Network Pharmacology and Traditional Chinese Medicine

Gynaecology & obstetric

Traditional Chinese Medicine: From Aqueous Extracts to Therapeutic Formulae

Traditional Chinese medicine (TCM) is one of the most established systems of medicine in the world. The therapeutic formulae used in TCM are frequently derived from aqueous decoctions of single plants or complex multicomponent formulae. There are aspects of plant cultivation and preparation of decoction pieces that are unique to TCM. These include Daodi cultivation, which is associated with high quality medicinal plant material that is grown in a defined geographical area, and Paozhi processing where the decoction pieces can be treated with excipients and are processed, which may fundamentally change the nature of the chemical metabolites. Therefore, a single plant part, processed in a variety of different ways, can each create a unique medicine. The quality of TCM materials, their safety and therapeutic efficacy are of critical importance. The application of metabolomic and chemometric techniques to these complex and multicomponent medicines is of interest to understand the interrelationships between composition, synergy and therapeutic activity. In this chapter, we present a short history of TCM, detail the role of Daodi and Paozhi in the generation of therapeutic formulae and look at the international practices and methodologies currently in use to ensure their sustainable production, quality, safety and efficacy

Network Pharmacology Approaches for Understanding Traditional Chinese Medicine

Traditional Chinese medicine (TCM) has obvious efficacy on disease treatments and is a valuable source for novel drug discovery. However, the underlying mechanism of the pharmacological effects of TCM remains unknown because TCM is a complex system with multiple herbs and ingredients coming together as a prescription. Therefore, it is urgent to apply computational tools to TCM to understand the underlying mechanism of TCM theories at the molecular level and use advanced network algorithms to explore potential effective ingredients and illustrate the principles of TCM in system biological aspects. In this thesis, we aim to understand the underlying mechanism of actions in complex TCM systems at the molecular level by bioinformatics and computational tools. In study Ⅰ, a machine learning framework was developed to predict the meridians of the herbs and ingredients. Finally, we achieved high accuracy of the meridians prediction for herbs and ingredients, suggesting an association between meridians and the molecular features of ingredients and herbs, especially the most important features for machine learning models. Secondly, we proposed a novel network approach to study the TCM formulae by quantifying the degree of interactions of pairwise herb pairs in study Ⅱ using five network distance methods, including the closest, shortest, central, kernel, as well as separation. We demonstrated that the distance of top herb pairs is shorter than that of random herb pairs, suggesting a strong interaction in the human interactome. In addition, center methods at the ingredient level outperformed the other methods. It hints to us that the central ingredients play an important role in the herbs. Thirdly, we explored the associations between herbs or ingredients and their important biological characteristics in study III, such as properties, meridians, structures, or targets via clusters from community analysis of the multipartite network. We found that herbal medicines among the same clusters tend to be more similar in the properties, meridians. Similarly, ingredients from the same cluster are more similar in structure and protein target. In summary, this thesis intends to build a bridge between the TCM system and modern medicinal systems using computational tools, including the machine learning model for meridian theory, network modelling for TCM formulae, as well as multipartite network analysis for herbal medicines and their ingredients. We demonstrated that applying novel computational approaches on the integrated high-throughput omics would provide insights for TCM and accelerate the novel drug discovery as well as repurposing from TCM.Perinteinen kiinalainen lääketiede (TCM) on ilmeinen tehokkuus taudin hoidoissa ja on arvokas lähde uuden lääkkeen löytämiseen. TCM: n farmakologisten vaikutusten taustalla oleva mekanismi pysyy kuitenkin tuntemattomassa, koska TCM on monimutkainen järjestelmä, jossa on useita yrttejä ja ainesosia, jotka tulevat yhteen reseptilääkkeeksi. Siksi on kiireellistä soveltaa Laskennallisia työkaluja TCM: lle ymmärtämään TCM-teorioiden taustalla oleva mekanismi molekyylitasolla ja käyttävät kehittyneitä verkkoalgoritmeja tutkimaan mahdollisia tehokkaita ainesosia ja havainnollistavat TCM: n periaatteita järjestelmän biologisissa näkökohdissa. Tässä opinnäytetyössä pyrimme ymmärtämään monimutkaisten TCM-järjestelmien toimintamekanismia molekyylitasolla bioinformaattilla ja laskennallisilla työkaluilla. Tutkimuksessa kehitettiin koneen oppimiskehystä yrttien ja ainesosien meridialaisista. Lopuksi saavutimme korkean tarkkuuden meridiaaneista yrtteistä ja ainesosista, mikä viittaa meridiaaneihin ja ainesosien ja yrtteihin liittyvien molekyylipiirin välillä, erityisesti koneen oppimismalleihin tärkeimmät ominaisuudet. Toiseksi ehdoimme uuden verkon lähestymistavan TCM-kaavojen tutkimiseksi kvantitoimisella vuorovaikutteisten yrttiparien vuorovaikutuksen tutkimuksessa ⅱ käyttämällä viisi verkkoetäisyyttä, mukaan lukien lähin, lyhyt, keskus, ydin sekä erottaminen. Osoitimme, että ylä-yrttiparien etäisyys on lyhyempi kuin satunnaisten yrttiparien, mikä viittaa voimakkaaseen vuorovaikutukseen ihmisellä vuorovaikutteisesti. Lisäksi Center-menetelmät ainesosan tasolla ylittivät muut menetelmät. Se vihjeitä meille, että keskeiset ainesosat ovat tärkeässä asemassa yrtteissä. Kolmanneksi tutkimme yrttien tai ainesosien välisiä yhdistyksiä ja niiden tärkeitä biologisia ominaisuuksia tutkimuksessa III, kuten ominaisuudet, meridiaanit, rakenteet tai tavoitteet klustereiden kautta moniparite-verkoston yhteisön analyysistä. Löysimme, että kasviperäiset lääkkeet samoilla klusterien keskuudessa ovat yleensä samankaltaisia ominaisuuksissa, meridiaaneissa. Samoin saman klusterin ainesosat ovat samankaltaisempia rakenteissa ja proteiinin tavoitteessa. Yhteenvetona tämä opinnäytetyö aikoo rakentaa silta TCM-järjestelmän ja nykyaikaisten lääkevalmisteiden välillä laskentatyökaluilla, mukaan lukien Meridian-teorian koneen oppimismalli, TCM-kaavojen verkkomallinnus sekä kasviperäiset lääkkeet ja niiden ainesosat Osoitimme, että uusien laskennallisten lähestymistapojen soveltaminen integroidulle korkean suorituskyvyttömiehille tarjosivat TCM: n näkemyksiä ja nopeuttaisivat romaanin huumeiden löytöä sekä toistuvat TCM: stä

Chinese herbal medicine for insomnia : evidence and experience

Insomnia, a condition with significant medical consequences, is becoming more and more prevalent worldwide. Hypnotic drugs are associated with dependence, adverse reactions and long-term risks. Psychotherapy is time- and resource-consuming and largely unavailable. As such, many people who present with insomnia also look for alternative treatments. Recent studies show that Chinese herbal medicine (CHM), a traditional herbal medicine based on holistic theories, could be a potential alternative. The aims of this doctoral research were to explore the potential benefits of CHM for the treatment of insomnia and provide guidance in the treatment of insomnia with CHM. For practical reasons, the empirical aspect of the investigation focuses on one specific CHM product, which is Zao Ren An Shen (ZRAS). The research questions include: (1) Is ZRAS a safe and effective treatment for insomnia disorder? (2) How do Chinese medicine clinicians diagnose and treat insomnia with CHM? This doctoral research consists of a narrative review and three major studies: one systematic review, one randomised, placebo-controlled trial and one clinical experience synthesis. In the systematic review, clinical trial that assessed the efficacy and/or safety of ZRAS for insomnia were systematically searched and screened. In the clinical trial, after one week of placebo run-in, 85 participants with insomnia disorder were randomly allocated to either take ZRAS capsule or placebo for four weeks. Insomnia severity, psychological status, fatigue levels, quality of life, subjective sleep parameters, objective sleep parameters, and adverse events were assessed through the intervention period and at a four-weeks follow-up. Both the investigator and the participants were blind to the treatment allocation. In the clinical experience synthesis (CES), clinical experience reports published in the literature, which described treatment of insomnia with CHM, were systematically reviewed and screened. The systematic review shows that ZRAS is safe and effective for insomnia. The randomised trial support ZRAS capsule as a safe and acceptable treatment, yet failed to improve significantly insomnia severity in insomnia patients. These differences may be explained by the poor quality of the studies included in the systematic review. The studies included in the systematic review and the randomised trial both used a standardised intervention approach. However, Chinese medicine clinician recommend an individualised approach, which may contribute to improved outcomes across a broader range of measures

Exploring the Ligand-Protein Networks in Traditional Chinese Medicine: Current Databases, Methods, and Applications

The traditional Chinese medicine (TCM), which has thousands of years of clinical application among China and other Asian countries, is the pioneer of the "multicomponent-multitarget" and network pharmacology. Although there is no doubt of the efficacy, it is difficult to elucidate convincing underlying mechanism of TCM due to its complex composition and unclear pharmacology. The use of ligand-protein networks has been gaining significant value in the history of drug discovery while its application in TCM is still in its early stage. This paper firstly surveys TCM databases for virtual screening that have been greatly expanded in size and data diversity in recent years. On that basis, different screening methods and strategies for identifying active ingredients and targets of TCM are outlined based on the amount of network information available, both on sides of ligand bioactivity and the protein structures. Furthermore, applications of successful in silico target identification attempts are discussed in detail along with experiments in exploring the ligand-protein networks of TCM. Finally, it will be concluded that the prospective application of ligand-protein networks can be used not only to predict protein targets of a small molecule, but also to explore the mode of action of TCM

Network Pharmacology: A New Approach for Chinese Herbal Medicine Research

The dominant paradigm of “one gene, one target, one disease” has influenced many aspects of drug discovery strategy. However, in recent years, it has been appreciated that many effective drugs act on multiple targets rather than a single one. As an integrated multidisciplinary concept, network pharmacology, which is based on system biology and polypharmacology, affords a novel network mode of “multiple targets, multiple effects, complex diseases” and replaces the “magic bullets” by “magic shotguns.” Chinese herbal medicine (CHM) has been recognized as one of the most important strategies in complementary and alternative medicine. Though CHM has been practiced for a very long time, its effectiveness and beneficial contribution to public health has not been fully recognized. Also, the knowledge on the mechanisms of CHM formulas is scarce. In the present review, the concept and significance of network pharmacology is briefly introduced. The application and potential role of network pharmacology in the CHM fields is also discussed, such as data collection, target prediction, network visualization, multicomponent interaction, and network toxicology. Furthermore, the developing tendency of network pharmacology is also summarized, and its role in CHM research is discussed

Ontologies and Computational Methods for Traditional Chinese Medicine

Perinteinen kiinalainen lääketiede (PKL) on tuhansia vuosia vanha hoitomuoto, jonka tarkoituksena on terveyden ylläpito, tautien ennaltaehkäisemisen ja terveydellisten ongelmien hoito. Useat vuosittain julkaistavat tutkimukset tukevat hoitojen tehokkuutta ja PKL onkin jatkuvasti kasvattamassa suosiotaan maailmanlaajuisesti. Kiinassa PKL ollut suosittu hoitomuoto jo pitkään ja nykyään sitä harjoitetaan rinnakkain länsimaisen lääketieteen kanssa. Viime vuosikymmeninä tapahtuneen tietotekniikan kehityksen ja yleistymisen myötä myös PKL:n menetelmät ovat muuttuneet ja tietotekniikkaa on alettu hyödyntämään PKL:n tutkimuksessa. PKL:n tietoa on tallennettu digitaaliseen muotoon, minkä seurauksena on syntynyt suuri määrä erilaisia tietokantoja. Tieto on jakautunut eri tietokantoihin, joiden terminologia ei ole yhtenevää. Tämä aiheuttaa ongelmia tiedon löytämisessä ja tietoa hyödyntävien sovellusten kehittämisessä. Tässä työssä selvitetään, mitä PKL on, ja mikä sen asema on nykyään Kiinassa ja muualla maailmalla. Työn tarkoituksena on tutkia PKL:n tietoteknisten sovelluksen kehittämistä ja siihen liittyviä haasteita. Työssä perehdytään PKL:n ontologioiden ja semanttisten työkalujen toimintaan, sekä PKL:n laskennallisiin menetelmiin ja niiden tarjoamiin mahdollisuuksiin. Lisäksi kerrotaan uusimmista kansainvälisesti merkittävistä projekteista ja pohditaan tulevaisuuden näkymiä. Jo kehitetyt PKL:n tietotekniset sovellukset tarjoavat uusia mahdollisuuksia tiedon etsimiseen ja parantavat tutkijoiden mahdollisuutta jakaa tietoa ja tehdä yhteistyötä. Tietokoneavusteiset diagnoosityökalut ja asiantuntijajärjestelmät tarjoavat mahdollisuuksia lääkärin tekemän diagnoosin varmistamiseen. Tulevaisuudessa laskennallisia menetelmiä hyödyntäen voitaisiin tarjota terveyttä ja hyvinvointia edistäviä palveluja verkossa.Traditional Chinese Medicine (TCM) has been used for thousands of years in China for the purposes of health maintenance, disease prevention and treatment of health problems. Several published studies support the effectiveness of TCM treatments and the global use of TCM is constantly increasing. In China, Western and Chinese medicine are practiced in parallel. During the past few decades, the use of information technology in medicine has increased rapidly. The development of information technology has opened up new possibilities for information storage and sharing, as well as communication and interaction between people. Along with the growing use of information technology, a wide variety of patient databases and other electronic sources of information have emerged. However, the information is fragmented and dispersed, and the terminology is ambiguous. The objective of the thesis is to examine the position of TCM today, and to find out what changes and new opportunities the modern information technology brings for different aspects of TCM. This study describes how ontologies and semantic tools can be utilized when collecting existing knowledge and combining different databases. Also different computational methods and TCM expert systems are introduced. Finally, the most recent projects in the field of TCM are discussed and the future challenges are reflected. The computational methods for TCM, such as diagnostic tools and expert systems, could be very useful in anticipating and preventing health problems. E-science and knowledge discovery offer new ways for knowledge sharing and cooperation. TCM expert systems can be used to generate diagnosis or automatic clinical alerts. In the future, a comprehensive and easily accessible online health service system could be developed and used to improve the health and well-being of people

Chinese herbal medicine for diabetic kidney disease: historical perspective, clinical evidence and new therapeutic development

Diabetic kidney disease (DKD) is the foremost microvascular complication of diabetes mellitus, which is characterised as persistent albuminuria and progressive loss of kidney function induced by diabetes. The health burden of DKD is substantial and continues to grow in parallel with the escalating prevalence of diabetes. Despite current pharmacotherapies including hypoglycaemic agents, hypotensive drugs and reninangiotensin system (RAS) inhibitors, substantial residual risk of DKD initiation and progression remains. Considering the increasing prevalence of DKD, novel renal protective therapeutics are in great need. Chinese herbal medicine (CHM) has been used since antiquity in some countries and regions, and is still being used to treat kidney diseases in combination with contemporary medicine. Guided by traditional knowledge and contemporary practice of herbal application, existing and potentially novel therapeutics for DKD may be evaluated and further developed from CHM. To-date, the development of therapeutics from CHM has been impeded by general lack of clinical evidence, complex chemical profiles and unclear mechanisms of action. Moreover, the conventional drug application of the “one target, one drug” approach has been a limitation when it comes to complex and multi-factorial clinical presentations such as DKD. CHM is a complex intervention that commonly involves a number of herbal ingredients clinically for treating individual patients with DKD. Objectives Guided by a “whole evidence” framework, the aims of this research are to: - Evaluate the classical literature evidence of CHM as a treatment for DKD - Evaluate the clinical trial evidence of CHM as adjunctive therapy for DKD - Explore and propose the bioactive compounds and pharmacological mechanisms of promising CHM for DKD Review of classical literature A search of the classical Chinese medicine literature was conducted in the Zhong Hua Yi Dian (ZHYD, 5th Edition, 2014). A total of 278 DKD-relevant classical citations with treatment information were identified and analysed. These citations were derived from 68 classical Chinese medicine books spanning from AD 583 to AD 1895. Based on the rating results, there were 23 citations that were most likely DKD. Ba wei wan, Liu wei di huang wan and Hui xiang san were the most frequently cited formulae for DKD. The herbs frequently used were huang qi (Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao), ren shen (Panax ginseng C. A. Mey.), wu wei zi (Schisandra chinensis (Turcz.) Baill.), tian hua fen (Trichosanthes kirilowii Maxim.) and huang lian (Coptis chinensis Franch.). It was found that citations with positive turbid urine symptoms used huang qi more often than other high-frequency herbs. Systematic reviews of randomised controlled trials The Cochrane handbook of systematic reviews of interventions (version 5.1.0) guided the methods of the systematic reviews. The first systematic review included 20 randomised controlled trials (RCT) with 2719 DKD patients comparing CHM with placebo. Meta-analysis suggested that CHM reduced greater albuminuria than placebo, regardless of whether RAS inhibitors were concurrently administered. When CHM was used as an adjunct to RAS inhibitors, estimated glomerular filtration rate (eGFR) was improved in the CHM group compared with the placebo group. The adverse events (AE) rates were low and similar between CHM and placebo groups. Huang qi was used most frequently among included RCTs. Accroding to the results of the first systematic review and classical literature review, the herb huang qi was selected as a subject for further study. The second systematic review included 66 RCTs employing sole huang qi preparations with 4785 DKD participants. Overall, the included studies have substantial risk of bias due to methodological shortfalls. The meta-analysis showed that additional use of huang qi injection reduced albuminuria, proteinuria and serum creatinine concentration compared to conventional therapy alone. An anti-albuminuria effect was also reported in the oral huang qi preparation group. The safety of huang qi prepareations was uncertain because AEs were only reported in one third of included studies. More detailed safety evaluation particularly for huang qi injections are needed due to severe allergic reactions after injections have been observed. Network pharmacology study Network pharmacology is a novel drug discovery approach that uses data from highthroughput experiments, omics studies and other biological research and integrates and analyses them as a whole. It was applied to visualise and predict the complex relationships underlying the numerous DKD targets and multiple herbal compounds. The herb huang qi was selected for the network pharmacology study based on the results reported above. Searching retrieved 103 distinct human targets related to DKD. Thirty-eight (38) bioactive compounds from huang qi were identified, with a corresponding 327 targets. The huang qi–DKD PPI network contained 2269 shared targets, and 127 of these were considered to play central communication roles. These key targets were enriched in 174 biological pathways and the most significant pathways were integrin-linked kinase (ILK) signalling, tumour necrosis factor-related apoptosisinducing ligand (TRAIL) signalling, transforming growth factor beta (TGFβ)/Smad2/3 signalling, vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) signalling network and glypican/glypican-1 pathway. Further analysis of the herbal compounds-key targets-pathways network revealed that quercetin, calycosin, formononetin, kaempferol, isorhamnetin, betulinic acid, gamma-sitosterol, (24S)-24-Propylcholesta-5-ene-3beta-ol and bifendate were directly associated with 21 key targets enriched in the top 10 pathways. Conclusion By employing a whole evidence strategy, this research systematically evaluated the current best available evidence about CHM as adjunctive therapy for DKD, from both historical and contemporary perspectives. Classical literature evidence indicated that huang qi was commonly used in DKD-like disorders, particularly for those presenting with turbid urine (cloudy or foamy urine). With moderate to low quality evidence from RCTs, CHM may have beneficial effects on renal function and albuminuria beyond those reported by conventional treatment alone in adults with DKD. Moreover, adjunctive use of sole huang qi preparations with RAS inhibitors appeared to lowering albuminuria/proteinuria, as well as reducing serum creatinine concentration in the short term. The pharmacological actions of huang qi could be mediated by ILK signalling, TGF-β/Smad signalling, NF-κB pathway and glypican/glypican-1 pathway. Eight compounds with direct potential to regulate key targets are provided as new therapeutic development candidates for DKD. Hence, further research is warranted to determine their clinical benefit