Background Postmenopausal osteoporosis (PMOP) is the most common primary osteoporosis, which is prone to fractures and affect the health and quality of life of the elderly and even shorten their lifetime. Traditional Chinese medicine can not only effectively improve osteoporosis and reduce fracture rate, but also have tonifying and analgesic effects. The purpose of this study was to investigate the effects of Zhuanggu Zhitong (ZGZT) Capsule on autophagy related genes and proteins in PMOP rats, so as to elucidate the molecular mechanism of tonifying deficiency and regulating stasis in the treatment of osteoporosis and analgesia. Methods The PMOP rat model was established by bilateral oophorectomy, and then the rats were randomly divided into control group, PMOP group, PMOP + ZGZT group and PMOP + E 2 group. The changes of mechanical pain threshold of rats were detected by von Frey filaments, and the changes of mechanical pain threshold of rats in each group were compared. Computed tomography (CT) and dual-energy X-ray were used to measure the bone mineral density of lumbar bone tissue. Enzyme-linked immunosorbent assay (ELISA) and tartrate-resistant acid phosphatase (TRAP) staining were used to detect inflammatory factors and bone metabolism related indicators. Hematoxylin-eosin (HE) staining was used to observe the tissue morphology of lumbar vertebra tissue. Western blot (WB) and quantitative polymerase chain reaction (qPCR) were used to detect AMPK/mTOR pathway- and autophagy-related factor expression. Results ZGZT can effectively restore the bone mineral density (BMD) of PMOP rats, improve the microstructure of lumbar vertebra of PMOP rats, restore the balance of bone metabolism, promote the expression of AMPK and autophagy related factors, inhibit the expression of mTOR and the release of inflammatory factors, and increase the mechanical pain threshold of PMOP rats, so as to effectively improve osteoporosis and relieving osteoporosis pain in PMOP rats. Conclusions ZGZT affects autophagy by regulating AMPK/mTOR pathway, restores the homeostasis of bone metabolism and inhibits the release of inflammatory factors. Moreover, the regulation of feedback pathways between bone metabolism and inflammatory factors finally plays the role of “bone strengthening” and “pain relieving”. ZGZT may be a new treatment for PMOP and relieving osteoporotic pain.
Background. Biejiajian pill (BJJP), a classical traditional Chinese formula, has been reported that it has an effective treatment for diabetic atherosclerosis in recent years, but its underlying mechanisms remain elusive. The study aimed to explore the potential mechanisms of BJJP on diabetic atherosclerosis by integrating network pharmacology, molecular docking, and molecular dynamics simulation. Methods. The active components of BJJP were collected by TCMSP and TCMID, and then the potential targets were obtained from the SwissTargetPrediction database. The targets related to diabetic atherosclerosis were identified from the GeneCards and OMIM databases. The intersection of the potential targets regulated by active components of BJJP and the targets of diabetic atherosclerosis were common targets, which were visualized by the Venn diagram. The common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. The network of “Medicine-Compound-Target” was constructed with Cytoscape 3.7.1 software. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using the DAVID database and visualized through bioinformatics. The intersecting targets were input into Cytoscape 3.7.1 software, and the Network Analyzer tool was employed to screen out the key targets. Then molecular docking was used to verify the binding affinity between the active compounds and the key targets, and molecular dynamics simulation was used to investigate the stability of the binding models. Results. A total of 81 active components, 186 targets of BJJP, and 4041 targets of diabetic atherosclerosis were obtained. Furthermore, 121 overlapping targets were identified. GO functional enrichment analysis revealed that these targets were correlated with the oxidation-reduction process, negative regulation of apoptotic process, inflammatory response, and other biological processes. The results of the KEGG pathway enrichment analysis showed that the common targets mainly participated in proteoglycans in cancer, PPAR signaling pathway, adherens junction, insulin resistance, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. The results of molecular docking confirmed that the core active components in BJJP could bind well to the key targets. Results from molecular dynamics simulation showed that the binding energies of AKT1-Luteolin, MMP9-quercetin, and MMP9-luteolin complexes were −28.93 kJ·mol−1, −37.12 kJ·mol−1, and −62.91 kJ·mol−1, respectively. Conclusion. The study revealed that BJJP is characterized as multicomponent, multitarget, and multipathway to treat diabetic atherosclerosis, which is helpful to provide ideas and a basis for pharmacological research and clinical application in the future.
Objective. To research the efficacy of Biejiajian pill (BJJ) on diabetes-associated atherosclerosis and explore its subsequent mechanisms. Methods. Diabetes-associated atherosclerosis (AS) was established in apolipoprotein E knockout (ApoE−/−) mice using high-fat diet and streptozotocin. Atorvastatin (ATV, 10 mg/kg/day) or BJJ-L (BJJ low-dose, 0.9 g/kg/day), BJJ-M (BJJ medium-dose, 1.8 g/kg/day), and BJJ-H (BJJ high-dose, 3.6 g/kg/day) were administered to diabetic ApoE−/− mice for 12 continuous weeks. The normal control group consisted of 10 male C57BL/6J mice. Atherosclerosis plaques, vascular endothelial function, fasting blood glucose, lipid metabolism, inflammatory factors, NLRP3 inflammasome expression, and mitochondria and autophagy changes were evaluated. Results. The atherosclerotic lesions areas in the aortas were analyzed through Oil Red O and H&E staining, and they were reduced in the BJJ-H and BJJ-M groups. In the BJJ group, endothelin-1 (ET-1) levels were decreased, whereas endothelial nitric oxide synthase (eNOS) was increased. Fasting blood glucose levels in the BJJ and ATV groups were gradually decreased. Lipid metabolism parameters such as TG, TC, and LDL-C were reduced, while HDL-C was elevated in BJJ groups. The serum IL-1β and IL-18 were decreased under BJJ therapy. The aortic mRNA and protein expressions of NF-κB, TXNIP, NLRP3, ASC, caspase-1, and IL-1β were inhibited in BJJ-H and BJJ-M groups, especially in the BJJ-H group. Electron microscopy revealed an increase in autophagy in each treatment group. Conclusions. The findings reveal that BJJ could alleviate diabetic atherosclerosis in diabetic ApoE−/− mice by inhibiting NLRP3 inflammasome.
Objective Our objective was to analyze the traditional Chinese medicine (TCM) syndrome and treatment laws of diabetic kidney disease (DKD) and the action mechanism of high-frequency Chinese herbs in the treatment of DKD based on real-world study. Methods The data of patients with DKD who had been treated in the First Hospital Affiliated to Henan University of Chinese Medicine from January 1, 2014 to December 31, 2021 were retrospectively analyzed through the hospital information management system. The contents of the cases were statistically analyzed using IBM SPSS Statistics 25 software, and the laws of DKD treatment were summarized. Network pharmacology and molecular docking were used to analyze the action mechanism of high-frequency Chinese herbs in the treatment of DKD. Results The data of a total of 1,201 patients with DKD were included, involving 72 kinds of TCM syndromes. Nine disease nature elements and six disease location elements were extracted, involving 405 Chinese herbs. The top five high-frequency Chinese herbs were Baizhu (Atractylodis Macrocephalae Rhizoma), Fuling (Poria), Huangqi (Astragali Radix), Chuanxiong (Chuanxiong Rhizoma), and Danshen (Salviae Miltiorrhizae Radix et Rhizoma). Thirty kinds of Chinese herbs with the frequency of ≥100 were mainly deficiency-tonifying herbs and blood-activating and stasis-eliminating herbs. The medicinal properties were mainly warm and mild, and the medicinal flavors were sweet and bitter mostly. For the meridian tropism, the main meridian tropism of these herbs is spleen meridian and lung meridian. The clustering method aggregated the 30 commonly used Chinese herbs into six categories. A total of 58 effective active ingredients of high-frequency Chinese herbs and 164 related targets were screened based on the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP); 1,434 targets of DKD and 90 potential targets of high-frequency Chinese herbs for DKD were obtained. “Active ingredient-potential target” network topology analysis indicated that quercetin, luteolin, 7-O-methylisoxitol, hederagenin, and 4-methylene miltirone were the five core chemical components of high-frequency Chinese herbs in the treatment of DKD. Protein–protein interaction network topology analysis indicated that protein kinase B1, interleukin-6, tumor necrosis factor, vascular endothelial growth factor A, tumor protein P53 were the core protein targets. Twenty signaling pathways were obtained by Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Molecular docking showed that luteolin, 4-methylene miltirone, and osthole had strong binding to AKT1. Conclusion The differentiation and treatment of DKD with TCM follows the principles of “taking kidney as the root, considering both the liver and spleen, tonifying qi and nourishing yin, promoting blood circulation and resolving blood stasis.” High-frequency Chinese herbs for the treatment of DKD have multicomponent, multitarget, and multipath characteristics.
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