Background: Patients with rheumatoid arthritis (RA) may be more susceptible to infection by coronavirus disease-19 (COVID-19) due to immune system dysfunction. However, there are still insufficient treatment strategies for patients with RA and COVID-19. Since Jingulian is a traditional Chinese medicine (TCM) with anti-viral and immune regulatory functions, our study aims to explore the detailed mechanisms of Jingulian in treating patients with RA and COVID-19.Methods: All the components of Jingulian were retrieved from pharmacology databases. Then, a series of network pharmacology-based analyses and molecular docking were used to understand the molecular functions, core targets, related pathways, and potential therapeutic targets of Jingulian in patients with RA/COVID-19.Results: A total of 93 genes were identified according to the disease-compound-target network. We investigated that the main targets, signaling pathways, and biological functions of Jingulian in RA and COVID-19. Our results indicated that Jingulian may treat patients with RA/COVID-19 through immune processes and viral processes. Moreover, the results of molecular docking revealed that tormentic acid was one of the top compounds of Jingulian, which had high affinity with Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and epidermal growth factor receptor (EGFR) in patients with RA/ COVID-19. Furthermore, 5 core targets of Jingulian were also identified, including JAK1, Janus kinase 2 (JAK2), STAT3, lymphocyte specific protein tyrosine kinase (LCK), and EGFR.Conclusions: Tormentic acid in Jingulian may regulate JAK1, STAT3, and EGFR, and might play a critical role in RA/COVID-19.
Background and Aim: This study aims to investigate the effect and mechanism of proprotein convertase subtilisin/Kexin type 9 (PCSK9) on myocardial ischemia-reperfusion injury (MIRI) and provide a reference for clinical prevention and treatment of acute myocardial infarction (AMI).METHODS: We established a rat myocardial ischemia/reperfusion (I/R) model and AC16 hypoxia/reoxygenation (H/R) model. A total of 48 adult male Sprague-Dawley rats were randomly assigned to three groups (n=16): control, I/R, and I/R +SiRNA. In I/R and I/R +siRNA groups, myocardial ischemia was induced via occlusion of the left anterior descending branch (LAD) of the coronary artery in rats in I/R group for 0.5 h and reperfused for three days. To assess the myocardial injury, the rats were subjected to an electrocardiogram (ECG), cardiac function tests, cardiac enzymes analysis, and 2,3,5triphenyl tetrazolium chloride (TTC)/Evan Blue (EB) staining. Meanwhile, hematoxylin-eosin (HE) staining was used to detect morphological changes in cardiomyocytes in each group, and the level of myocardial brosis was quanti ed using Masson trichrome staining. Differences in the expression of autophagylevel proteins and Bcl-2/adenovirus E1B 19-kDa interacting protein (Bnip3) signaling-related proteins were determined by protein blotting. RESULTS: I/R and H/R injury increased the expression level of PCSK9, activated the downstream Bnip3, and subsequently triggered autophagy. In vitro and in vivo experimental studies revealed that siRNA knockdown of PCSK9 resulted in reduced expression of the autophagic protein Beclin-1, light chain 3 (LC3) compared to normal control-treated cells and control-operated groups. Simultaneously, the presentation of the autophagic pathway Bnip3 was downregulated. Furthermore, PCSK9-mediated small interfering RNA (siRNA) group injected into the left ventricular wall signi cantly improved cardiac function and myocardial infarct size, as well as the expression of mRNA of Recombinant Human Interleukin-1β IL-1β. Moreover, Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)was signi cantly downregulated and reduced the in ammatory response compared with the I/R group.CONCLUSIONS: In ischemic/hypoxic circumstances, PCSK9 expression was dramatically increased. PCSK9 knockdown alleviated MIRI via the Bnip3-mediated autophagic pathway and improved in ammatory response, myocardial infarct size, and cardiac function.
Our study aimed to detect the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) on exacerbating cardiomyocyte hypoxia/reoxygenation (H/R) injury and the possible mechanism. A cell model of H/R was constructed. PCSK9 mRNA and protein levels were significantly upregulated during AC16 cardiomyocyte H/R. Flowmetry detection of apoptosis, as well as JC-1, confirmed that PCSK9 upregulation of autophagy levels was accompanied by apoptosis. Furthermore, in the H/R+si-PCSK9 group, the expression of autophagy-related protein LC3 decreased and P62 increased. At the same time, the presentation of the autophagic pathway Pink1/Parkin was also downregulated. In conclusion, in AC16 cardiomyocytes treated with H/R, PCSK9 expression and autophagy levels were increased; a possible molecular mechanism was the activation of the Pink1/ Parkin pathway.
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