RESUMO
The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-ß-ribofuranoside (AICAR) or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that, consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy and improves hepatic insulin sensitivity in high-fat-diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Linhagem Celular Transformada , Dieta Hiperlipídica , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Proteínas F-Box , Humanos , Hipoglicemiantes/síntese química , Resistência à Insulina , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Dinâmica Mitocondrial/efeitos dos fármacos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Poliubiquitina/genética , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ribonucleotídeos/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Computer-assisted navigation (CAN) and robotic-assisted (RA) knee arthroplasty procedures carry unique risks of tracking pin-related complications. This systematic review aimed to quantitatively assess the incidence, timing, treatment, and clinical outcomes of all tracking pin-related complications following CAN and RA knee arthroplasty. METHODS: A systematic review was performed using PubMed, Cochrane Central and Scopus databases. All clinical studies that documented pin-related complications associated with the use of CAN or RA for total or partial knee arthroplasty were included. Descriptive statistics were analyzed when data were available. RESULTS: Thirty-six studies were included: 18 case reports (25 cases) and 18 randomized controlled trials, cohort studies and case series i.e., non-case reports (7,336 cases). The most common pin-related complication among case reports was fracture (n = 22; 81%). The overall rate of pin-related complications among non-case reports was 1.4%. The intraoperative and postoperative complication with the highest incidence were pin dislodgement (0.6%) and superficial pin site infections (0.6%), respectively. Most postoperative complications were related to the tibial site (69%). All complications were effectively treated and resolved at follow-up. CONCLUSION: Pin-related complications following CAN and RA knee arthroplasty are relatively uncommon. While pin loosening, superficial infections and fractures have been most commonly documented, other complications such as vascular injury, myositis ossificans, and osteomyelitis can also occur. The potential for pin-related complications should be considered by arthroplasty surgeons, especially during early stages of adoption. Further studies investigating patient risk factors for pin-related complications are warranted.
Assuntos
Artroplastia do Joelho , Osteoartrite do Joelho , Procedimentos Cirúrgicos Robóticos , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Computadores , Humanos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Tíbia/cirurgiaRESUMO
By using catalytic amounts of copper(II), 4-picoline, and dimethylphenylsilylpinacol borane, a series of allenoates were silylated on the ß carbon in good to excellent yields and high (E)-selectivity. The mild and efficient silylation method is conducted in water under atmospheric conditions to afford vinylsilanes.