Gibberellic acid targeting ZBTB16 reduces NF-κB dependent inflammatory stress in sepsis-induced neuroinflammation.

OBJECTIVE: Sepsis is frequently complicated by neuroinflammation. Gibberellic acid (GA3) is recognized for its anti-inflammatory properties. In this study, our objective was to investigate whether GA3 could alleviate Nuclear factor-kappa B (NF-κB) -dependent inflammatory stress in sepsis-induced neuroinflammation. METHODS: C57BL/6 J mice were administered 10 mg/kg lipopolysaccharide (LPS) to induce sepsis. BV2 cells were pre-incubated with GA3 and subjected lipopolysaccharide stimulation to replicate the inflammatory microglia during sepsis. Subsequently, we assessed the release of IL-6, TNF-α, and IL-1ß, along with the expression of Zbtb16, NF-κB, and IκB. To investigate whether any observed anti-inflammatory effects of GA3 were mediated through a Zbtb16-dependent mechanism, Zbtb16 was silenced using siRNA. RESULTS: GA3 improved the survival of sepsis mice and alleviated post-sepsis cognitive impairment. Additionally, GA3 attenuated microglial M1 activation (pro-inflammatory phenotype), inflammation, and neuronal damage in the brain. Moreover, GA3 inhibited the release of TNF-α, IL-6, and IL-1ß in microglia stimulated with LPS. The NF-κB signaling pathway emerged as one of the key molecular pathways associated with the impact of GA3 on LPS-stimulated microglia. Lastly, GA3 upregulated Zbtb16 expression in microglia that had been downregulated by LPS. The inhibitory effects of GA3 on microglial M1 activation were partially reversed through siRNA knockdown of Zbtb16. CONCLUSIONS: Pre-incubation of microglia with GA3 led to the upregulation of the NF-κB regulator, Zbtb16. This process counteracted LPS-induced microglial M1 activation, resulting in an anti-inflammatory effect upon subsequent LPS stimulation.

Identification of Differentially Expressed Genes and Signaling Pathways in Acute Myocardial Infarction Based on Integrated Bioinformatics Analysis.

BACKGROUND: Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality around the world. The aim of this research was to determine the differentially expressed genes (DEGs), which may serve as potential therapeutic targets or new biomarkers in AMI. METHODS: From the Gene Expression Omnibus (GEO) database, three gene expression profiles (GSE775, GSE19322, and GSE97494) were downloaded. To identify the DEGs, integrated bioinformatics analysis and robust rank aggregation (RRA) method were applied. These DEGs were performed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses by using Clusterprofiler package. In order to explore the correlation between these DEGs, the interaction network of protein-protein internet (PPI) was constructed using the STRING database. Utilizing the MCODE plug-in of Cytoscape, the module analysis was performed. Utilizing the cytoHubba plug-in, the hub genes were screened out. RESULTS: 57 DEGs in total were identified, including 2 down- and 55 upregulated genes. These DEGs were mainly enriched in cytokine-cytokine receptor interaction, chemokine signaling pathway, TNF signaling pathway, and so on. The module analysis filtered out 18 key genes, including Cxcl5, Arg1, Cxcl1, Spp1, Selp, Ptx3, Tnfaip6, Mmp8, Serpine1, Ptgs2, Il6, Il1r2, Il1b, Ccl3, Ccr1, Hmox1, Cxcl2, and Ccl2. Ccr1 was the most fundamental gene in PPI network. 4 hub genes in total were identified, including Cxcl1, Cxcl2, Cxcl5, and Mmp8. CONCLUSION: This study may provide credible molecular biomarkers in terms of screening, diagnosis, and prognosis for AMI. Meanwhile, it also serves as a basis for exploring new therapeutic target for AMI.

Malignant Arrhythmia with Variants of Desmocollin-2 and Desmoplakin Genes.

Malignant arrhythmia is a fast cardiac arrhythmia that can lead to a hemodynamic abnormality within a short time, most of which is ventricular tachycardia or ventricular fibrillation (VF), which should be managed in time. Both organic and nonorganic cardiac diseases have the potential to cause malignant arrhythmia. We report a noteworthy case of malignant arrhythmia in a teenager during exercise. Transthoracic echocardiography, cardiac magnetic resonance (CMR), electrophysiological study, magnetic resonance imaging of the brain, electroencephalography, chest X-ray, and blood tests were all normal. Twelve-lead electrocardiography showed incomplete right bundle branch block (IRBBB). Two heterozygous missense variants of the desmocollin-2 gene (DSC2, c.G2446A/p.V816M) and desmoplakin gene (DSP, c.G3620A/p.R1207K) were detected in the peripheral blood of this teenager and his father by genetic testing, which encoded a desmosomal protein that was related to arrhythmogenic right ventricular cardiomyopathy (ARVC). In these two rare variants, DSC2 V816M has been reported but uncertain significance, whereas DSP R1207K is never reported. Therefore, the two site variants in DSC2 and DSP genes are likely to become a new research focus for diagnosis and treatment of ARVC in the future. Meanwhile, this report emphasizes that, in addition to a standard set of laboratory tests and examinations, genetic testing may be useful for analyzing the causes of malignant arrhythmia.