Network pharmacology and bioinformatics analysis identified essential genes of Jingulian in the treatment of rheumatoid arthritis and COVID-19.

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.

T1AM Attenuates the Hypoxia/Reoxygenation-Induced Necroptosis of H9C2 Cardiomyocytes via RIPK1/RIPK3 Pathway.

Purpose: To investigate the detailed mechanism of 3-iodothyronamine (T1AM) in cell apoptosis and programmed necrosis of hypoxia/reoxygenation- (H/R-) induced H9C2 injury. Materials and Methods: Cardiomyocyte H9C2 cells were cultured in vitro for the establishment of cardiomyocyte H/R models. Cells were randomly divided into four groups: the control group, H/R group, T1AM pretreatment group, T1AM pretreatment and H/R (6 µm T1AM+H/R) group. The degree of myocardial injury was determined by the detection of the cardiomyocyte inhibition rate by CCK8 and the detection of lactic dehydrogenase (LDH) activity. Cell apoptosis was assessed through TUNEL assay and flow cytometry analysis. The protein level and mRNA level of RIPK1, RIPK3, and CAMKII were detected by western blotting and qRT-PCR. Results: Compared with the control group, the cell inhibition rate was dramatically elevated in the H/R group. LDH release of cardiomyocytes was significantly increased. Protein and mRNA expressions of RIPK1, RIPK3, and CAMKII were significantly enhanced. Compared with the H/R group, the cell inhibition rate, LDH release, cardiomyocyte necroptosis rate, and protein and mRNA levels of RIPK1, RIPK3, and CAMKII of the T1AM+H/R group were significantly decreased. Conclusion: Pretreatment with T1AM could alleviate cardiomyocytes' H/R injury and inhibit necroptosis of cardiomyocytes, which might exert a protective function upon activation of the RIPK1/RIPK3 pathway.

3-iodothyronamine inhibits apoptosis induced by myocardial ischemia reperfusion via the Akt/FoxO1 signaling pathway.

Background: This study investigated the potential effects of 3-iodothyronamine (T1AM) on myocardial ischemia reperfusion injury (MIRI) and the underlying molecular mechanisms. Methods: A total of 16 adult male Sprague-Dawley rats were randomly divided into 4 groups and administered the following: control [60% dimethyl sulfoxide (DMSO) and 40% saline, pH 7.4], T1AM (25 mg/kg), T1AM (50 mg/kg), or T1AM (100 mg/kg). The rectal temperatures of the rats were measured at different time points. A further 30 adult male Sprague-Dawley rats were randomized and divided into the following 3 groups (n=10 in each group): sham operation, ischemia/reperfusion (I/R), and I/R + T1AM. In the I/R and I/R + T1AM groups, the left anterior descending (LAD) coronary artery of the rats were occluded for 0.5 hour to induce myocardial ischemia, followed by reperfusion for 3 hours in the I/R group. The electrocardiography (ECG), cardiac function, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were examined in rats to evaluate the myocardial injury. The differences in the expression of apoptosis-related and Akt-FoxO1 signaling-related proteins were determined via Western blot. Results: This work verified that T1AM reduced the body temperature of rats in a dose-dependent manner. Additionally, T1AM improved cardiac function and decreased the infarction size caused by MIRI. T1AM reduced the expression of biochemical parameters and apoptosis of myocardial cells. In addition, after treatment with T1AM, the expression of Glut1, pFoxO1 and Akt were reduced, while the expression of FoxO1 and PPARα were increased significantly. Conclusions: Pretreatment of cardiomyocytes with T1AM inhibited apoptosis and protected against ischemia reperfusion injury via the Akt/FoxO1 signaling pathway.