11): 1212-24, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16858692

RESUMO

We examined patterns of cell proliferation in the auditory midbrain (torus semicircularis) of the bullfrog, Rana catesbeiana, over larval and early postmetamorphic development, by visualizing incorporation of 5-bromo-2'-deoxyuridine (BrdU) in cycling cells. At all developmental stages, BrdU-labeled cells were concentrated around the optic ventricle. BrdU-labeled cells also appeared within the torus semicircularis itself, in a stage-specific manner. The mitotic index, quantified as the percent of BrdU-positive cells outside the ventricular zone per total cells available for label, varied over larval development. Mitotic index was low in hatchling, early larval, and late larval stages, and increased significantly in deaf period, metamorphic climax, and froglet stages. Cell proliferation was higher in metamorphic climax than at other stages, suggesting increased cell proliferation in preparation for the transition from an aquatic to an amphibious existence. The change in mitotic index over development did not parallel the change in the total numbers of cells available for label. BrdU incorporation was additionally quantified by dot-blot assay, showing that BrdU is available for label up to 72 h postinjection. The pattern of change in cell proliferation in the torus semicircularis differs from that in the auditory medulla (dorsal medullary nucleus and superior olivary nucleus), suggesting that cell proliferation in these distinct auditory nuclei is mediated by different underlying mechanisms.


Assuntos
Vias Auditivas/embriologia , Mesencéfalo/embriologia , Rana catesbeiana/fisiologia , Animais , Western Blotting , Proliferação de Células , Processamento de Imagem Assistida por Computador , Immunoblotting , Imuno-Histoquímica , Larva
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