Network-based identification and mechanism exploration of active ingredients against Alzheimer's disease via targeting endoplasmic reticulum stress from traditional chinese medicine.

Alzheimer's disease is a neurodegenerative disease that leads to dementia and poses a serious threat to the health of the elderly. Traditional Chinese medicine (TCM) presents as a promising novel therapeutic therapy for preventing and treating dementia. Studies have shown that natural products derived from kidney-tonifying herbs can effectively inhibit AD. Furthermore, endoplasmic reticulum (ER) stress is a critical factor in the pathology of AD. Regulation of ER stress is a crucial approach to prevent and treat AD. Thus, in this study, we first collected kidney-tonifying herbs, integrated chemical ingredients from multiple TCM databases, and constructed a comprehensive drug-target network. Subsequently, we employed the endophenotype network (network proximity) method to identify potential active ingredients in kidney-tonifying herbs that prevented AD via regulating ER stress. By combining the predicted outcomes, we discovered that 32 natural products could ameliorate AD pathology via regulating ER stress. After a comprehensive evaluation of the multi-network model and systematic pharmacological analyses, we further selected several promising compounds for in vitro testing in the APP-SH-SY5Y cell model. Experimental results showed that echinacoside and danthron were able to effectively reduce ER stress-mediated neuronal apoptosis by inhibiting the expression levels of BIP, p-PERK, ATF6, and CHOP in APP-SH-SY5Y cells. Overall, this study utilized the endophenotype network to preliminarily decipher the effective material basis and potential molecular mechanism of kidney-tonifying Chinese medicine for prevention and treatment of AD.

Systems pharmacology dissection of pharmacological mechanisms of Xiaochaihu decoction against human coronavirus.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) pandemic is still rage worldwide, there are still very limited treatments for human coronaviruses (HCoVs) infections. Xiaochahu decoction (XCHD), which is one of the traditional Chinese medicine (TCM) prescriptions in Qingfeipaidu decoction (QFPDD), is widely used for COVID-19 treatment in China and able to relieve the symptoms of fever, fatigue, anorexia, and sore throat. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study. METHODS: We constructed a global herb-compound-target (H-C-T) network of XCHD against HCoVs. Multi-level systems pharmacology analyses were conducted to highlight the key XCHD-regulated proteins, and reveal multiple HCoVs relevant biological functions affected by XCHD. We further utilized network-based prediction, drug-likeness analysis, combining with literature investigations to uncover the key ani-HCoV constituents in XCHD, whose effects on anit-HCoV-229E virus were validated using cytopathic effect (CPE) assay. Finally, we proposed potential molecular mechanisms of these compounds against HCoVs via subnetwork analysis. RESULTS: Based on the systems pharmacology framework, we identified 161 XCHD-derived compounds interacting with 37 HCoV-associated proteins. An integrated pathway analysis revealed that the mechanism of XCHD against HCoVs is related to TLR signaling pathway, RIG-I-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signaling pathway. Five compounds from XCHD, including betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1 exerted inhibitory activity against HCoV-229E virus in Huh7 cells using in vitro CPE assay. CONCLUSION: Our work presented a comprehensive systems pharmacology approach to identify the effective molecules and explore the molecular mechanism of XCHD against HCoVs.

Network Proximity Analysis Deciphers the Pharmacological Mechanism of Osthole against D-Galactose Induced Cognitive Disorder in Rats.

Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer's disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole against cognitive impairment in rats induced by D-galactose and elucidate its pharmacological mechanism. The rat model was established by subcutaneously injecting D-galactose at a dose of 150 mg/kg/day for 56 days. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to verify the network-based predictions, using western blot, Nissl staining, and immunofluorescence. The results demonstrate that Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rats. A network proximity-based approach and integrated pathways analysis highlight two key AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, i.e., neuroinflammation. Among them, the pro-apoptotic markers (Bax), anti-apoptotic protein (Bcl-2), the microgliosis (Iba-1), Astro-cytosis (GFAP), and inflammatory cytokines (TNF-R1) were evaluated in both hippocampus and cortex. The results indicated that Osthole significantly ameliorated neuronal apoptosis and neuroinflammation in D-galactose-induced cognitive impairment rats. In conclusion, this study sheds light on the pharmacological mechanism of Osthole in mitigating D-galactose-induced memory impairment and identifies Osthole as a potential drug candidate for AD treatment, targeting multiple signaling pathways through network proximity and integrated pathways analysis.

Chemical Distance Measurement and System Pharmacology Approach Uncover the Novel Protective Effects of Biotransformed Ginsenoside C-Mc against UVB-Irradiated Photoaging.

Long-term exposure to ultraviolet light induces photoaging and may eventually increase the risk of skin carcinogenesis. Rare minor ginsenosides isolating from traditional medicine Panax (ginseng) have shown biomedical efficacy as antioxidation and antiphotodamage agents. However, due to the difficulty of component extraction and wide variety of ginsenoside, the identification of active antiphotoaging ginsenoside remains a huge challenge. In this study, we proposed a novel in silico approach to identify potential compound against photoaging from 82 ginsenosides. Specifically, we calculated the shortest distance between unknown and known antiphotoaging ginsenoside set in the chemical space and applied chemical structure similarity assessment, drug-likeness screening, and ADMET evaluation for the candidates. We highlighted three rare minor ginsenosides (C-Mc, Mx, and F2) that possess high potential as antiphotoaging agents. Among them, C-Mc deriving from American ginseng (Panax quinquefolius L.) was validated by wet-lab experimental assays and showed significant antioxidant and cytoprotective activity against UVB-induced photodamage in human dermal fibroblasts. Furthermore, system pharmacology analysis was conducted to explore the therapeutic targets and molecular mechanisms through integrating global drug-target network, high quality photoaging-related gene profile from multiomics data, and skin tissue-specific expression protein network. In combination with in vitro assays, we found that C-Mc suppressed MMP production through regulating the MAPK/AP-1/NF-κB pathway and expedited collagen synthesis via the TGF-ß/Smad pathway, as well as enhanced the expression of Nrf2/ARE to hold a balance of endogenous oxidation. Overall, this study offers an effective drug discovery framework combining in silico prediction and in vitro validation, uncovering that ginsenoside C-Mc has potential antiphotoaging properties and might be a novel natural agent for use in oral drug, skincare products, or functional food.

In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L.

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health. Isatis tinctoria L. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-based in silico framework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were built via the integration of compound-target networks and influenza virus-host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for the in silico identification of novel drug candidates from complex components of herbal medicine.

Systems pharmacology approach uncovers the therapeutic mechanism of medicarpin against scopolamine-induced memory loss.

BACKGROUND: Medicarpin is a natural pterocarpan-type phytoalexin widely distributed in many traditional Chinese medicines, such as Astragali Radix. A previous study showed that Astragali Radix demonstrated promising protective effects in neurons. However, there is no reported study on the neuroprotective function and the underlying mechanism of Medicarpin. PURPOSE: This study aimed to demonstrate the neuroprotective effect of Medicarpin on Alzheimer's disease (AD) and explore the therapeutic mechanisms. METHOD: First, we carried out animal behavioral tests and biochemical analysis to assess the anti-AD potential of Medicarpin for ameliorating spatial learning and memory and modulating cholinergic metabolism in scopolamine-induced amnesic mice. Subsequently, network proximity prediction was used to measure the network distance between the Medicarpin target network and AD-related endophenotype module. We identified Medicarpin-regulated AD pathological processes and highlighted the key disease targets via network analysis. Finally, experimental approaches including Nissl staining and Western blotting were conducted to validate our network-based findings. RESULT: In this study, we first observed that Medicarpin can ameliorate cognitive and memory dysfunction and significantly modulate cholinergic metabolism in scopolamine-induced amnesic mice. We then proposed an endophenotype network-based framework to comprehensively explore the AD therapeutic mechanisms of Medicarpin by integrating 25 AD-related endophenotype modules, gold-standard AD seed genes, an experimentally validated drug-target network of Medicarpin, and a global human protein-protein interactome. In silico prediction revealed that the effect of Medicarpin is highly relevant to neuronal apoptosis and synaptic plasticity, which was validated by experimental assays. Network analysis and Western blotting further identified two key targets, GSK-3ß and MAPK14 (p38), in the AD-related protein regulatory network, which play key roles in the regulation of neuronal apoptosis and synaptic plasticity by Medicarpin. CONCLUSIONS: This study presented a powerful endophenotype network-based strategy to explore the mechanisms of action (MOAs) of new AD therapeutics, and first identified Medicarpin as a potential anti-AD candidate by targeting multiple pathways.

In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy.

Advances in immunotherapy have revolutionized treatments in many types of cancer. Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant application against cancer, is emerging as an important medical resource for developing innovative cancer treatments, including immunotherapy. In this study, we developed a quantitative and systems pharmacology-based framework to identify TCM-derived natural products for cancer immunotherapy. Specifically, we integrated 381 cancer immune response-related genes and a compound-target interaction network connecting 3273 proteins and 766 natural products from 66 cancer-related herbs based on literature-mining. Via systems pharmacology-based prediction, we uncovered 182 TCM-derived natural products having potential anti-tumor immune responses effect. Importantly, 32 of the 49 most promising natural products (success rate = 65.31%) are validated by multiple evidence, including published experimental data from clinical studies, in vitro and in vivo assays. We further identified the mechanism-of-action of TCM in cancer immunotherapy using network-based functional enrichment analysis. We showcased that three typical natural products (baicalin, wogonin, and oroxylin A) in Huangqin (Scutellaria baicalensis Georgi) potentially overcome resistance of known oncology agents by regulating tumor immunosuppressive microenvironments. In summary, this study offers a novel and effective systems pharmacology infrastructure for potential cancer immunotherapeutic development by exploiting the medical wealth of natural products in TCM.

Systems pharmacology-based approach to investigate the mechanisms of Danggui-Shaoyao-san prescription for treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterized by a progressive and irreversible loss of memory and cognitive abilities. Currently, the prevention and treatment of AD still remains a huge challenge. As a traditional Chinese medicine (TCM) prescription, Danggui-Shaoyao-san decoction (DSS) has been demonstrated to be effective for alleviating AD symptoms in animal experiments and clinical applications. However, due to the complex components and biological actions, its underlying molecular mechanism and effective substances are not yet fully elucidated. METHODS: In this study, we firstly systematically reviewed and summarized the molecular effects of DSS against AD based on current literatures of in vivo studies. Furthermore, an integrated systems pharmacology framework was proposed to explore the novel anti-AD mechanisms of DSS and identify the main active components. We further developed a network-based predictive model for identifying the active anti-AD components of DSS by mapping the high-quality AD disease genes into the global drug-target network. RESULTS: We constructed a global drug-target network of DSS consisting 937 unique compounds and 490 targets by incorporating experimental and computationally predicted drug-target interactions (DTIs). Multi-level systems pharmacology analyses revealed that DSS may regulate multiple biological pathways related to AD pathogenesis, such as the oxidative stress and inflammatory reaction processes. We further conducted a network-based statistical model, drug-likeness analysis, human intestinal absorption (HIA) and blood-brain barrier (BBB) penetration prediction to uncover the key ani-AD ingredients in DSS. Finally, we highlighted 9 key ingredients and validated their synergistic role against AD through a subnetwork. CONCLUSION: Overall, this study proposed an integrative systems pharmacology approach to disclose the therapeutic mechanisms of DSS against AD, which also provides novel in silico paradigm for investigating the effective substances of complex TCM prescription.

TCMIO: A Comprehensive Database of Traditional Chinese Medicine on Immuno-Oncology.

Advances in immuno-oncology (IO) are making immunotherapy a powerful tool for cancer treatment. With the discovery of an increasing number of IO targets, many herbs or ingredients from traditional Chinese medicine (TCM) have shown immunomodulatory function and antitumor effects via targeting the immune system. However, knowledge of underlying mechanisms is limited due to the complexity of TCM, which has multiple ingredients acting on multiple targets. To address this issue, we present TCMIO, a comprehensive database of Traditional Chinese Medicine on Immuno-Oncology, which can be used to explore the molecular mechanisms of TCM in modulating the cancer immune microenvironment. Over 120,000 small molecules against 400 IO targets were extracted from public databases and the literature. These ligands were further mapped to the chemical ingredients of TCM to identify herbs that interact with the IO targets. Furthermore, we applied a network inference-based approach to identify the potential IO targets of natural products in TCM. All of these data, along with cheminformatics and bioinformatics tools, were integrated into the publicly accessible database. Chemical structure mining tools are provided to explore the chemical ingredients and ligands against IO targets. Herb-ingredient-target networks can be generated online, and pathway enrichment analysis for TCM or prescription is available. This database is functional for chemical ingredient structure mining and network analysis for TCM. We believe that this database provides a comprehensive resource for further research on the exploration of the mechanisms of TCM in cancer immunity and TCM-inspired identification of novel drug leads for cancer immunotherapy. TCMIO can be publicly accessed at http://tcmio.xielab.net.

Systems Pharmacology Approach to Investigate the Mechanism of Kai-Xin-San in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD.

In silico Identification and Mechanism Exploration of Hepatotoxic Ingredients in Traditional Chinese Medicine.

BACKGROUNDS AND AIMS: Recently, a growing number of hepatotoxicity cases aroused by Traditional Chinese Medicine (TCM) have been reported, causing increasing concern. To date, the reported predictive models for drug induced liver injury show low prediction accuracy and there are still no related reports for hepatotoxicity evaluation of TCM systematically. Additionally, the mechanism of herb induced liver injury (HILI) still remains unknown. The aim of the study was to identify potential hepatotoxic ingredients in TCM and explore the molecular mechanism of TCM against HILI. MATERIALS AND METHODS: In this study, we developed consensus models for HILI prediction by integrating the best single classifiers. The consensus model with best performance was applied to identify the potential hepatotoxic ingredients from the Traditional Chinese Medicine Systems Pharmacology database (TCMSP). Systems pharmacology analyses, including multiple network construction and KEGG pathway enrichment, were performed to further explore the hepatotoxicity mechanism of TCM. RESULTS: 16 single classifiers were built by combining four machine learning methods with four different sets of fingerprints. After systematic evaluation, the best four single classifiers were selected, which achieved a Matthews correlation coefficient (MCC) value of 0.702, 0.691, 0.659, and 0.717, respectively. To improve the predictive capacity of single models, consensus prediction method was used to integrate the best four single classifiers. Results showed that the consensus model C-3 (MCC = 0.78) outperformed the four single classifiers and other consensus models. Subsequently, 5,666 potential hepatotoxic compounds were identified by C-3 model. We integrated the top 10 hepatotoxic herbs and discussed the hepatotoxicity mechanism of TCM via systems pharmacology approach. Finally, Chaihu was selected as the case study for exploring the molecular mechanism of hepatotoxicity. CONCLUSION: Overall, this study provides a high accurate approach to predict HILI and an in silico perspective into understanding the hepatotoxicity mechanism of TCM, which might facilitate the discovery and development of new drugs.