Melatonin safeguards against fatty liver by antagonizing TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner.     

Silsesquioxane‐Containing Hybrid Nanomaterials: Fascinating Platforms for Advanced Applications

Silsesquioxanes (SSQs), with the general formula, (RSiO_1.5)_n—where R stands for an organic group, such as alkyl, aryl, alkoxy, or H—are a type of molecular‐level organic/inorganic hybrid silica‐based material. These materials contain reactive or nonreactive organic moieties as well as inorganic Si–O–Si frameworks. In the past few years, extensive efforts have been made using SSQs to construct multifunctional nanocomposites with suitable properties for a range of applications. In this review, the recent various applications of SSQ‐containing hybrid materials are discussed, in addition to updates of the nanocomposite applications. Various physical structures and chemical reactions in SSQ‐based hybrid nanomaterials are emphasized with regard to applications in the field of polymer nanocomposites, catalysts, adsorption, sensors, and biomedicine. This review focuses on results reported in the recent five years (2013–2018).     

立体定向软通道穿刺术对高血压脑出血患者应激状态及脑血流的影响

目的分析立体定向软通道穿刺术治疗高血压脑出血的疗效,分析其对患者应激状态和脑血流的影响。方法将160例高血压脑出血患者随机分为2组,对照组和观察组各80例。对照组患者采用常规开颅手术治疗,观察组则进行立体定向软通道穿刺术。比较2组间治疗效果,并观察氧化应激相关指标[包括超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-PX)、脂质过氧化产物(LPO)及总抗氧化能力(TAC)]和大脑中动脉血流指标[包括收缩期峰值流速(PSV)、舒张压末期血流速度(EDV)、血流速度(Vm)、血管搏动指数(PI)及阻力指数(RI)]的变化。结果治疗后第1、3、12个月2组间疗效均无显著差异(分别为85.00%vs.87.50%,86.25%vs.88.75%,93.75%vs.93.75%,P>0.05)。与治疗前比较,治疗第1天2组患者SOD、GSH-PX水平显著降低,MDA、LPO水平和TAC值则显著升高(P<0.05),而治疗第7天均有所恢复。治疗第1、7天后,观察组血清MDA和LPO水平显著低于对照组,SOD、GSH-PX水平和TAC值显著高于对照组(P<0.05)。治疗第1、7天,2组PSV、EDV、Vm、Pl与治疗前相比显著升高,RI则显著降低(P<0.05)。治疗1、7天后,观察组患者PSV、EDV、Vm、PI均显著大于对照组,Rl则显著低于对照组(P<0.05)。结论采用立体定向软通道穿刺术治疗高血压脑出血相比于传统开颅手术,具有对患者应激影响小,术后脑血流恢复快的优点,且长期疗效良好。     

National Priority Setting of Clinical Practice Guidelines Development for Chronic Disease Management

By November 2013, a total of 125 clinical practice guidelines (CPGs) have been developed in Korea. However, despite the high burden of diseases and the clinical importance of CPGs, most chronic diseases do not have available CPGs. Merely 83 CPGs are related to chronic diseases, and only 40 guidelines had been developed in the last 5 yr. Considering the rate of the production of new evidence in medicine and the worsening burden from chronic diseases, the need for developing CPGs for more chronic diseases is becoming increasingly pressing. Since 2011, the Korean Academy of Medical Sciences and the Korea Centers for Disease Control and Prevention have been jointly developing CPGs for chronic diseases. However, priorities have to be set and resources need to be allocated within the constraint of a limited funding. This study identifies the chronic diseases that should be prioritized for the development of CPGs in Korea. Through an objective assessment by using the analytic hierarchy process and a subjective assessment with a survey of expert opinion, high priorities were placed on ischemic heart disease, cerebrovascular diseases, Alzheimer''s disease and other dementias, osteoarthritis, neck pain, chronic kidney disease, and cirrhosis of the liver.     

Morphological analyses and a novel de novo DLX3 mutation associated with tricho–dento–osseous syndrome in a Chinese family

Tricho–dento–osseous (TDO) syndrome, an autosomal‐dominant disorder, affects the morphological appearance of the tooth enamel, hair, and bone. Previous studies have confirmed that mutations in the DLX3 gene are responsible for TDO. In this study, we describe a Chinese patient with the typical traits of TDO – kinky hair, enamel hypoplasia, skull and jaw bones thickening, and sclerosis. Unfortunately, as a result of excessive attrition, we were unable to assess taurodontism. Examination of the tooth ground section showed a thin layer of enamel with no rods on the patient's tooth and abnormalities in Tomes' granular layer and the dentinal tubules. Scanning electron microscopy and energy‐dispersive X‐ray spectroscopy of the tooth enamel showed significant differences between the patient and the control individuals. A hair sample from the patient observed under a laser‐scanning microscope showed longitudinal grooves in the hair shaft. Dual‐energy X‐ray absorptiometry measurement showed that the bone mineral density values of the patient's bones was much higher than normal. Finally, genetic analysis revealed a novel de novo missense mutation c.533A>G (p.Q178R) in the conserved homeodomain of the DLX3 gene. This DLX3 mutation is the sixth causative mutation for TDO to be identified so far.     

Effect of individualized therapy for AIDS patients with cytomegalovirus retinitis in intravitreal ganciclovir injections

The effect of intravitreal ganciclovir injection combined with intravenous infusion on acquired immune deficiency syndrome (AIDS) patients with cytomegalovirus retinitis (CMVR) was investigated. A total of 32 eyes in 23 AIDS patients diagnosed as CMVR from 2017 to 2018 were included in the retrospective study. All patients underwent induction therapy by using intravenous drip of the anti-cytomegalovirus (CMV) agent ganciclovir (5 mg/kg q12h) combined with intravitreal ganciclovir injection (3 mg/time, 2 times/wk). The visual acuity, fundus photographs, lesion location, and number of intravitreal injections were observed preoperatively and postoperatively. Totally 14 eyes were cured during induction therapy. The number of injections [4.13 (2 to 6)] in CMVR patients with peripherally fundus lesions were significantly lower than those with central lesions [4.89 (2 to 6)]. The individualized therapy of intravitreal ganciclovir injections for AIDS patients with CMVR can effectively reduce the numbers of intravitreal injections.