RNF149 Destabilizes IFNGR1 in Macrophages to Favor Post-Infarction Cardiac Repair.

BACKGROUND: Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. METHODS: We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (RING finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RESULTS: RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. CONCLUSIONS: These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.

Heart proteomic profiling discovers MYH6 and COX5B as biomarkers for sudden unexplained death.

Sudden unexplained death (SUD) is not uncommon in forensic pathology. Yet, diagnosis of SUD remains challenging due to lack of specific biomarkers. This study aimed to screen differentially expressed proteins (DEPs) and validate their usefulness as diagnostic biomarkers for SUD cases. We designed a three-phase investigation, where in the discovery phase, formalin-fixed paraffin-embedded (FFPE) heart specimens were screened through label-free proteomic analysis of cases dying from SUD, mechanical injury and carbon monoxide (CO) intoxication. A total of 26 proteins were identified to be DEPs for the SUD cases after rigorous criterion. Bioinformatics and Adaboost-recursive feature elimination (RFE) analysis further revealed that three of the 26 proteins (MYH6, COX5B and TNNT2) were potential discriminative biomarkers. In the training phase, MYH6 and COX5B were verified to be true DEPs in cardiac tissues from 29 independent SUD cases as compared with a serial of control cases (n = 42). Receiver operating characteristic (ROC) analysis illustrated that combination of MYH6 and COX5B achieved optimal diagnostic sensitivity (89.7 %) and specificity (84.4 %), with area under the curve (AUC) being 0.91. A diagnostic software based on the logistic regression formula derived from the training phase was then constructed. In the validation phase, the diagnostic software was applied to eight authentic SUD cases, seven (87.5 %) of which were accurately recognized. Our study provides a valid strategy towards practical diagnosis of SUD by integrating cardiac MYH6 and COX5B as dual diagnostic biomarkers.

Comparison of the full-length sequence and sub-regions of 16S rRNA gene for skin microbiome profiling.

The skin microbiome plays a pivotal role in human health by providing protective and functional benefits. Furthermore, its inherent stability and individual specificity present novel forensic applications. These aspects have sparked considerable research enthusiasm among scholars across various fields. However, the selection of specific 16S rRNA hypervariable regions for skin microbiome studies is not standardized and should be validated through extensive research tailored to different research objectives and targeted bacterial taxa. Notably, third-generation sequencing (TGS) technology leverages the full discriminatory power of the 16S gene and enables more detailed and accurate microbial community analyses. Here, we conducted full-length 16S sequencing of 141 skin microbiota samples from multiple human anatomical sites using the PacBio platform. Based on this data, we generated derived 16S sub-region data through an in silico experiment. Comparisons between the 16S full-length and the derived variable region data revealed that the former can provide superior taxonomic resolution. However, even with full 16S gene sequencing, limitations arise in achieving 100% taxonomic resolution at the species level for skin samples. Additionally, the capability to resolve high-abundance bacteria (TOP30) at the genus level remains generally consistent across different 16S variable regions. Furthermore, the V1-V3 region offers a resolution comparable with that of full-length 16S sequences, in comparison to other hypervariable regions studied. In summary, while acknowledging the benefits of full-length 16S gene analysis, we propose the targeting of specific sub-regions as a practical choice for skin microbial research, especially when balancing the accuracy of taxonomic classification with limited sequencing resources, such as the availability of only short-read sequencing or insufficient DNA.IMPORTANCESkin acts as the primary barrier to human health. Considering the different microenvironments, microbial research should be conducted separately for different skin regions. Third-generation sequencing (TGS) technology can make full use of the discriminatory power of the full-length 16S gene. However, 16S sub-regions are widely used, particularly when faced with limited sequencing resources including the availability of only short-read sequencing and insufficient DNA. Comparing the 16S full-length and the derived variable region data from five different human skin sites, we confirmed the superiority of the V1-V3 region in skin microbiota analysis. We propose the targeting of specific sub-regions as a practical choice for microbial research.

Coenzyme Q deficiency may predispose to sudden unexplained death via an increased risk of cardiac arrhythmia.

Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD.

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.

Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors.

Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.

Effects of kinesio taping on static balance performance and muscle activity in children with developmental coordination disorder: a single-group pretest-posttest study.

OBJECTIVE: To compare the effects of various kinesio tape applications on static balance and muscle activity in children with developmental coordination disorder.  Methods: Four taping conditions were applied to 48 children with developmental coordination disorder: no taping, gastrocnemius taping, tibialis anterior taping; and peroneus longus taping. Postural sway and electromyographic data were assessed, with eyes closed (30 s), standing still in 2-leg stance, dominant-leg stance, and non-dominant-leg stance. RESULTS: Kinesio taping significantly reduced postural sway in both anteroposterior and mediolateral directions for dominant-leg stance and non-dominant-leg stance, but not 2-leg stance. During single-leg stances, anteroposterior sway was significantly lower for the gastrocnemius taping condition than for the no taping, tibialis anterior and peroneus longus taping conditions, and significantly lower in the tibialis anterior and peroneus longus taping conditions than in the no taping condition (gastrocnemius < tibialis anterior = peroneus longus < no taping). In addition, mediolateral sway was significantly lower in the tibialis anterior and peroneus longus taping conditions than in the no taping and gastrocnemius taping conditions, and significantly lower in the gastrocnemius taping condition than in the no taping condition (tibialis anterior = peroneus longus < gastrocnemius < no taping). Electromyographic data showed that muscle activity was significantly greater only for muscles where kinesio tape was applied. CONCLUSION: Various kinesio tape applications can differentially reduce postural sway and increase muscle activity during single-leg stances in children with developmental coordination disorder.

Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study.

Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18-40 years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings.

Cardiac-specific BACH1 ablation attenuates pathological cardiac hypertrophy by inhibiting the Ang II type 1 receptor expression and the Ca2+/CaMKII pathway.

AIMS: BACH1 is up-regulated in hypertrophic hearts, but its function in cardiac hypertrophy remains largely unknown. This research investigates the function and mechanisms of BACH1 in the regulation of cardiac hypertrophy. METHODS AND RESULTS: Male cardiac-specific BACH1 knockout mice or cardiac-specific BACH1 transgenic (BACH1-Tg) mice and their respective wild-type littermates developed cardiac hypertrophy induced by angiotensin II (Ang II) or transverse aortic constriction (TAC). Cardiac-specific BACH1 knockout in mice protected the hearts against Ang II- and TAC-induced cardiac hypertrophy and fibrosis, and preserved cardiac function. Conversely, cardiac-specific BACH1 overexpression markedly exaggerated cardiac hypertrophy and fibrosis and reduced cardiac function in mice with Ang II- and TAC-induced hypertrophy. Mechanistically, BACH1 silencing attenuated Ang II- and norepinephrine-stimulated calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, the expression of hypertrophic genes, and hypertrophic growth of cardiomyocytes. Ang II stimulation promoted the nuclear localization of BACH1, facilitated the recruitment of BACH1 to the Ang II type 1 receptor (AT1R) gene promoter, and then increased the expression of AT1R. Inhibition of BACH1 attenuated Ang II-stimulated AT1R expression, cytosolic Ca2+ levels, and CaMKII activation in cardiomyocytes, whereas overexpression of BACH1 led to the opposite effects. The increased expression of hypertrophic genes induced by BACH1 overexpression upon Ang II stimulation was suppressed by CaMKII inhibitor KN93. The AT1R antagonist, losartan, significantly attenuated BACH1-mediated CaMKII activation and cardiomyocyte hypertrophy under Ang II stimulation in vitro. Similarly, Ang II-induced myocardial pathological hypertrophy, cardiac fibrosis, and dysfunction in BACH1-Tg mice were blunted by treatment with losartan. CONCLUSION: This study elucidates a novel important role of BACH1 in pathological cardiac hypertrophy by regulating the AT1R expression and the Ca2+/CaMKII pathway, and highlights potential therapeutic target in pathological cardiac hypertrophy.

BACH1 deficiency prevents neointima formation and maintains the differentiated phenotype of vascular smooth muscle cells by regulating chromatin accessibility.

The transcription factor BTB and CNC homology 1(BACH1) has been linked to coronary artery disease risk by human genome-wide association studies, but little is known about the role of BACH1 in vascular smooth muscle cell (VSMC) phenotype switching and neointima formation following vascular injury. Therefore, this study aims to explore the role of BACH1 in vascular remodeling and its underlying mechanisms. BACH1 was highly expressed in human atherosclerotic plaques and has high transcriptional factor activity in VSMCs of human atherosclerotic arteries. VSMC-specific loss of Bach1 in mice inhibited the transformation of VSMC from contractile to synthetic phenotype and VSMC proliferation and attenuated the neointimal hyperplasia induced by wire injury. Mechanistically, BACH1 suppressed chromatin accessibility at the promoters of VSMC marker genes via recruiting histone methyltransferase G9a and cofactor YAP and maintaining the H3K9me2 state, thereby repressing VSMC marker genes expression in human aortic smooth muscle cells (HASMCs). BACH1-induced repression of VSMC marker genes was abolished by the silencing of G9a or YAP. Thus, these findings demonstrate a crucial regulatory role of BACH1 in VSMC phenotypic transition and vascular homeostasis and shed light on potential future protective vascular disease intervention via manipulation of BACH1.

Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries.

BACKGROUND: Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. METHODS: Type 2 diabetes models were established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. RESULTS: Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1, Rip3, and Mlkl. Under hyperglycemic conditions, high glucose induced CB2R internalization in a ß-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. CONCLUSIONS: CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.

Sudden unexplained death in schizophrenia patients: An autopsy-based comparative study from China.

Explainable sudden deaths in schizophrenia patients due to both cardiac (SCD) and non-cardiac causes (SNCD) have been extensively documented. However, sudden unexplained death (SUD) in this cohort remains to be elucidated. This study retrospectively analyzed 18 SUD cases that underwent systematic autopsy at our institutes during the period 2010-2022. The etiological, demographic, and autopsy features of the SUD cases were then compared with 37 year-matched sudden explainable deaths (23 SCD cases and 14 SNCD cases). Our results showed that the average age of the SUD was 39.0 ( ± 8.4) years, with the disease duration of 11.8 ( ± 8.1) years and a male/female ratio of 11:7. Most cases occurred during daytime (72.2%) and outside of hospital (77.8%). A large proportion of the SUD cases (77.8%) had persistent psychiatric episodes before death. Clozapine was found to be the most commonly used antipsychotic (33.3%), followed by Olanzapine (27.8%), Risperidone (27.8%) and Chlorpromazine (27.8%) in the SUD cases. When compared among groups, the SUD cases showed significantly younger ages (p = 0.035), lower heart weight (p = 0.004) and lower proportion of Clozapine use (p = 0.045). The presence of persistent psychiatric episodes was significantly higher in the SUD group than in any explainable deaths (p = 0.018) and was an independent risk factor for SUD (OR = 4.205, p = 0.040). This is the first autopsy-based study of SUD cases from China. We conclude that a stable mental state maintained by antipsychotics (i.e., Clozapine) is vital to schizophrenia patients.

Serum SELENBP1 and VCL Are Effective Biomarkers for Clinical and Forensic Diagnosis of Coronary Artery Spasm.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of many ischemic heart entities; however, there are no established diagnostic biomarkers for CAS in clinical and forensic settings. This present study aimed to identify such serum biomarkers by establishing a rabbit CAS provocation model and integrating quantitative serum proteomics, parallel reaction monitoring/mass spectrometry-based targeted proteomics, and partial least-squares discriminant analysis (PLS-DA). Our results suggested that SELENBP1 and VCL were potential candidate biomarkers for CAS. In independent clinical samples, SELENBP1 and VCL were validated to be significantly lower in serum but not blood cells from CAS patients, with the reasons for this possibly due to the decreased secretion from cardiomyocytes. The areas under the curve of the receiver operating characteristics (ROC) analysis were 0.9384 for SELENBP1 and 0.9180 for VCL when diagnosing CAS. The CAS risk decreased by 32.3% and 53.6% for every 10 unit increases in the serum SELENBP1 and VCL, respectively. In forensic samples, serum SELENBP1 alone diagnosed CAS-induced deaths at a sensitivity of 100.0% and specificity of 72.73%, and its combination with VCL yielded a diagnostic specificity of 100.0%, which was superior to the traditional biomarkers of cTnI and CK-MB. Therefore, serum SELENBP1 and VCL could be effective biomarkers for both the clinical and forensic diagnosis of CAS.

Cardiotoxicity of current antipsychotics: Newer antipsychotics or adjunct therapy?

Use of newer antipsychotics for substitution of current antipsychotics might be one way awaiting to be clinically verified to address antipsychotic cardiotoxic effects. Alternatively, the combination of existing antipsychotics with cardioprotective agents is also beneficial for patients with mental disorders for avoiding cardiotoxicity to the maximum.

Use of potassium ion channel and spliceosome proteins as diagnostic biomarkers for sudden unexplained death in schizophrenia.

Sudden unexplained death in schizophrenia (SUD-SCZ) is not uncommon and its incidence is approximately three times higher than that in the general population. However, diagnosis of SUD-SCZ remains a great challenge in forensic pathology. This study designed a two-phase study to investigate whether three proteins, namely two potassium ion channel proteins (KCNJ3 and KCNAB1) and one spliceosome protein (SF3B3) that were identified in our previous work, could be applied in the postmortem diagnosis of SUD-SCZ. Immunohistochemical staining of the three biomarkers, followed by a rigorous quantitative analysis, was performed on heart specimens from both SUD-SCZ and control groups. A diagnostic software based on the logistic regression formula derived from the test phase data was then constructed. In the test phase, we found that the staining intensities of KCNJ3, KCNAB1, and SF3B3 were all significantly lower in the SUD-SCZ group (n = 20) as compared with the control group that died from non-natural causes (n = 25), with fold-changes being 14.85 (p < 0.001), 4.13 (p = 0.028) and 2.12 (p = 0.048), respectively. Receiver operating characteristic analysis further illustrated that combination of the three biomarkers achieved the optimal diagnostic specificity (92%) and area under the curve (0.886). In the validation phase, the diagnostic software was confirmed to be a promising tool for predicting the risk of SUD-SCZ in authentic cases. Our study provided a valid strategy towards the practical diagnosis of SUD-SCZ by using KCNJ3, KCNAB1, and SF3B3 proteins as diagnostic biomarkers.

CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity.

Long-term use of antipsychotics is a common cause of myocardial injury and even sudden cardiac deaths that often lead to drug withdrawn or discontinuation. Mechanisms underlying antipsychotics cardiotoxicity remain largely unknown. Herein we performed RNA sequencing and found that NLRP3 inflammasome-mediated pyroptosis contributed predominantly to multiple antipsychotics cardiotoxicity. Pyroptosis-based small-molecule compound screen identified cannabinoid receptor 1 (CB1R) as an upstream regulator of the NLRP3 inflammasome. Mechanistically, antipsychotics competitively bond to the CB1R and led to CB1R translocation to the cytoplasm, where CB1R directly interacted with NLRP3 inflammasome via amino acid residues 177-209, rendering stabilization of the inflammasome. Knockout of Cb1r significantly alleviated antipsychotic-induced cardiomyocyte pyroptosis and cardiotoxicity. Multi-organ-based investigation revealed no additional toxicity of newer CB1R antagonists. In authentic human cases, the expression of CB1R and NLRP3 inflammasome positively correlated with antipsychotics-induced cardiotoxicity. These results suggest that CB1R is a potent regulator of the NLRP3 inflammsome-mediated pyroptosis and small-molecule inhibitors targeting the CB1R/NLRP3 signaling represent attractive approaches to rescue cardiac side effects of antipsychotics.

Valosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication.

Background: Acute coronary syndrome (ACS) consists of a range of acute myocardial ischemia-related manifestations. The adverse events of ACS are usually associated with ventricular dysfunction (VD), which could finally develop to heart failure. Currently, there is no satisfactory indicator that could specifically predict the development of ACS and its prognosis. Valosin-containing protein (VCP) has recently been proposed to protect against cardiac diseases. Hence, we aimed to assess whether VCP in serum can serve as a valuable biomarker for predicting ACS and its complication. Methods: Human serum samples from 291 participants were collected and classified into four groups based on their clinical diagnosis, namely healthy control (n = 64), ACS (n = 40), chronic coronary syndrome (CCS, n = 99), and nonischemic heart disease (non-IHD, n = 88). Clinical characteristics of these participants were recorded and their serum VCP levels were detected by enzyme-linked immunosorbent assay (ELISA). Association of serum VCP with the development of ACS and its complication VD was statistically studied. Subsequently, GWAS and eQTL analyses were performed to explore the association between VCP polymorphism and monocyte count. A stability test was also performed to investigate whether VCP is a stable biomarker. Results: Serum VCP levels were significantly higher in the ACS group compared with the rest groups. Besides, the VCP levels of patients with ACS with VD were significantly lower compared to those without VD. Multivariate logistic regression analysis revealed that VCP was associated with both the risk of ACS (P = 0.042, OR = 1.222) and the risk of developing VD in patients with ACS (P = 0.035, OR = 0.513) independently. The GWAS analysis also identified an association between VCP polymorphism (rs684562) and monocyte count, whereas the influence of rs684562 on VCP mRNA expression level was further verified by eQTL analysis. Moreover, a high stability of serum VCP content was observed under different preservation circumstances. Conclusion: Valosin-containing protein could act as a stable biomarker in predicting the development of ACS and its complication VD.

Endoplasmic reticulum stress-related secretory proteins as biomarkers of early myocardial ischemia-induced sudden cardiac deaths.

Early myocardial ischemia-induced sudden cardiac deaths (EMI-SCD) remain a great diagnostic challenge for forensic pathologists due to no gross or non-specific histological pathology. The goal of this study was to assess whether three secretory proteins, related with cellular endoplasmic reticulum stress, can be applied in forensic diagnosis of EMI-SCD. These markers included LMAN2, CAPN-1, and VCP and were compared with two clinically used markers (CK-MB and cTnI). A total of 21 EMI-SCD cases with a mean age of 53.0 (± 10.5) years and a mean ischemia interval of < 2.77 (± 2.56) hours were collected. Another 23 cases (mean 44.6 ± 15.0 year old) that died from non-cardiac causes served as control. Enzyme-linked immunosorbent assay (ELISA) was performed to detect target proteins' serum concentrations in the EMI-SCD and control groups. We found that LMAN2, CAPN-1, and VCP were all significantly increased in the EMI-SCD group as compared with control serum, with the fold changes ranging from 1.48 (p = 0.0022, LMAN2), 1.33 (p = 0.041, CAPN-1), to 1.26 (p = 0.021, VCP), respectively. The concentrations of these proteins remained highly stable within 6 h and were not affected by death time, postmortem interval (< 4 h), age, and month at death. Receiver operating characteristic (ROC) curves showed that the areas under the curve (AUC) were 0.8178 (LMAN2), 0.6988 (CAPN-1), and 0.7267 (VCP), all of which were higher than CK-MB (AUC 0.5590) and cTn-I (AUC 0.5911). The diagnostic specificity (all above 60%) was obviously higher than CK-MB (43.48%) and cTnI (34.78%). In conclusion, LMAN-2, CAPN-1, and VCP could be stable serological biomarkers for diagnosis of EMI-SCD cases.