Inhibition of Piezo1/Ca2+/calpain signaling in the rat basal forebrain reverses sleep deprivation-induced fear memory impairments.

In this study, we tested the hypothesis that the Piezo1/Ca2+/calpain pathway of the basal forebrain (BF) modulates impaired fear conditioning caused by sleep deprivation. Adult male Wistar rats were subjected to 6 h of total sleep deprivation using the gentle handling protocol. Step-down inhibitory avoidance tests revealed that sleep deprivation induced substantial short- and long-term fear memory impairment in rats, which was accompanied by increased Piezo1 protein expression (P < 0.01) and increased cleavage of full-length tropomyocin receptor kinase B (TrkB-FL) (P < 0.01) in the BF area. Microinjection of the Piezo1 activator Yoda1 into the BF mimicked these sleep deprivation-induced phenomena; TrkB-FL cleavage was increased (P < 0.01) and short- and long-term fear memory was impaired (both P < 0.01) by Yoda1. Inhibition of Piezo1 by GsMTx4 in the BF area reduced TrkB-FL degradation (P < 0.01) and partially reversed short- and long-term fear memory impairments in sleep-deprived rats (both P < 0.01). Inhibition of calpain activation, downstream of Piezo1 signaling, also improved short- and long-term fear memory impairments (P = 0.038, P = 0.011) and reduced TrkB degradation (P < 0.01) in sleep-deprived rats. Moreover, sleep deprivation induced a lower pain threshold than the rest control, which was partly reversed by microinjection of GsMTx4 or PD151746. Neither sleep deprivation nor the abovementioned drugs affected locomotion and sedation. Taken together, these results indicate that BF Piezo1/Ca2+/calpain signaling plays a role in sleep deprivation-induced TrkB signaling disruption and fear memory impairments in rats.

Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-κB pathway and NLRP3 inflammasome.

BACKGROUND: Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. METHODS: The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1ß, IL-6, and TNF-α were evaluated using ELISA. RESULTS: There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. CONCLUSIONS: Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.

Prevalence of acute liver injury and hypertransaminemia in patients with COVID-19: a protocol for a systematic review.

INTRODUCTION: COVID-19 has spread rapidly in China and around the world. Published studies have revealed that some patients with COVID-19 had abnormal liver function in laboratory tests. However, the results were inconsistent and the analysis of epidemiological data stratified by the severity of COVID-19 was not available in previous meta-analyses. Furthermore, these meta-analyses were suspected of overestimating the incidence of liver injury in patients with COVID-19 because some studies considered transaminase elevation as liver injury, which might partially result from cardiac and muscle injury. This systematic review aims to enrol published literatures related to COVID-19 without language restriction, analyse the data based on the severity of the COVID-19 and explore the impact of varied definitions of liver injury on the incidence of liver injury. METHODS AND ANALYSIS: We have conducted a preliminary search on PubMed and Excerpta Medica Database on 13 April 2020, for the studies published after December 2019 on the prevalence of acute liver injury and hypertransaminemia in patients with COVID-19. Two reviewers will independently screen studies, extract data and assess the risk of bias. We will estimate the pooled incidence of hypertransaminemia and acute liver injury in patients with COVID-19 by using the random-effects model. The I ² test will be used to identify the extent of heterogeneity. Publication bias will be assessed by funnel plot and performing the Begg's and Egger's test if adequate studies are available. We will perform a risk of bias assessment using the Joanna Briggs Institute's critical appraisal checklist. ETHICS AND DISSEMINATION: Since this study will be based on the published data, it does not require ethical approval. The final results of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020179462.

Activation of brain-derived neurotrophic factor signaling in the basal forebrain reverses acute sleep deprivation-induced fear memory impairments.

INTRODUCTION: The mechanisms underlying sleep deprivation-induced memory impairments and relevant compensatory signaling pathways remain elusive. We tested the hypothesis that increased brain-derived neurotrophic factor (BDNF) expression in the basal forebrain following acute sleep deprivation was a compensatory mechanism to maintain fear memory performance. METHODS: Adult male Wistar rats were deprived of 6-hr total sleep from the beginning of the light cycle. The effects of sleep deprivation on BDNF protein expression and activation of downstream tropomyosin receptor kinase B (TrkB)/phospholipase C-γ1 (PLCγ1) signaling in the basal forebrain and fear memory consolidation were examined. BDNF or selective downstream TrkB receptor antagonist ANA-12 was further injected into the basal forebrain bilaterally to observe the changes in fear memory consolidation in response to modulation of the BDNF/TrkB signaling. RESULTS: Six hours of sleep deprivation-induced both short- and long-term fear memory impairments. Increased BDNF protein expression and TrkB and PLCγ1 phosphorylation in the basal forebrain were observed after sleep deprivation. Microinjection of BDNF into the basal forebrain partly reversed fear memory deficits caused by sleep deprivation, which were accompanied by increased BDNF protein levels and TrkB/PLCγ1 activation. After ANA-12 microinjection, sleep deprivation-induced activation of the BDNF/TrkB pathway was inhibited and impairments of fear memory consolidation were further aggravated. CONCLUSIONS: Acute sleep deprivation induces compensatory increase of BDNF expression in the basal forebrain. Microinjection of BDNF into the basal forebrain mitigates the fear memory impairments caused by sleep deprivation by activating TrkB/PLCγ1 signaling.

[Prognostic analysis of plantar fasciitis treated by pneumatic ballistic extracorporeal shock wave versus ultrasound guided intervention].

OBJECTIVE: To compare the medium- and long-term effect of pneumatic ballistic extracorporeal shock wave versus ultrasound-guided hormone injection in the treatment of plantar fasciitis. METHODS: The clinical data were collected from patients with plantar fasciitis admitted to PLA General Hospital pain department from September, 2015 to February, 2017. The patients were randomly divided into ultrasound-guided drug injection group and shock wave group. The therapeutic parameters including the numerical rating scale (NRS) scores in the first step pain in the morning, American Orthopedic Foot and Ankle Society (AOFAS) Ankle Hindfoot Scale, and thickness of the plantar fascia were monitored before and at 1 week, 1 month, 3 months, and 6 months after the treatment. The recurrence rate, effectiveness, and patient satisfaction were compared between the two groups at 6 months after the treatment. RESULTS: Thirty-nine patients were enrolled in shock wave group and 38 patients in ultrasound group. The NRS scores in the first step pain in the morning were lowered after treatment in both groups (P<0.05), and the scores were significantly lower in ultrasound group than in shock wave group at 1 week and 1 month (P<0.01), but significantly higher in ultrasound group than in shock wave group at 3 and 6 months after treatment (P<0.05). The AOFAS functional scores were increased in both groups (P<0.05) at 6 months after treatment, was significantly lower in ultrasound group than in shock wave group than group B (90.44∓13.27 vs 75.76∓21.40; P<0.05). The effective rates in shock wave group and ultrasound group were 92.31% and 76.32%, respectively (P<0.05). Recurrence was found in 1 patient (2.56%) in shock wave group and in 8 (21.05%) in ultrasound group (P<0.05). The patient satisfaction scores were significantly higher in shock wave group than in ultrasound group (8.13∓2.67 vs 6.63∓3.75, P=0.048). CONCLUSION: Pneumatic ballistic extracorporeal shock achieves better medium- and long-term outcomes than ultrasound-guided hormone injection in the treatment of plantar fasciitis.

[Improvement of carbon tetrachloride drug-induced liver injury model in vitro].

OBJECTIVE: To establish an ideal CCl4 drug-induced liver injury model in vitro. METHOD: Traditional method and improved method were adopted for preparing CCl4 injury liquid and drug-induced human liver HepG2 cell injury. Cell morphological change was observed under a bright-field microscope. The level of alanine aminotransferase (ALT) in supernatant was detected by biochemical method. 4-Methyl-tetrazolium (MTT) chromatometry was adopted for determining cell activity. RESULT: The improved method showed better CCl4-induced injury effect than the traditional method. With the increase in the concentration of CCl4 injury liquid, the ALT level significantly increased, whereas the cell activity notably decreased. Particularly, 70% CCl4 injury liquid use for 4 hours could achieve the best injury effect. CONCLUSION: The improved method could be used to establish an ideal CCl4 drug-induced liver injury model in vitro, which can lay foundation for further in vitro studies.