Corrigendum: An integrative pharmacology model for decoding the underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid arthritis.

[This corrects the article DOI: 10.3389/fphar.2022.801350.].

A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis.

Overexpressed matrix metalloproteinases, hypoxia microenvironment, and metabolic abnormality are important pathological signs of rheumatoid arthritis (RA). Designing a delivery carrier according to the pathological characteristics of RA that can control drug release in response to disease severity may be a promising treatment strategy. Psoralen is the main active ingredient isolated from Psoralea corylifolia L. and possesses excellent anti-inflammatory activities as well as improving bone homeostasis. However, the specific underlying mechanisms, particularly the possible relationships between the anti-RA effects of psoralen and related metabolic network, remain largely unexplored. Furthermore, psoralen shows systemic side effects and has unsatisfactory solubility. Therefore, it is desirable to develop a novel delivery system to maximize psoralen's therapeutic effect. In this study, a self-assembled degradable hydrogel platform is developed that delivers psoralen and calcium peroxide to arthritic joints and controls the release of psoralen and oxygen according to inflammatory stimulation, to regulate homeostasis and the metabolic disorder of the anoxic arthritic microenvironment. Therefore, the hydrogel drug delivery system based on the responsiveness of the inflammatory microenvironment and regulation of metabolism provides a new therapeutic strategy for RA treatment.

Quantification of promoting efficiency and reducing toxicity of Traditional Chinese Medicine: A case study of the combination of Tripterygium wilfordii hook. f. and Lysimachia christinae hance in the treatment of lung cancer.

Traditional Chinese medicine (TCM) usually acts in the form of compound prescriptions in the treatment of complex diseases. The herbs contained in each prescription have the dual nature of efficiency and toxicity due to their complex chemical component, and the principle of prescription is usually to increase efficiency and reduce toxicity. At present, the studies on prescriptions have mainly focused on the consideration of the material basis and possible mechanism of the action mode, but the quantitative research on the compatibility rule of increasing efficiency and reducing toxicity is still the tip of the iceberg. With the extensive application of computational pharmacology technology in the research of TCM prescriptions, it is possible to quantify the mechanism of synergism and toxicity reduction of the TCM formula. Currently, there are some classic drug pairs commonly used to treat complex diseases, such as Tripterygium wilfordii Hook. f. with Lysimachia christinae Hance for lung cancer, Aconitum carmichaelii Debeaux with Glycyrrhiza uralensis Fisch. in the treatment of coronary heart disease, but there is a lack of systematic quantitative analysis model and strategy to quantitatively study the compatibility rule and potential mechanism of synergism and toxicity reduction. To address this issue, we designed an integrated model which integrates matrix decomposition and shortest path propagation, taking into account both the crosstalk of the effective network and the propagation characteristics. With the integrated model strategy, we can quantitatively detect the possible mechanisms of synergism and attenuation of Tripterygium wilfordii Hook. f. and Lysimachia christinae Hance in the treatment of lung cancer. The results showed the compatibility of Tripterygium wilfordii Hook. f. and Lysimachia christinae Hance could increase the efficacy and decrease the toxicity of lung cancer treatment through MAPK pathway and PD-1 checkpoint pathway in lung cancer.

Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a complex issue in cancer treatment in the world at present. Matrine is the main active ingredient isolated from Sophora flavescens air and possesses excellent antitumor effects in HCC. However, the specific underlying mechanisms, especially the possible relationships between the anti-HCC effect of matrine and the related metabolic network of HCC, are not yet clear and need further clarification. In this study, an integrative metabolomic-based bioinformatics algorithm was designed to explore the underlying mechanism of matrine on HCC by regulating the metabolic network. Cell clone formation, invasion, and adhesion assay were utilized in HCC cells to evaluate the anti-HCC effect of matrine. A cell metabolomics approach based on LC-MS was used to obtain the differential metabolites and metabolic pathways regulated by matrine. The maximum activity contribution score model was developed and applied to calculate high contribution target genes of matrine, which could regulate a metabolic network based on the coexpression matrix of matrine-regulated metabolic genes and targets. Matrine significantly repressed the clone formation and invasion, enhanced cell-cell adhesion, and hampered cell matrix adhesion in SMMC-7721 cells. Metabolomics results suggested that matrine markedly regulated the abnormal metabolic network of HCC by regulating the level of choline, creatine, valine, spermidine, 4-oxoproline, D-(+)-maltose, L-(-)-methionine, L-phenylalanine, L-pyroglutamic acid, and pyridoxine, which are involved in D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, etc. Our proposed metabolomic-based bioinformatics algorithm showed that the regulating metabolic networks of matrine exhibit anti-HCC effects through acting on MMP7, ABCC1, PTGS1, etc. At last, MMP7 and its related target ß-catenin were validated. Together, the metabolomic-based bioinformatics algorithm reveals the effects of the regulating metabolic networks of matrine in treating HCC relying on the unique characteristics of the multitargets and multipathways of traditional Chinese medicine.

Detecting Key Functional Components Group and Speculating the Potential Mechanism of Xiao-Xu-Ming Decoction in Treating Stroke.

Stroke is a cerebrovascular event with cerebral blood flow interruption which is caused by occlusion or bursting of cerebral vessels. At present, the main methods in treating stroke are surgical treatment, statins, and recombinant tissue-type plasminogen activator (rt-PA). Relatively, traditional Chinese medicine (TCM) has widely been used at clinical level in China and some countries in Asia. Xiao-Xu-Ming decoction (XXMD) is a classical and widely used prescription in treating stroke in China. However, the material basis of effect and the action principle of XXMD are still not clear. To solve this issue, we designed a new system pharmacology strategy that combined targets of XXMD and the pathogenetic genes of stroke to construct a functional response space (FRS). The effective proteins from this space were determined by using a novel node importance calculation method, and then the key functional components group (KFCG) that could mediate the effective proteins was selected based on the dynamic programming strategy. The results showed that enriched pathways of effective proteins selected from FRS could cover 99.10% of enriched pathways of reference targets, which were defined by overlapping of component targets and pathogenetic genes. Targets of optimized KFCG with 56 components can be enriched into 166 pathways that covered 80.43% of 138 pathways of 1,012 pathogenetic genes. A component potential effect score (PES) calculation model was constructed to calculate the comprehensive effective score of components in the components-targets-pathways (C-T-P) network of KFCGs, and showed that ferulic acid, zingerone, and vanillic acid had the highest PESs. Prediction and docking simulations show that these components can affect stroke synergistically through genes such as MEK, NFκB, and PI3K in PI3K-Akt, cAMP, and MAPK cascade signals. Finally, ferulic acid, zingerone, and vanillic acid were tested to be protective for PC12 cells and HT22 cells in increasing cell viabilities after oxygen and glucose deprivation (OGD). Our proposed strategy could improve the accuracy on decoding KFCGs of XXMD and provide a methodologic reference for the optimization, mechanism analysis, and secondary development of the formula in TCM.

An Integrative Pharmacology Model for Decoding the Underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid Arthritis.

As a systemic inflammatory arthritis disease, rheumatoid arthritis (RA) is complex and hereditary. Traditional Chinese medicine (TCM) has evident advantages in treating complex diseases, and a variety of TCM formulas have been reported that have effective treatment on RA. Clinical and pharmacological studies showed that Ermiao Powder, which consists of Phellodendron amurense Rupr. (PAR) and Atractylodes lancea (Thunb.) DC. (ALD), can be used in the treatment of RA. Currently, most studies focus on the anti-inflammatory mechanism of PAR and ALD and are less focused on their coordinated molecular mechanism. In this research, we established an integrative pharmacological strategy to explore the coordinated molecular mechanism of the two herbs of Ermiao Powder in treating RA. To explore the potential coordinated mechanism of PAR and ALD, we firstly developed a novel mathematical model to calculate the contribution score of 126 active components and 85 active components, which contributed 90% of the total contribution scores that were retained to construct the coordinated functional space. Then, the knapsack algorithm was applied to identify the core coordinated functional components from the 85 active components. Finally, we obtained the potential coordinated functional components group (CFCG) with 37 components, including wogonin, paeonol, ethyl caffeate, and magnoflorine. Also, functional enrichment analysis was performed on the targets of CFCG to explore the potential coordinated molecular mechanisms of PAR and ALD. The results indicated that the CFCG could treat RA by coordinated targeting to the genes involved in immunity and inflammation-related signal pathways, such as phosphatidylinositol 3­kinase/protein kinase B signaling pathway, mitogen-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, and nuclear factor-kappa B signaling pathway. The docking and in vitro experiments were used to predict the affinity and validate the effect of CFCG and further confirm the reliability of our method. Our integrative pharmacological strategy, including CFCG identification and verification, can provide the methodological references for exploring the coordinated mechanism of TCM in treating complex diseases and contribute to improving our understanding of the coordinated mechanism.

Uncovering Hidden Mechanisms of Different Prescriptions Treatment for Osteoporosis via Novel Bioinformatics Model and Experiment Validation.

Osteoporosis (OP) is a systemic disease susceptible to fracture due to the decline of bone mineral density and bone mass, the destruction of bone tissue microstructure, and increased bone fragility. At present, the treatments of OP mainly include bisphosphonates, hormone therapy, and RANKL antibody therapy. However, these treatments have observable side effects and cannot fundamentally improve bone metabolism. Currently, the prescription of herbal medicine and their derived proprietary Chinese medicines are playing increasingly important roles in the treatment of OP due to their significant curative effects and few side effects. Among these prescriptions, Gushukang Granules (GSK), Xianling Gubao Capsules (XLGB), and Er-xian Decoction (EXD) are widely employed at the clinic on therapy of OP, which also is in line with the compatibility principle of "different treatments for the same disease" in herbal medicine. However, at present, the functional interpretation of "different treatments for the same disease" in herbal medicine still lacks systematic quantitative research, especially on the detection of key component groups and mechanisms. To solve this problem, we designed a new bioinformatics model based on random walk, optimized programming, and information gain to analyze the components and targets to figure out the Functional Response Motifs (FRMs) of different prescriptions for the therapy of OP. The distribution of high relevance score, the number of reported evidence, and coverage of enriched pathways were performed to verify the precision and reliability of FRMs. At the same time, the information gain and target influence of each component was calculated, and the key component groups in all FRMs of each prescription were screened to speculate the potential action mode of different prescriptions on the same disease. Results show that the relevance score and the number of reported evidence of high reliable genes in FRMs were higher than those of the pathogenic genes of OP. Furthermore, the gene enrichment pathways in FRMs could cover 79.6, 81, and 79.5% of the gene enrichment pathways in the component-target (C-T) network. Functional pathway enrichment analysis showed that GSK, XLGB, and EXD all treat OP through osteoclast differentiation (hsa04380), calcium signaling pathway (hsa04020), MAPK signaling pathway (hsa04010), and PI3K-Akt signaling pathway (hsa04151). Combined with experiments, the key component groups and the mechanism of "different treatments for the same disease" in the three prescriptions and proprietary Chinese medicines were verified. This study provides methodological references for the optimization and mechanism speculation of Chinese medicine prescriptions and proprietary Chinese medicines.

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis.

Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of "bacteria, poison and inflammation" and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1ß, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.