Pyroptosis inhibitors MCC950 and VX-765 mitigate myocardial injury by alleviating oxidative stress, inflammation, and apoptosis in acute myocardial hypoxia.

Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI.

Anaphylactic deaths: A retrospective study of forensic autopsy cases from 2009 to 2019 in Shanghai, China.

Anaphylaxis is a rare but well-known cause of sudden unexpected death, although data from forensic autopsies in anaphylactic deaths are limited. Herein, a retrospective study of a series of allergic deaths from 2009 through 2019 in Shanghai, China, was conducted to investigate the demographic, medical, and forensic pathological characteristics of fatal anaphylaxis to improve medicolegal understanding on anaphylactic death. Sixty-two autopsy cases of anaphylactic death were registered in this study. Males dominated the cases (74.2%) against females (25.8%), with an average age of 38.8 years. Medications (98.4%), particularly antibiotics (72.6%), were the most frequent cause of anaphylaxis, and 44 cases (71.0%) occurred in clinics administered illegally by unlicensed clinicians. The anaphylactic symptoms began within a few minutes to less than 1 h in 53 cases, with dyspnea (56.5%) and sudden shock (46.8%) being the most common clinical signs. Thirty cases (48.4%) of anaphylaxis resulted in death within 1 h. Laryngeal edema and multiple tissue eosinophil infiltration (85.5%) were the most prevalent autopsy findings, followed by pulmonary edema and congestion (24.2%), which were considered to be non-specific but suggestive. The comorbidities were mainly cardiovascular disease (33.9%), pneumonia (8.1%) and asthma (8.1%). Serum IgE were measured in 11 of 62 cases, ranging from 43.3 to 591 IU/ml, severed as a helpful marker. Therefore, we suggested a thorough analysis of allergen exposure, clinical history and autopsy findings is required for the diagnosis of anaphylactic death currently.

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus.

Status epilepticus (SE) is a life-threatening disorder that can result in death or severe brain damage, and there is a substantial body of evidence suggesting a strong association between pyroptosis and SE. Sterol regulatory element binding protein 1 (SREBP1) is a significant transcription factor participating in both lipid homeostasis and glucose metabolism. However, the function of SREBP1 in pyroptosis during SE remains unknown. In this study, we established a SE rat model by intraperitoneal injection of lithium chloride and pilocarpine in vivo. Additionally, we treated HT22 hippocampal cells with glutamate to create neuronal injury models in vitro. Our results demonstrated a significant induction of SREBP1, inflammasomes, and pyroptosis in the hippocampus of SE rats and glutamate-treated HT22 cells. Moreover, we found that SREBP1 is regulated by the mTOR signaling pathway, and inhibiting mTOR signaling contributed to the amelioration of SE-induced hippocampal neuron pyroptosis, accompanied by a reduction in SREBP1 expression. Furthermore, we conducted siRNA-mediated knockdown of SREBP1 in HT22 cells and observed a significant reversal of glutamate-induced cell death, activation of inflammasomes, and pyroptosis. Importantly, our confocal immunofluorescence analysis revealed the co-localization of SREBP1 and NLRP1. In conclusion, our findings suggest that deficiency of SREBP1 attenuates glutamate-induced HT22 cell injury and hippocampal neuronal pyroptosis in rats following SE. Targeting SREBP1 may hold promise as a therapeutic strategy for SE.

Low Distortion of Noise Filter Realization with 6.34 V/µs Fast Slew Rate and 120 mVp-p Output Noise Signal.

In order to reduce Gaussian noise, this paper proposes a method via taking the average of the upper and lower envelopes generated by capturing the high and low peaks of the input signal. The designed fast response filter has no cut-off frequency, so the high order harmonics of the actual signal remain unchanged. Therefore, it can immediately respond to the changes of input signal and retain the integrity of the actual signal. In addition, it has only a small phase delay. The slew rate, phase delay and frequency response can be confirmed from the simulation results of Multisim 13.0. The filter outlined in this article can retain the high order harmonics of the original signal, achieving a slew rate of 6.34 V/µs and an almost zero phase difference. When using our filter to physically test the input signal with a noise level of 3 Vp-p Gaussian noise, a reduced noise signal of 120 mVp-p is obtained. The noise can be suppressed by up to 4% of the raw signal.

MicroRNA-20b suppresses the expression of ZFP-148 in viral myocarditis.

Viral myocarditis is a common cardiovascular disease, which seriously endangers the health of people and even leads to sudden unexpected death. MicroRNAs play very important roles in various physical and pathological processes including cardiogenesis and heart diseases. In recent years, miR-20b has been implicated in various diseases such as breast cancer, gastric cancer, hepatocellular carcinoma, cardiovascular diseases. However, the function of miR-20b in the pathological progress of viral myocarditis has not been reported. In this study, we found that miR-20b was up-regulated in mouse heart tissues post Coxsackievirus B3 (CVB3) infection. Bioinformatics analysis identified ZFP-148, a transcription factor that plays essential roles in the regulation of virus replication, is one of the predicted targets of miR-20b. MiR-20b expression was found to be up-regulated and ZFP-148 protein level was markedly repressed during viral myocarditis. Further studies demonstrated that miR-20b directly binds to the 3'-UTR of ZFP-148 and suppresses its translation. Moreover, aberrant expression of miR-20b promoted the expression of anti-apoptosis proteins Bcl-2 and Bcl-xL, suggesting that altered gene expression might promote cardiomyocytes survival in viral myocarditis. Our findings indicated that miR-20b might be a potential therapeutic target for CVB3-induced viral myocarditis and a useful marker for the diagnosis of viral myocarditis.

Unnatural deaths in Shanghai from 2000 to 2009: a retrospective study of forensic autopsy cases at the Shanghai Public Security Bureau.

Shanghai is the most developed city in China and has a soaring population. This study uses forensic epidemiology to determine the relationship between unnatural deaths and the development in Shanghai, based on recently released forensic autopsy cases from the 2000s at the Shanghai Public Security Bureau (SPSB). There were 5425 accidental deaths, 2696 homicides, 429 suicides, 186 natural deaths, and 1399 deaths of undetermined cause. There was a male-to-female ratio of 2.02:1, and the average age was 40.9±18.7 years. Traffic accidents (84.2%) were the number one cause of accidental deaths, which decreased during the study period. Sharp force injury (50.6%) was the leading cause of homicides, different from Western countries, where firearms are the leading cause. Hanging (24.5%) was the leading cause of suicides, whereas drug and chemical intoxication was the leading cause in the previous decade; pesticide ingestion decreased in the 2000s. In addition to traffic accidents, manual strangulation was the leading cause of death in childhood fatalities. Children under age 2 were vulnerable to homicides. In the 2000s, there were a large number of drug overdoses, and illegal medical practices and subway-related deaths first appeared in Shanghai. A new type of terrorist attack that involved injecting people with syringes in public places was reflected in the SPSB archives. The forensic epidemiology and changes in unnatural deaths in this decade reflected their relationship with the law, policy and changes in Shanghai. Illegal medical practices, subway-related deaths and terrorist attacks were closely related to the development in Shanghai. Identifying the risks of unnatural deaths will improve public health.

Suicidal drownings with psychiatric disorders in Shanghai: a retrospective study from 2010.1 to 2014.6.

Psychiatric disorders exhibited in 13% suicidal drownings in Southwestern Croatia and 63% in Milan, but in China is unknown. This study is committed to outline the feature of a suicidal drowning with psychiatric disorder, show mental status and reveal key factor to high incidence in China. Immersed corpses were handled by SPSBMPH in its jurisdiction range. Half of immersed corpses were suicidal, and nearly half of suicides had psychiatric disorders. 104 suicidal drownings with psychiatric disorders cases from 2010.1 to 2014.6 were reviewed (21.5% of all immersed corpses, 42.1% of suicides). Most victims clothed normally, and only 2 fastened attached weights. Male victims were more and younger than female. Psycho were prone to commit suicidal drowning in warm and hot season. Psycho were prone to choose familiar area to commit suicide, 45 decedents were found in their familiar areas. Suicidal drowings were occult without suicide attempts, suicide note or abnormal clothing, but showed abnormal mental or behavior changes prior to suicide. The three leading psychiatric disorders were depression (33.7%), depression status (30.8%) and schizophrenia (20.2%). Only 44.2% decedents had visited psychiatric disorder specialist, and merely less than 10% patients could adhere to regular medication. No regular medication on psychiatric disorder was the key factor contributing to high incidence of suicide in psycho. Professional psychiatric and psychological intervention should be taken as soon as possible when they had psychiatric symptoms or suffered misfortune. Guardians should be alert to patients' abnormality to detect their suicidal ideation and intervene, especially in warm season.