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Background: Salvia miltiorrhiza (SM) is an effective traditional Chinese medicine for treating DKD, but the exact mechanism is elusive. In this study, we aimed to investigate and confirm the method underlying the action of the active components of SM in the treatment of DKD. Methods: Renal tissue transcriptomics and network pharmacology of DKD patients was performed to identify the active components of SM and the disease targets of DKD. Next, the point of convergence among these three groups was studied. Potential candidate genes were identified and analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The component-target networks were modelled and visualized with Cytoscape. In addition, docking studies were performed to validate our potential target predictions. Lastly, in vitro and in vivo experiments were performed to understand the role of Dehydromiltirone (DHT), the active component of SM, in the phenotypic switching of mesangial cells. Results: Transcriptomics of DKD patients' renal tissues screened 4,864 differentially expressed genes. Eighty-nine active components of SM and 161 common targets were found. Functional enrichment analysis indicated that 161 genes were enriched in apoptosis, the PI3K-AKT signaling pathway, and the AGE-RAGE signaling pathway in diabetes complications. Molecular docking and molecular dynamic simulations show that DHT can bind to functional PIK3CA pockets, thereby becoming a possible inhibitor of PIK3CA. In vitro study demonstrated that DHT reduced the expression of phenotypic switching markers α-SMA, Col-I, and FN in HMCs by downregulating the over-activation of the PI3K-AKT signaling pathway through the inhibition of PIK3CA. Furthermore, the DKD mouse model confirmed that DHT could reduce proteinuria and improve glomerular hypertrophy in vivo. Conclusion: DHT was identified as the key active component of SM, and its therapeutic effect on DKD was achieved by inhibiting the phenotypic switching of mesangial cells via the PIK3CA signaling pathway.
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Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1ß, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.
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To analyze the academic characteristics and medication rules of traditional Chinese medical master Liu Zu-yi for treating insomnia. Totally 178 cases of insomnia treated by Professor Liu were collected,and the treatment data were input into traditional Chinese medicine inheritance support system( TCMISS) by using data mining methods,such as essential information,frequency statistics of symptoms,syndrome type statistics,extraction of syndrome elements,frequency statistics of drugs; and four properties and five tastes of drugs,distribution of meridians,regularity of prescriptions,new prescription analysis were mined. It was found that the most commonly used drugs( over 100 times) were Albiziae Cortex,Longgu,Polygoni Multiflori Caulis,Ostreae Concha,Ziziphi Spinosae Semen,Crataegi Fructus; the commonly used couplet medicines were Longgu-Ostreae Concha,Ziziphi Spinosae Semen-Polygoni Multiflori Caulis,Ziziphi Spinosae Semen-Albiziae Cortex-Polygoni Multiflori Caulis; and seven new prescriptions in treating insomnia were explored,such as prescriptions containing Hordei Fructus Germinatus,Ziziphi Spinosae Semen,Galli Gigerii Endothelium Corneum,Rehmanniae Radix,Lilii Bulbus. Based on the introduction and discussion of Professor Liu's academic views and characteristics on insomnia treatment and the illustrative evidences added to the typical case list,this paper combines the academic characteristics,data support and typical medical records to verify each other,and objectively summarizes his academic experience for treating insomnia. Treatment shall focus on the primary cause of disease in three aspects; syndrome differentiation shall distinguish between excessive disease and deficient disease; therapy shall reinforce deficiency and reduce diarrhea,regulate the five internal organs,and emphasizes the heart and liver,particularly the liver; medication shall focus on the drugs for calming the mind and protecting the stomach and spleen,which are commonly combined with three types of traditional Chinese medicine with effect in introducing Yangqi( Pinelliae Rhizoma Praeparatum,Prunellae Spica,Polygoni Multiflori Caulis) and restraining Yangqi( Longgu,Ostreae Concha,Ziziphi Spinosae Semen); nursing care focuses on preserving the body and tranquilizing the mind by means of three methods for tranquilizing the mind and three methods for preserving the body.