Deciphering the Mechanism of Siwu Decoction Inhibiting Liver Metastasis by Integrating Network Pharmacology and In Vivo Experimental Validation.

BACKGROUND: Siwu Decoction (SWD) is a well-known classical TCM formula that has been shown to be effective as a basis for preventing and reducing liver metastases (LM). However, the active ingredients and potential molecular mechanisms remain unclear. OBJECTIVE: This study aimed to systematically analyze the active ingredients and potential molecular mechanisms of SWD on LM and validate mechanisms involved. MATERIALS AND METHODS: The active ingredients in SWD were extracted by UHPLC-MS/MS in a latest study. Protox II was retrieved to obtain toxicological parameters to detect safety. Swiss Target Prediction database was exploited to harvest SWD targets. Five databases, Gene Cards, DisGeNET, Drugbank, OMIM, and TTD, were employed to filter pathogenic targets of LM. STRING database was utilized to construct the protein-protein interaction network for therapeutic targets, followed by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. GEPIA database and the Human Protein Atlas were taken to observe the expression of core genes and proteins. ImmuCellAI algorithm was applied to analyze the immune microenvironment and survival relevant to core genes. Molecular docking was performed to verify the affinity of SWD effective ingredients to core targets. In vivo experiments were carried out to validate the anti-LM efficacy of SWD and verify the pivotal mechanisms of action. RESULTS: Eighteen main bioactive phytochemicals identified were all non-hepatotoxic. PPI network acquired 118 therapeutic targets, of which VEGFA, CASP3, STAT3, etc. were identified as core targets. KEGG analysis revealed that HIF-1 pathway and others were critical. After tandem targets and pathways, HIF-1/VEGF was regarded as the greatest potential pathway. VEGFA and HIF-1 were expressed differently in various stages of cancer and normal tissues. There was a negative regulation of immunoreactive cells by VEGFA, which was influential for prognosis. Molecular docking confirmed the tight binding to VEGFA. This study revealed the exact effect of SWD against LM, and identified significant inhibition the expression of HIF-1α, VEGF, and CD31 in the liver microenvironment. CONCLUSION: This study clarified the active ingredients of SWD, the therapeutic targets of LM and potential molecular mechanisms. SWD may protect against LM through suppressing HIF-1/VEGF pathway.

The recent advance and prospect of natural source compounds for the treatment of heart failure.

Heart failure is a continuously developing syndrome of cardiac insufficiency caused by diseases, which becomes a major disease endangering human health as well as one of the main causes of death in patients with cardiovascular diseases. The occurrence of heart failure is related to hemodynamic abnormalities, neuroendocrine hormones, myocardial damage, myocardial remodeling etc, lead to the clinical manifestations including dyspnea, fatigue and fluid retention with complex pathophysiological mechanisms. Currently available drugs such as cardiac glycoside, diuretic, angiotensin-converting enzyme inhibitor, vasodilator and ß receptor blocker etc are widely used for the treatment of heart failure. In particular, natural products and related active ingredients have the characteristics of mild efficacy, low toxicity, multi-target comprehensive efficacy, and have obvious advantages in restoring cardiac function, reducing energy disorder and improving quality of life. In this review, we mainly focus on the recent advance including mechanisms and active ingredients of natural products for the treatment of heart failure, which will provide the inspiration for the development of more potent clinical drugs against heart failure.

Mechanism of icariin for the treatment of osteoarthritis based on network pharmacology and molecular docking method.

BACKGROUND: Icarin's mechanism of action in osteoarthritis (OA) was explored using network pharmacology and the GEO database, and then further validated using molecular docking. METHODS: GEO database using network pharmacology identified differential genes in OA based on Icariin's possible targets predicted by pharmmapper database. Combining the differentially expressed genes in OA with the OA-related targets, the overlapping targets were removed. In order to determine what Icariin's core targets are for treating OA, PPI network analysis was performed using OA-related targets and possible Icariin targets. Furthermore, molecular docking was used to verify the chemical's binding to the targets. Final steps included Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Cytoscape was used to construct a network of compound-target-pathway-disease. RESULTS: Protein-protein interactions between overlapping targets revealed 151 intersection targets based on a network analysis. The top ten targets with the highest enrichment scores were SRC, MAPK1, HSP90AA1, AKT1, PTPN11, ESR1, EGFR, RhoA, JAK2, and MAPK14. KEGG enrichment analysis showed that the pathways at which Icariin intervention occurs include the OA including FOXO signaling pathway, and estrogen signaling pathway. The GO analysis result showed that various biologic processes such as proteolysis, angiogenesis, innate immune response, and positive regulation of inflammatory response were involved in treatment. Molecular docking analysis confirmed that Icariin could bind well to the targets through intermolecular forces. CONCLUSION: With its multi-targeting and multi-pathway characteristics, Icariin is a promising candidate drug for treating OA.

[Finite element analysis on stress concentration improvement in patellofemoral joint by releasing lateral patellar retinaculum with stiletto needle based on the theory of Jinshugu()].

OBJECTIVE: To study mechanism of improvement of stress concentration on patellofemoral joint by stiletto needle releasing lateral patellar retinaculum guided by the theory of Jinshugu() and based on the finite element model of knee joint. and to elucidate the biomechanical mechanism of stiletto needle releasing changing patellar trajectory and reducing patellofemoral joint pressure. METHODS: CT data of knee joint from a normal male (aged 29, heighted 171 cm, weighted 58 kg) was selected. Starting with construction of three-dimensional model of knee joint by using finite element software, the finite element model of knee joint with complete tendonand bone structures were established through several steps, such as geometric reconstruction, reverse engineering, meshing, material assignment and loading analysis. The loading condition was set as 500 N load on knee joint, and the average tensile stress of quadriceps femoris tendon was about 200 N. To simulate the release of lateral patellar retinaculum by stiletto needle at 30 and 90 position of knee flexion in finite element model separately, and to compare the improvement of stress concentration of patellofemoral joint by stiletto needle intervention under different knee flexion conditions. RESULTS: The peak stress of patellofemoral joint and tibiofemoral joint decreased after stiletto needle releasing of patellofemoral lateral retinaculum compared with before intervention, which was(1) knee flexion at 30 degrees:patellar cartilage decreased by 0.498 MPa (decreased 9.06%), femoral trochlea decreased by 0.886 MPa(decreased 16.27%);(2) knee flexion at 90 degrees:patellar cartilage decreased by 0.558 MPa (decreased 8.6%), femoral trochlea decreasedby 0.607 MPa (decreased 9.94%). CONCLUSION: Releasing lateral patellofemoral retinaculum with stiletto needle could effectively alleviate the stress concentration of patellofemoral joint and reduce local stress peak value, which it is helpful to improve patellar trajectory and make stress distribution more uniform.

Study on the Mechanism of Ginseng in the Treatment of Lung Adenocarcinoma Based on Network Pharmacology.

BACKGROUND: Ginseng, a traditional Chinese medicine, was used to prevent and treat many diseases such as diabetes, inflammation, and cancer. In recent years, there are some reports about the treatment of lung adenocarcinoma with ginseng monomer compounds, but there is no systematic study on the related core targets and mechanism of ginseng in the treatment of lung adenocarcinoma up to now. Therefore, this study systematically and comprehensively studied the molecular mechanism of ginseng in the treatment of lung adenocarcinoma based on network pharmacology and further proved the potential targets by A549 cell experiments for the first time. METHODS: The targets of disease and drug were obtained from Gene database. Subsequently, the compound-target network was constructed, and the core potential targets were screened out by plug-in into Cytoscape. Furthermore, the core targets and mechanism of ginseng in the treatment of lung adenocarcinoma were verified by MTT test, cell scratch test, immunohistochemistry, and qRT-PCR. RESULTS: 1791 disease targets and 144 drug targets were obtained by searching the Gene database. Meanwhile, 15 core targets were screened out: JUN, MAPK8, PTGS2, CASP3, VEGFA, MMP9, AKT1, TNF, FN1, FOS, MMP782, IL-1ß, IL-2, ICAM1, and HMOX1. The results of cell experiments indicate that ginseng could treat lung adenocarcinoma by cell proliferation, migration, and apoptosis. In addition, according to the results of the 15 core targets by qRT-PCR, JUN, IL-1ß, IL-2, ICAM1, HMOX1, MMP9, and MMP2 are upregulated core targets, while PTGS2 and TNF are downregulated core targets. CONCLUSION: This study systematically and comprehensively studied 15 core targets by network pharmacology for the first time. Subsequently, it is verified that 9 core targets for ginseng treatment of lung adenocarcinoma, namely, JUN, IL-1ß, IL-2, ICAM1, HMOX1, MMP9, MMP2, PTGS2, and TNF, are closely related to the proliferation, migration, and apoptosis of lung adenocarcinoma cells. This study has reference value for the clinical application of ginseng in the treatment of lung adenocarcinoma.

Patellar resurfacing versus patellar nonresurfacing in primary total knee arthroplasty: A protocol for systematic review and meta analysis.

BACKGROUND: Total knee arthroplasty (TKA) is one of the most common orthopedic procedures. However, the decision to resurface the patella during a primary TKA remains controversial. Therefore, a systematic review and meta-analysis were conducted to determine whether patellar resurfacing is needed in primary total knee arthroplasty. METHODS: A systematic literature research will be conducted in 7 databases including PubMed, Embase, Cochrane Library website, ClinicalTrials.gov databases, Chinese National Knowledge Infrastructure Database, Wanfang database, and VIP database for Chinese Technical Periodicals. The quality of studies will be assessed according to Cochrane risk of bias tool and Methodological index for non-randomized studies (MINORS) scale. The level of the evidence will be estimated by grading of recommendations assessment, development, and evaluation system. Data analysis and synthesis will be completed by the Review Manager 5.3. CONCLUSIONS: The conclusion of this study will provide clinicians performing TKA with a recommendation whether to conduct patellar resurfacing and further guide the clinical decision-making.PROSPERO registration number: CRD42019129711.

[Construction and simulation mechanical analysis of dynamic knee joint finite element model based on CT image].

OBJECTIVE: To construct a dynamic knee joint finite element model based on CT image data and verify the validity of the model. To provide a simulation model and basic data for biomechanical research of the knee joint by further finite element analysis. METHODS: The CT data of a healthy male knee joint was selected. With the help of Mimics 19.0 and Hypermesh 12.0 software, a high simulation finite element model of knee joint was established following steps, including geometric reconstruction, reverse engineering, meshing and material characterization. The dynamic knee flexion model was generated by determining the boundary conditions and torque loading, and the validity of themodel was confirmed. The biomechanical changes of the tibiofemoral and patellofemoral joints under different knee flexion angles were analyzed by applying the loads (500 N) to the finite element model during knee flexion. RESULTS: A finite element model of knee joint was established based on CT images and anatomical characteristics. The model included three-dimensional elements such as bone, ligament, cartilage, meniscus and patellar retinaculum. The different finite element models of knee flexion states were produced by applying different torques after establishing boundary conditions. According to equivalent conditions (knee flexion 30 degrees, quadriceps tendon under 200 N stretch), the peak stress value of patella was 2.209 MPa and the average Mises stress was 1.132 MPa; the peak stress value of femoral trochlear was 1.405 MPa and the average Mises stress was 0.936 MPa. The validity of the model was proved by the difference between the model and previous studies of 1% to 13.5%. Dynamic model loading showed that the Mises stressof tibiofemoral joint decreased with the increase of knee flexion angle, while the Mises stress of patellofemoral joint was positively correlated with knee flexion angle. The Mises stress of cartilage stress planes at different knee flexion angles was significantly different(P<0.05). CONCLUSION: The finite element model established in this study is more comprehensive and can effectively simulate the biomechanical characteristics of dynamic knee joint, which provides support for further simulation mechanics researches of the knee joint.

The short-term efficacy of mud therapy for knee osteoarthritis: A meta-analysis.

The objective of this review is to systematically evaluate the short-term efficacy of mud therapy in the treatment of knee osteoarthritis (KOA).Randomized controlled trials, in which treatment of KOA is mud therapy, were included by systematically searching the PubMed, Embase, and the Cochrane Library databases.According to inclusion criteria and searching method, 11 articles, containing a total of 1106 patients, were included in the study. Our results showed significant differences in visual analog scale pain score and Western Ontario and McMaster Universities Osteoarthritis Index (pain, stiffness, function). In addition, the heterogeneity of study included is lower (I < 25%).According to the results of this meta-analysis, mud therapy can effectively alleviate the pain and improve joint function for KOA.

[Stiletto needle combined with massotherapy for pain in patients with knee osteoarthritis].

OBJECTIVE: To compare the clinical effect between Stiletto needle combined with massotherapy and articular injection of sodium hyaluronate for pain in patients with knee osteoarthritis (KOA). METHODS: A total of 156 patients with KOA were randomly divided into an observation group and a control group, 78 cases in each group. The patients in the observation group were treated with Stiletto needle (once a week) combined with massotherapy (twice a week); the patients in the control group were treated with articular injection of sodium hyaluronate (once a week). The treatment period were 5 weeks in total. The visual analogue scale (VAS) score, local tenderness value, knee joint activity and Lysholm knee joint score were recorded before treatment, 3 weeks and 5 weeks of treatment. RESULTS: Compared before treatment, the VAS score, local tenderness value, knee joint activity and Lysholm knee joint score in the two groups were improved 5 weeks of treatment (P<0.05). After 5 weeks of treatment, The local tenderness value and Lysholm knee joint score in the observation group were significantly improved compared with the control group (P<0.05), but the knee joint activity in the control group was superior to that in the observation group (P<0.05). CONCLUSION: The Stiletto needle combined with massotherapy are superior to articular injection of sodium hyaluronate in relieving pain and improving knee joint function in patients with early-to-moderate KOA, but its effect on joint activity is inferior to sodium hyaluronate.

Comparison between Tonifying Kidney Yang and Yin in Treating Segmental Bone Defects Based on the Induced Membrane Technique: An Experimental Study in a Rat Model.

Tonifying kidney therapy consisting of tonifying kidney yang and yin is the basic principle of Chinese medicine in treating segmental bone defects (SBDs). Previous studies have demonstrated the presence of the differences between tonifying kidney yang and yin in bone metabolism of osteoporosis and distraction osteogenesis models. However, whether the difference between the two tonifying kidney methods in bone repair for the induced membrane (IM) technique occurs or what is the difference remain unclear. Angiogeneic-osteogenic coupling plays an important role in bone repair and the induced membrane couples angiogenesis with the later osteogenesis during the IM process. This study aimed at investigating the effects of tonifying kidney yang (total flavonoids of Rhizoma Drynariae, TFRD) and yin (plastrum testudinis extract, PTE) on angiogenesis and osteogenesis in the IM-treated SBDs. Rats of 6 mm tibia bone defect model treated with IM were divided into five groups: the control group, the model group, the tonifying kidney yang group (TFRD-treated group), the tonifying kidney yin group (PTE-treated group), and the western medicine group. At 4 weeks after insertion of the polymethylmethacrylate (PMMA), three caudal vertebrae from the tail in each rat were implanted into the 6 mm defect gap. Radiographical, histological, immunohistochemical, and immunofluorescent analyses were performed to assess bone and vessel formation at 4 or 12 weeks after insertion of the PMMA, respectively. Our results revealed that TFRD and PTE were beneficial to both angiogenesis and osteogenesis. TFRD exerted a better effect on angiogenesis than PTE and achieved a better result in stage 1 rather than in stage 2 of IM, whereas PTE was superior to TFRD in osteogenesis and achieved a better result in stage 2 instead of stage 1. Collectively, these findings elucidated the beneficial effects of tonifying kidney yang and yin on angiogenesis and osteogenesis of SBD repair during the IM process, as well as the difference that tonifying kidney yang surpasses tonifying kidney yin in angiogenesis while tonifying kidney yin outperforms tonifying kidney yang in osteogenesis, which suggests that the combination between the application of tonifying kidney yang method in stage 1 of IM and tonifying kidney yin method in stage 2 may achieve better repair efficiency.