RESUMO
Acetaminophen (APAP) overdose is the major cause of acute liver failure in the US. Prompt liver regeneration is critical for recovery after APAP hepatotoxicity, but mechanisms remain elusive. Extracellular matrix (ECM)-mediated signaling via integrin-linked kinase (ILK) regulates liver regeneration after surgical resection. However, the role of ECM signaling via ILK in APAP toxicity and compensatory regeneration is unknown, which was investigated in this study using liver-specific ILK knockout (KO) mice. ILK KO and wild-type (WT) mice were treated with 300 mg/kg APAP, and injury and regeneration were studied at 6 and 24 h after APAP treatment. ILK KO mice developed lower liver injury after APAP overdose, which was associated with decreased JNK activation (a key mediator of APAP toxicity). Further, higher glutathione levels after APAP treatment and lower APAP protein adducts levels, along with lower levels of CYP2E1, suggest decreased metabolic activation of APAP in ILK KO mice. Interestingly, despite lower injury, ILK KO mice had rapid and higher liver regeneration after APAP overdose accompanied with increased ß-catenin signaling. In conclusion, liver-specific deletion of ILK improved regeneration, attenuated toxicity after APAP overdose, and decreased metabolic activation of APAP. Our study also indicates that ILK-mediated ECM signaling plays a role in the regulation of CYP2E1 and may affect toxicity of several centrilobular hepatotoxicants including APAP.
Assuntos
Acetaminofen/farmacologia , Hepatócitos/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Overdose de Drogas/metabolismo , Overdose de Drogas/patologia , Glutationa/metabolismo , Hepatócitos/metabolismo , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 × 10(-5)) and diastolic BP (P = 7.61 × 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 × 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
Assuntos
Pressão Sanguínea/genética , Fator 1 de Crescimento de Fibroblastos/genética , Hipertensão/genética , Rim/química , Adolescente , Adulto , Idoso , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Neprilisina/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/análise , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Renina/genética , Transdução de Sinais/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Proteína Quinase 1 Deficiente de Lisina WNK , Adulto JovemRESUMO
Background. Tai Chi is a form of exercise that is accessible to people from different socioeconomic backgrounds, making it a potentially valuable activity for health promotion of older adults. Purpose. The objective of this scoping review was to summarize the current knowledge about the effectiveness of Tai Chi for older adults across a range of general health outcomes from published, peer reviewed, unique meta-analyses. Methods. Meta-analyses were retrieved from Medline, Embase, AMED, CINAHL, SPORTDiscus, PsychINFO, Web of Science, PubMed Health, and the Cochrane Library from database inception to late August 2019. Multistage deduplication and screening processes identified eligible full-length meta-analyses. Two people independently appraised 27 meta-analyses based on the GRADE system and organized results into 3 appendices subsequently collated into heterogeneous, statistically significant, and statistically insignificant tables. Results. "High" and "moderate" quality evidence extracted from these meta-analyses demonstrated that practicing Tai Chi can significantly improve balance, cardiorespiratory fitness, cognition, mobility, proprioception, sleep, and strength; reduce the incidence of falls and nonfatal stroke; and decrease stroke risk factors. Conclusions. Health care providers can now recommend Tai Chi with high level of certainty for health promotion of older adults across a range of general health outcomes for improvement of overall well-being.