Background: Microscopic residual tumor often occurs after thermal ablation for medium-large hepatocellular carcinoma (HCC), leading to early aggressive recurrence or late relapse during follow-up. The mechanism how microscopic residual HCC cells survive sublethal heat stress and develop rapid outgrowth remains poorly understood.
Methods: HCC cells were exposed to sublethal heat treatment and co-cultured with conditioned media from activated HSCs (HSC-CM). Changes of cell proliferation, parameters of cell autophagy and activation of signaling pathways in heat-treated residual HCC cells were analyzed. An HCC orthotopic model was subjected to partial thermal ablation and antitumor effects of a combined treatment regimen were studied.
Results: HCC cells survived sublethal heat stress via activation of autophagy. HSC-CM enhanced autophagic survival within 24?h and then promoted proliferation of heat-treated residual HCC cells through HGF/c-Met signaling. Inhibition of autophagy or c-Met increased apoptosis of heat-treated residual HCC cells and reversed the protective effect of HSC-CM. HGF modulated biological status in autophagic survival or proliferation of heat-treated residual HCC through HGF/c-Met/ERK signaling and downstream components of ATG5/Beclin1 or cyclinD1. In an animal model, inhibiting autophagy in combination with c-Met inhibitor significantly thwarted tumor progression of residual HCC after incomplete thermal ablation via the suppressed autophagy, the decreased proliferation and the increased apoptosis.
Conclusions: Activated HSCs promote progression of residual HCC cells after sublethal heat treatment from autophagic survival to proliferation via HGF/c-Met signaling. A combined treatment regimen of inhibiting autophagy and c-Met signaling could be used to suppress tumor progression of residual HCC after incomplete thermal ablation. 相似文献
High levels of consumption of saturated lipids have been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance (IR). Scutellarin (Scu) is one of the effective traditional Chinese medicines considered beneficial for liver diseases and diabetes. In this study, we investigated the effect of Scu on IR and lipid metabolism disorders in vitro and in high fat diet (HFD)‐fed mice. In vitro, we found that Scu decreased insulin‐dependent lipid accumulation and the mRNA expression of CD36, Fasn, and ACC in PA‐treated HepG2 cells. Additionally, Scu upregulated Akt phosphorylation and improved the insulin signalling pathway. Moreover, Scu downregulated mammalian target of rapamycin (mTOR) phosphorylation and the n‐SREBP‐1c protein level and also reduced lipid accumulation via the mTOR‐dependent pathway, as confirmed by the molecular docking of Scu to mTOR. In HFD‐fed C57BL/6 mice, Scu improved oral glucose tolerance, pyruvate tolerance and the IR index and also increased the Akt phosphorylation level. Moreover, Scu reduced hepatocyte steatosis, decreased lipid accumulation and triglyceride levels, inhibited mTOR phosphorylation, and decreased the SREBP‐1c level in the liver. Taken together, these findings suggest that Scu ameliorates hepatic IR by regulating hepatocyte lipid metabolism via the mTOR‐dependent pathway through SREBP‐1c suppression. 相似文献
Sudden focal neurological symptoms or ‘brain attacks’ in children are a common scenario for acute paediatric care givers. A small proportion will have had a vascular stroke. Suspected stroke in adults, signalled by FAST (Face, Arms, Speech, Time) test positivity, is an accepted medical emergency. Children are rarely dealt with urgently unless there is coma. Barriers to stroke recognition and response in children are multifactorial. Childhood stroke is rare and may be ‘FAST negative’. Overall, there is low awareness, low clinical suspicion and many logistic obstacles to timely detection and aspired treatment delivery. Yet stroke continues to affect hundreds of children in the UK each year, causing life-changing disability and, in some, death. This article highlights current key recommendations for the diagnosis and management of acute stroke set out in the 2017 Royal College of Paediatrics and Child Health (RCPCH) Stroke in childhood guideline. Evidence and rationale are discussed, and important practice points offered. There is focus on arterial ischaemic stroke in light of the proposed hyperacute management pathway, which includes thrombolysis. Ongoing challenges on the ground and how these may be overcome are considered. 相似文献
Background and aimsConsuming pulses (dry beans, dry peas, chickpeas, lentils) over several weeks can improve vascular function and decrease cardiovascular disease risk; however, it is unknown whether pulses can modulate postprandial vascular responses. The objective of this study was to compare different bean varieties (black, navy, pinto, red kidney) and white rice for their acute postprandial effects on vascular and metabolic responses in healthy individuals.Methods and resultsThe study was designed as a single-blinded, randomized crossover trial with a minimum 6 days between consumption of the food articles. Vascular tone (primary endpoint), haemodynamics and serum biochemistry (secondary endpoints) were measured in 8 healthy adults before and at 1, 2, and 6 h after eating ¾ cup of beans or rice. Blood pressure and pulse wave velocity (PWV) were lower at 2 h following red kidney bean and pinto bean consumption compared to rice and navy bean, respectively (p < 0.05). There was greater vasorelaxation 6 h following consumption of darker-coloured beans, as shown by decreased vascular tone: PWV was lower after consuming black bean compared to pinto bean, augmentation pressure was lower after consuming black bean compared to rice and pinto bean, and wave reflection magnitude was lower after consuming red kidney bean and black bean compared to rice, navy bean, and pinto bean (p < 0.05). LDL-cholesterol concentrations were lower 6 h after black bean consumption compared to rice (p < 0.05).ConclusionOverall, red kidney and black beans, the darker-coloured beans, elicited a positive effect on the tensile properties of blood vessels, and this acute response may provide insight for how pulses modify vascular function. 相似文献