Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.

BACKGROUND: Sepsis is an abnormal immune-inflammatory response that is mainly caused by infection. It can lead to life-threatening organ dysfunction and death. Severely damaged tissue cells will release intracellular histones into the circulation as damage-related molecular patterns (DAMPs) to accelerate the systemic immune response. Although various histone-related cytotoxicity mechanisms have been explored, those that affect extracellular histones involved in vascular smooth muscle cell (VSMC) dysfunction are yet to be determined. METHODS: Mouse aortic vascular smooth muscle cells (VSMCs) were stimulated with different concentrations of histones, and cell viability was detected by CCK-8 assay. Cellular senescence was assessed by SA ß-gal staining. C57BL/6 mice were treated with histones with or without BML-275 treatment. RT-qPCR was performed to determine the expression of inflammatory cytokines. Western blotting was used to analyze the expression of NLRP3, ASC and caspase-1 inflammasome proteins. The interaction of NLRP3 and ASC was detected by CoIP and immunofluorescence staining. RESULTS: In this study, we found that extracellular histones induced senescence and inflammatory response in a dose-dependent manner in cultured VSMCs. Histone treatment significantly promoted apoptosis-associated speck-like protein containing CARD (ASC) as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3) interaction of inflammasomes in VSMCs. Forkhead box protein O4 (FOXO4), which is a downstream effector molecule of extracellular histones, was found to be involved in histone-regulated VSMC inflammatory response and senescence. Furthermore, the 5'-AMP-activated protein kinase (AMPK) signaling pathway was confirmed to mediate extracellular histone-induced FOXO4 expression, and blocking this signaling pathway with an inhibitor can suppress vascular inflammation induced by extracellular histones in vivo and in vitro. CONCLUSION: Extracellular histones induce inflammation and senescence in VSMCs, and blocking the AMPK/FOXO4 pathway is a potential target for the treatment of histonemediated organ injury.

Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children.

To investigate the feasibility and efficacy of transcanal endoscopic treatment for congenital middle ear cholesteatoma in children. Eleven children diagnosed with congenital middle ear cholesteatoma, who underwent total ear endoscopic surgery under general anesthesia, were included from the Huazhong University of Science and Technology Union Shenzhen Hospital between January 2016 and December 2020. We retrospectively analyzed their operation process and surgical complications through the surgical video; moreover, we compared the pre- and postoperative hearing outcomes. One child underwent a planned second operation to reconstruct the ossicular chain. At 6 postoperative months, all 11 children underwent reexamination. There was no significant change and a significant decrease in the mean bone and air conduction hearing thresholds, respectively (P > .05 and P < .05); moreover, there was a significant reduction in the air-bone conduction difference (P < .05). Further, the air-bone conduction difference was reduced to >20 dB and >10 dB in 11 and 7 children, respectively. Follow-up of the children did not reveal sensorineural deafness, facial paralysis, and other serious complications; further, there were no cases of recurrence. Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children is feasible, minimally invasive, and functional.

Canalplasty using underwater bone drilling in transcanal endoscopic myringoplasty for patients with a narrow external auditory canal.

BACKGROUND: Canalplasty is important in microscopic ear surgery, but it has rarely been studied in otoendoscopic surgery. OBJECTIVES: The aim of this study was to investigate the application of canalplasty due to external auditory canal stenosis caused by bony bulges in endoscopic myringoplasty. MATERIALS AND METHODS: The procedures and effects of canalplasties and myringoplasties were analysed. During the canalplasties, depending on the location of the bulges, the meatal skin flaps were elevated in different manners, and the underwater bone drilling technique was adopted to remove the bulges to enlarge the osseous canals. RESULTS: Canalplasties were performed in 18.5% (33/178) of myringoplasties. All surgeries were completed exclusively via the transcanal endoscopic approach. No iatrogenic injuries were found. Most of the canalplasties required drilling off bulges on multiple walls. The mean total duration of the canalplasties and myringoplasties was 76.6 ± 4.5 min, and the proportion of time required for the canalplasties was 47.3 ± 2.4%. CONCLUSION: Only approximately one in five endoscopic myringoplasties require antecedent canalplasties due to concurrent canal stenosis. With the underwater bone drilling technique, transcanal endoscopic canalplasty can be safely and efficiently conducted.

Modeling and Inverse Compensation of Cross-Coupling Hysteresis in Piezoceramics under Multi-Input.

In the fast tool servo (FTS) system for microstructure surface cutting, the dynamic voltage hysteresis of piezoelectric actuators (PEAs) and the cutting force produced in the manufacturing affect the driving accuracy and the cutting performance. For a multi-input-single-output (MISO) cutting system, in this paper, a dynamic hysteresis model based on a rate-dependent Prandtl-Ishlinskii model is proposed. A backpropagation neural network (BPNN) is established to describe the cross-coupling effect between the applied voltage and external load. An inverse dynamic model is developed to compensate the nonlinearity of PEAs. The accuracy of the model and its inverse is discussed and the performance of the inverse feedforward compensator is validated through experiments.

Flexible Ultrasonic Transducer Array with Bulk PZT for Adjuvant Treatment of Bone Injury.

Flexible electronic devices are developing rapidly, especially in medical applications. This paper reports an arrayed flexible piezoelectric micromachined ultrasonic transducer (FPMUT) with a sandwich structure for adjuvant treatment of bone injury. To make the device conformable and stretchable for attaching to the skin surface, the flexible substrate of polydimethylsiloxane (PDMS) was combined with the flexible metal line interconnection between the bulk lead zirconate titanate (PZT) arrays. Simulations and experiments were carried out to verify the resonant frequency and tensile property of the reported FPMUT device. The device had a resonant frequency of 321.15 KHz and a maximum sound pressure level (SPL) of 180.19 dB at the distance of 5 cm in water. In addition, detailed experiments were carried out to test its acoustic performance with different pork tissues, and the results indicated good ultrasound penetration. These findings confirm that the FPMUT shows unique advantages for adjuvant treatment of bone injury.

Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque.

Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE-/- mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE-/- mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.