ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes.

Recent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway.

[Two Cases of Convulsive Seizures after Cardiac Surgery Suspiciously Caused by Tranexamic Acid Administration in Patients on Chronic Hemodialysis].

Tranexamic acid (TA), an antifibrinolytic agent, is commonly used in cardiac surgery with cardiopulmo- nary bypass to reduce bleeding. We report two cases of convulsive seizures after cardiac surgery with chronic kidney disease on hemodialysis. The two patients underwent aortic valve replacement, one for aortic valve regurgitation and another for aortic valve stenosis, with cardiopulmonary bypass uneventfully. A total dose of 8 g of TA was administered intravenously; 4 g during and 4 g after cardiopulmonary bypass. Both patients developed two episodes of gener- alized convulsive seizures post-operative day 1, which were suppressed by administration of diazepam intra- venously. The blood test, brain CT and electroenceph- alogram revealed no significant abnormalities. They were discharged without any neurological complica- tions. The high dose of TA was considered to have caused the seizures, since in previous reports the use of TA during surgery was associated with increased risk for postoperative seizures. It was demonstrated that approximately 40 to 70% of TA is excreted in the urine following intravenous administration. We posit that this might have led to excessive serum concen- tration of TA in our patients. Therefore, the dosage of TA should be decreased judiciously in patients with chronic kidney disease especially on hemodialysis to prevent postoperative seizures.

[Anesthetic Induction in a Patient with Giant Ovarian Tumor Who Developed Severe Hemodynamic Instability].

A 45 year-old woman underwent a laparotomy for a giant ovarian tumor under general anesthesia. Preoperative CT scan revealed a 30 cm-diameter tumor compressing IVC. She had slight respiratory discomfort on supine position, but respiratory function test showed no abnormalities. In the operating room, after oxygenation for 3 minutes, general anesthesia was induced with fentanyl 100 µg, propofol 90 mg and rocuronium 40 mg on supine position. Immediately after the induction, her systolic blood pressure and heart rate fell to 45 mmHg and 40 beats per minute, respectively. We considered that her hemodynamic instability was supine hypotensive syndrome due to giant ovarian tumor. Therefore we placed her 30 degree right side up and pushed her tumor to the left so as not to compress the IVC. We rapidly injected acetated Ringer's solution 500 ml, ephedrine 12 mg and phenylephrine 0.1 mg, and her hemodynamic status soon recovered to normal ranges. The anesthetic induction of a patient with a giant ovarian tumor is challenging. Some reports recommend strategies such as induction on lateral position or suctioning tumor contents before induction. Careful induction of general anesthesia is required for these patients.

Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that activates the downstream MAPKs, c-Jun N-terminal kinase (JNK) and p38. ASK1 is activated by various types of stress, such as oxidative stress, endoplasmic reticulum stress, and infection, and regulates various cellular functions. Recently, it has been reported that ASK1 is associated with various diseases induced by oxidative stress. In this review, we introduce recent findings of the regulatory mechanisms of ASK1 and the oxidative stress-induced diseases mediated by the ASK1 signaling pathway.