Investigating the Mechanistic of Danhong Injection in Brain Damage Caused by Cardiac I/R Injury via Bioinformatics, Computer Simulation, and Experimental Validation.

OBJECTIVE: Cardiac ischemia-reperfusion (I/R) injury has negative effects on the brain and can even lead to the occurrence of ischemic stroke. Clinical evidence shows that Danhong injection (DHI) protects the heart and brain following ischemic events. This study investigated the mechanisms and key active compounds underlying the therapeutic effect of DHI against brain damage induced by cardiac I/R injury. METHODS: The gene expression omnibus database provided GSE66360 and GSE22255 data sets. The R programming language was used to identify the common differentially expressed genes (cDEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed, and protein-protein interaction network was constructed. Active compounds of DHI were collected from the Traditional Chinese Medicine Systems Pharmacology database. Molecular docking and molecular dynamics simulations were performed. The MMPBSA method was used to calculate the binding-free energy. The pkCSM server and DruLiTo software were used for Absorption, Distribution, metabolism, excretion, and toxicity (ADMET) analysis and drug-likeness analysis. Finally, in vitro experiments were conducted to validate the results. RESULTS: A total of 27 cDEGs had been identified. The PPI and enrichment results indicated that TNF-α was considered to be the core target. A total of 80 active compounds were retrieved. The molecular docking results indicated that tanshinone I (TSI), tanshinone IIA (TSIIA), and hydroxyl safflower yellow A (HSYA) were selected as core active compounds. Molecular dynamics verification revealed that the conformations were relatively stable without significant fluctuations. MMPBSA analysis revealed that the binding energies of TSI, TSIIA, and HSYA with TNF-α were -36.01, -21.71, and -14.80 kcal/mol, respectively. LEU57 residue of TNF-α has the highest contribution. TSI and TSIIA passed both the ADMET analysis and drug-likeness screening, whereas HSYA did not. Experimental verification confirmed that DHI and TSIIA reduced the expression of TNF-α, NLRP3, and IL-1ß in the injured H9C2 and rat brain microvascular endothelial cells. CONCLUSION: TNF-α can be considered to be a key target for BD-CI/R. TSIIA in DHI exerts a significant inhibitory effect on the inflammatory damage of BD-CI/R, providing new insights for future drug development.

Network pharmacology and in vitro experimental verification to reveal the mechanism of Astragaloside IV against kidney ischemia-reperfusion injury.

Ischemic acute kidney injury (AKI) is a prevalent disorder among hospitalized patients worldwide. Astragaloside IV (AS-IV) has been shown to protect against ischemic AKI. However, the specific effects and mechanisms of AS-IV on alleviating kidney ischemia-reperfusion (I/R) injury remain unclear. The objective of this research was to elucidate the regulatory targets and mechanisms through which AS-IV protects kidney I/R injury. A combination of network pharmacology, molecular docking, molecular dynamics (MD) simulation, pharmacodynamic study and Western blot were employed to explore the underlying mechanisms. Network pharmacology revealed that ferroptosis was a potential mechanism of AS-IV against kidney I/R injury. Molecular docking and MD simulations demonstrated strong binding affinity between the GPX4/SLC7A11 and AS-IV. The experimental verification demonstrated that AS-IV improved cell proliferation, decreased the level of ROS and Fe2+, and increased the expressions of GPX4 and SLC7A11 as same as Ferrostatin-1 in OGD/R-injured HUVECs. In conclusion, AS-IV had a significant inhibition on ferroptosis in kidney I/R injury, providing a new perspective for drug development on kidney I/R injury. Definitely, further exploration in vivo is necessary to fully understand whether AS-IV alleviates kidney I/R injury through inhibiting endothelial ferroptosis.

Prevalence and severity of thrombocytopenia in patients with hyperferritinemia.

BACKGROUND: In patients with tumors, inflammation, and blood disorders, hyperferritinemia has been associated with the severity of the underlying disease and is frequently accompanied by a co-occurring low platelet count or thrombocytopenia. Despite this, no established correlation has been identified between hyperferritinemia and platelet count. In this retrospective, double-center study, we sought to describe the prevalence and severity of thrombocytopenia in patients with hyperferritinemia. STUDY AND DESIGN: A total of 901 samples were enrolled in this study, all of which had significantly high ferritin levels (>2000 µg/L) between January 2019 and June 2021. We analyzed the general distribution, incidence of thrombocytopenia in patients with hyperferritinemia, and the relationship between ferritin level and platelet count. p-values < 0.05 were considered statistically significant. RESULTS: The total incidence of thrombocytopenia in patients with hyperferritinemia was 64.7%. Hematological diseases were the most frequent cause of hyperferritinemia (43.1%), followed by solid tumors (29.5%) and infectious diseases (11.7%). Patients with thrombocytopenia (<150 × 109/L) had significantly higher ferritin levels than those with platelet counts exceeding 150 × 109/L, with median ferritin levels of 4011 and 3221 µg/L, respectively (P < 0.001). Additionally, the results showed that the incidence of thrombocytopenia was higher in hematological patients with chronic transfusion than in those without chronic blood transfusions (93% vs 69%). CONCLUSIONS: In conclusion, our results suggest that hematological diseases are the most common cause of hyperferritinemia and that patients with chronic blood transfusions are more susceptible to thrombocytopenia. Elevated ferritin levels may act as a trigger for thrombocytopenia.

[Identification of a novel FUT1 allele in a Chinese individual featuring para-Bombay phenotype].

OBJECTIVE: To explore the genetic basis for an individual with a para-Bombay phenotype. METHODS: A proband with mismatched forward and reverse serotypes for the ABO blood group was identified. Weakly expressed ABH blood type antigen on the surface of red blood cells was verified by absorption and release test, and the blood group substances in saliva was detected by sialic acid test. Exons 6 and 7 of the ABO gene and exons of the FUT1 and FUT2 genes were subjected to direct sequencing. RESULTS: The proband was found to be of O type by forward ABO serotyping and AB type by reverse ABO serotyping, though H and substance A and B were detected in her saliva. DNA sequencing revealed that she has harbored c.35C/T, c.328G/A, and c.504delC compound heterozygous variants of the FUT1 gene. Haploid analysis showed that her FUT1 genotype was h328A/h35T+504delC, which has been uploaded to the NCBI website (No. MW323551). CONCLUSION: The para-Bombay phenotype of the proband may be attributed to the novel compound heterozygous variants including c.504delC of the FUT1 gene, which may affect its function by altering the activity of FUT1 glycotransferase.