PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.

Surgical treatment of Budd-Chiari syndrome: analysis of 221 cases.

BACKGROUND: Budd-Chiari syndrome (B-CS) refers to post-hepatic portal hypertension and/or inferior vena cava hypertension caused by obstruction of blood flow at the portal cardinal hepatic vein. The treatments of B-CS include operations on pathological membrane lesions, shunting and combined operations. Studies have shown that China, Japan, India and South Africa have a high incidence of B-CS. In China, the Yellow River Basin in Henan, Shandong, Jiangsu and Anhui Provinces also have a high incidence, around 10 per 100 000. METHODS: The clinical data of 221 B-CS patients were analyzed retrospectively. We focused on pathological types, surgical methods, effectiveness and complications of treatment, and follow-up. RESULTS: Based on imaging findings such as color ultrasonography, angiography or magnetic resonance angiography, the 221 patients were divided into 3 types (five subtypes): type Ia (72 patients), type Ib (20), type II (72), type IIIa (33), and type IIIb (24). Surgical procedures included balloon membranotomy with or without stent (65 patients), improved splenopneumopexy (18), radical resection of membrane and thrombus (17), inferior vena cava bypass [29, with cavocaval transflow (13) and cavoatrial transflow (16)], mesocaval shunt (41), splenocaval shunt (25), splenoatrial shunt (12), splenojugular shunt (6), and combined methods (8). The complication rate was 9.05% (20/221) and the perioperative death rate was 2.26% (5/221). All of the patients were followed up from 6 months to 5 years. The success rate was 84.6% (187/221), and the recurrence rate was 8.9% (9/101) and 13.5% (13/96) after 1- and 5-year follow-up, respectively. CONCLUSION: The rational choice of surgical treatment based on B-CS pathological typing may increase the success rate and decrease the recurrence.

The use of remifentanil in critically ill patients undergoing percutaneous dilatational tracheostomy: A prospective randomized-controlled trial.

Remifentanil was a µ-agonist, with a rapid onset, a powerful narcotic analgesic activity and a fast nonspecific esterases hydrolyzation and theoretically an ideal opioid for percutaneous dilatational tracheostomy (PDT). The present study discussed use of remifentanil in critically ill patients undergoing PDT. Ninety-nine patients were randomly assigned to the propofol/remifentanil group (PR group, n = 49) or the propofol group (P group, n = 50). Two patients (one in P group and one in PR group) were excluded and transferred to surgical way of tracheostomy because of uncontrolled bleeding. The primary outcomes were critical care pain observation (CPOT) scores during PDT; hemodynamic response and side effects, such as bleeding and muscle rigidity (MR). CPOT scores in P group were significantly higher than in PR group during incision and dilation stages (P < 0.05 and P < 0.01). Systolic blood pressure had a significant drop after a bolus of remifentanil in PR group compared with patients in P group (P < 0.056). The incidence of MR was significantly higher in PR group than in P group (P < 0.05). Recovery time in PR group was significantly shorter than in P group (P < 0.05). The occurrence of tachycardia, bleeding, vomiting, and nausea had no statistically differences in both groups. Patients in PR group were undergoing shorter recovery time and better experience of pain in PDT compared with patients in P group, but MR seemed to be higher in PR group. Remifentanil seemed to be a safe and effective opioid used in critically ill patients undergoing PDT.

Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation.

SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice, AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia. In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases.

A cell-based assay for screening spindle checkpoint inhibitors.

In eukaryotes, the spindle checkpoint acts as a surveillance mechanism that ensures faithful chromosome segregation. The spindle checkpoint prevents premature separation of sister chromatids and the onset of anaphase until every chromosome is properly attached to the mitotic spindle. Tumorigenesis might result from generation of aneuploidy by dysfunction of the spindle checkpoint. Differences of the checkpoint system in normal cells versus tumor cells might provide a new opportunity in cancer drug development; therefore, efforts to identify the spindle checkpoint inhibitors have been fostered. Based on spindle checkpoint inhibitors being able to induce cells to exit mitotic arrest caused by microtubule drug treatment, we developed a cell-based assay to screen compounds that were potential spindle checkpoint inhibitors. This assay was validated with a known spindle checkpoint inhibitor and was easy to adapt to a large-scale screening. It also had the advantages of being high in sensitivity and low in cost.