Online pharmaceutical process analysis of Chinese medicine using a miniature mass spectrometer: Extraction of active ingredients as an example

The automation of traditional Chinese medicine(TCM)pharmaceuticals has driven the development of process analysis from offline to online.Most of common online process analytical technologies are based on spectroscopy,making the identification and quantification of specific ingredients still a challenge.Herein,we developed a quality control(QC)system for monitoring TCM pharmaceuticals based on paper spray ionization miniature mass spectrometry(mini-MS).It enabled real-time online qualitative and quantitative detection of target ingredients in herbal extracts using mini-MS without chromatographic separation for the first time.Dynamic changes of alkaloids in Aconiti Lateralis Radix Praeparata(Fuzi)during decoction were used as examples,and the scientific principle of Fuzi compatibility was also investigated.Finally,the system was verified to work stably at the hourly level for pilot-scale extraction.This mini-MS based online analytical system is expected to be further developed for QC applications in a wider range of pharmaceutical processes.

Optimization of evidence-based research in the prevention and treatment of coronary heart disease with traditional Chinese medicine:A comprehensive review

Coronary heart disease(CHD) has severely impacted the lives and health of patients for ages. Although the modern methods used for the prevention and treatment of CHD have been increasingly perfected,clinical problems remain that require solutions. In the prevention and treatment of CHD with traditional Chinese medicine(TCM), great therapeutic advantages have been demonstrated. However, the expression of its advantages relies on scientific evidence-based research and evaluation, which require further optimization and improvement. Therefore, this review aims to comprehensively emphasize our understanding of the current deficiencies in TCM evidence-based studies and the necessity of adopting scientific evidence-based optimization methods for use in research. In this process, evidence should be produced in a standard manner, and the advantages of TCM patterns should be accurately stated because these factors contribute to efficient transformation and proper verification of the obtained evidence.Additionally, focusing on patient-oriented medicine and doctor-patient relationships is also essential.These methods are of great significance to prove the clinical efficacy of TCM and promote its development.

Clinical evidence of traditional Chinese medicine for the prevention and treatment of chronic heart failure

Objective: To summarize clinical evidence of traditional Chinese medicine for the prevention and treatment of chronic heart failure systematically and comprehensively. Method:By retrieving in the database of VIP, WanFang, CNKI, PubMed, Cochrane Library, the qualifying results obtained in the databases above are summarized into the grading evidence including systematic reviews, randomized controlled trials, observational studies, case studies, basic research these five levels. Results: The numbers of the articles included are 12 systematic reviews, 413 randomized controlled trials, 68 observational studies, 15 case reports and 187 fundamental researches. Conclusion: It is concluded that basing on the clinical evidence of different levels, traditional Chinese medicine has prominent ability of preventing and treatment chronic heart failure.

Application of artificial intelligence in tongue diagnosis of traditional Chinese medicine:A review

Tongue diagnosis is an important process to non-invasively assess the condition of a patient’s internal organs in traditional Chinese medicine(TCM)and each part of the tongue is related to corresponding internal organs.Due to continuing computer technological advances,especially the artificial intelligence(AI)methods have achieved significant success in tackling tongue image acquisition,processing,and classification,novel AI methods are being introduced in traditional Chinese medicine tongue diagnosis medical practices.Traditional tongue diagnose depends on observations of tongue characteristics,such as color,shape,texture,moisture,etc.by traditional Chinese medicine physicians.The appearance of the tongue color,texture and coating reflects the improvement or deterioration of patient’s conditions.Moreover,AI can now distinguish patient’s condition through tongue images,texture or coating,which is all possible increasingly with help from traditional Chinese medicine physicians under the traditional Chinese medicine tongue theory.AI has enabled humans to do what was previously unimagined:traditional Chinese medicine tongue diagnosis with feeding a large amount of tongue image and tongue texture/coating data to train the AI modes.This review focuses on the research advances of AI in TCM tongue diagnosis thus far to identify the major scientific methods and prospects.In this article,we tried to review the AI application in resolving the tongue diagnosis of traditional Chinese medicine on color correction,tongue image extraction,tongue texture/coating segmentation.

Isolation and identification of chemical constituents from the vinegar-prepared Corydalis yanhusuo

Phytochemical investigation of the vinegar-prepared Corydalis yanhusuo led to the isolation of one aristolactam derivative,1,2,8,9-tetramethoxy-5-methyldibenzo[cd,f]indol-4-(5H)-one(1),and seven aporphine alkaloids,including 2,9,10-trimethoxydibenz[de,g]quinolin-7-one(2),1-hydroxy-2,9,10-trimethoxy-7H-dibenzo(de,g)quinoline-7-one(3),oxoglaucine(4),N-methyloxoglaucine trifluoroacetate trifluoroacetate(5),corunine acetate(6),pontevedrine(7),and oxoglaucidaline trifluoroacetate(8).The structures of the isolated compounds were elucidated by extensive spectroscopic data analysis and comparison with the previous reports.Among them,compounds 1 and 2 were obtained as natural products for the first time,and their NMR data were unambiguously assigned.In addition,compound 1 exhibited moderate cytotoxic activity against HepG2 cells with an IC50 value of 16.0±6.4μM.

The global registry of COVID-19 clinical trials: indicating the design of traditional Chinese medicine clinical trials

Objective:To analyze the registration information of Corona Virus Disease 2019(COVID-19)related clinical trials from all the clinical trial registry accepted by the International Committee of Medical Journal Editors(ICMJE).Methods:All the database of ICMJE-accepted clinical trial registry platform were searched for COVID-19 related clinical trials that registered from December 8,2019 to February 19,2020.Results:All the database totally contained data of 209 COVID-19 related clinical trials,including 66(31.6%)traditional Chinese medicine(TCM)related studies and 143(68.4%)non-TCM related studies.176(84.2%)clinical trials were registered in ChiCTR,as 33(15.8%)were registered in ClinicalTrials.gov.There were 152(72.7%)intervention trials,including 9(4.3%in total)preventive trials,136(65.1%in total)therapeutic trials and 7(3.3%in total)convalescent trials.Conclusion:At the present stage,clinical studies are still aiming at exploring the effective treatment of COVID-19,and the existing treatments need more high-quality clinical evidence supporting.Traditional Chinese medicine may have played an important role in all stages of the epidemic preventing and control,and the enthusiasm of carrying out scientific research has also been greatly improved.The relevant policies of clinical trial registration should be popularized among researchers,including traditional Chinese medicine researchers.And the methodological quality of clinical trials’design urges improving.

Artificial intelligence for the development and implementation guidelines for traditional Chinese medicine and integrated traditional Chinese and western medicine

The translation and implementation of clinical practice guidelines(CPGs)for Traditional Chinese Medicine(TCM)and Integrated Traditional Chinese and Western medicine is crucial to the adoption of medical science and technology,but the low operability and slow update of integrated traditional Chinese and Western Medicine guidelines,and the lack of integration between guidelines and clinical practice,result in the guidelines not having the desired clinical effects in practice.The application of Artificial Intelligence(AI)to the field of CPGs development aims to shorten the development time,optimize and accelerate the whole process of CPG’s development.This article summarized the current research and application status of AI in development and implementation CPGs for TCM and Integrated Traditional Chinese and Western medicine and proposed the method of Combining real world data and AI technology to enrich for TCM and Integrated Traditional Chinese and Western medicine.

The research idea of Xuebijing injection in influencing severe pneumonia-pulmonary fibrosis with blood stasis syndrome evolution by inhibiting inflammation, endotoxin and dispersing blood stasis

Severe pneumonia is one of the most serious infectious diseases.Delayed intervention may lead to pulmonary fibrosis,which greatly threatens people’s life and health.Blood stasis syndrome is an important underlying syndrome throughout the evolution of severe pneumonia-pulmonary fibrosis.Xuebijing injection(XBJ)was developed under the theoretical system of“Three syndromes and three methods”,demonstrating a good efficacy in treating severe pneumonia and pulmonary fibrosis due to its effect of removing blood stasis and dispersing toxins.Previous studies have shown that XBJ can protect vascular endothelial function,improve coagulation function and regulate immunity by inhibiting inflammatory.Hence,the research hypothesis is put forward that XBJ treats blood stasis syndrome by removing blood stasis and dredging blood vessels,to inhibit the disease progress of severe pneumonia to pulmonary fibrosis.Further researches are need to confirm the function and explore the mechanism of XBJ.

The roles of traditional Chinese herbal medications in regulating mitochondrial activity to reverse cancer

Cancer was gradually regarded as a metabolic disease,which might be linked to impairment of mitochondrial function.There are really some essential differences between the mitochondria of normal and cancer cells,which might become promising target for cancer chemotherapy.According to western pharmacology,a known target was needed for drug development.Unfortunately,the number of therapeutic agents relating to the mitochondrion are severely limited because of lacking of knowledge about mitochondrial biology.Unlike the“Western Medicine”,some traditional Chinese herbal medicine(TCHM)might be prone to targeting mitochondria despite the lack of precise molecular mechanisms.If it is the case,we might be able to screen and identify active anti-cancer drugs from traditional Chinese therapeutics by using mitochondrial functional assay.In this review,we would give an overview of the effect of TCHM on the mitochondrion,and the challenges and breakthroughs remaining in cancer treatment.

Uncovering the multi-target pharmacological mechanism of Xuebijing injection against sepsis by a systems pharmacology approach

Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The purpose of this research is to decipher the underlying multi-target pharmacological mechanism of XBJ in the treatment of sepsis using a systems pharmacology approach.Compounds in XBJ were collected by literature retrieval.The corresponding putative targets of XBJ were screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP),Swiss Target Prediction(STP),and Search Tool for Interacting Chemicals(STITCH)databases.Sepsis-related targets were summarized using the Genecards,DrugBank,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection targets were obtained with Venny 2.1.Subsequently,protein-protein interaction(PPI)networks were constructed with the STRING database and Cytoscape 3.7.1.Then,degree,betweenness,and closeness were calculated to recognize the core targets in the PPI network.Moreover,the pharmacological mechanism of XBJ against sepsis was predicted via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.After the literature review,the 33 most commonly cited chemical ingredients,were screened out as major compounds.Bioinformatics analysis revealed that the major compounds of XBJ modulated 218 common targets associated with sepsis.Through PPI network analysis,41 genes,including IL-6,AKT1,STAT3,TP53,and MAPK1,were identified as core targets.The results of GO and KEGG enrichment revealed that the potential biological functions of XBJ against sepsis were mainly involved in cytokine receptor binding,cytokine activity,growth factor receptor binding,growth factor activity,and chemokine activity.The crucial pathways were closely associated with initial immune activation(CLR/TLR4-NF-κB/MAPK pathway),the acute inflammatory response(TNFMAPK/caspase and IL-MAPK/STAT pathways),and the late inflammation and coagulation process(HMGB1-RAGE and HIF-1 signaling pathways).This study revealed that the multiple components of XBJ exert multitarget effects against sepsis by regulating initial immune activation,the acute inflammatory response,and the late inflammation and coagulation process.

Network pharmacology-based analysis on bioactive compounds and mechanisms in Yiqifumai formula in the treatment of heart failure

Objective To predict the main bioactive components and potential mechanisms of Yiqifumai formula on heart failure by network pharmacology.Methods The bioactive compounds of Yiqifumai formula were screened by TCMSP database.The target genes of heart failure were obtained by entering PharmMapper and GeneCards database.R 3.6.3 was used to intercept intersection network for candidate targets.The network of“drug-compound-target-disease”was established via Cytoscape 3.7.2 and STRING platform.The DAVID database was used for GO enrichment analysis and KEGG pathway based on the candidate targets.Results Eleven key compounds(such as Schizandrin C,Gomisin G,ginsenoside rh2,Ruscogenin etc.,),426 non-repeated targets and 382 heart failure targets were obtained from Yiqifumai formula.There were 565 GO items(P<0.05),among which 412 were biological process(BP)items,63 were cell components(CC)items,and 93 were molecular function(MF)items.One hundred and seventeen signal pathways were enriched by KEGG pathway(P<0.05).Conclusion The bioactive compounds in Yiqifumai formula can play the“multi-target”role of enhancing resistance and eliminating pathogenic factors via regulation of angiogenesis and immune in the treatment of heart failure.

Efficacy and safety of Shen Zhi Ling oral liquid(a Chinese patent)for Alzheimer's disease:A meta-analysis of randomized controlled trials

Objective:To evaluate the efficacy and safety of Shen Zhi Ling oral liquid(SZL)alone or combined with basic treatment in treating Alzheimer's Disease(AD).Methods:Databases including PubMed,the Cochrane Library,Embase,Web of science,China National Knowledge Infrastructure(CNKI),Wanfang Database and the Chinese Science and Technology Journal Database(VIP)were searched from inception to September 20,2020 to collect relevant randomized controlled trials(RCTs)comparing SZL with other nootropic drugs for AD.The primary clinical outcomes were scores of the Mini Mental State Examination(MMSE)and the Activities of Daily Living(ADL)during treatment.The secondary outcomes of our study included other neuropsychological scale scores including Rapid Verbal Retrieve(RVR),Digit Span(DS),Fuld Object-Memory Evaluation(FOM)and adverse events or reactions.Two authors searched and screened the literature independently,then extracted the data and evaluated the methodological quality by using the handbook of Cochrane Collaboration,and analyzed the data via the Review Manager 5.3 software.Results:In total,we included four studies,covering 217 participants.All studies were in a low methodological quality.The result of MMSE score,ADL score,RVR score,DS score and FOM score in the meta-analysis showed that no statistically significant difference(P>0.05)between the treatment groups and control groups,and the statistical heterogeneity of all meta-analyses was small(I2<50%).SZL was indicated no better than other nootropic drugs.Among the included studies,no study described adverse events.Conclusions:Considering the low quality of the included trials and the different levels of AD patients,we are unable to come to any conclusion about the efficacy and safety of SZL compared with other nootropic drugs.Moreover,we still need rigorously designed,multi-center,large-scale trials to further confirm the efficacy and safety of SZL.

Progress of ubiquitin-proteasome system in the pathophysiology of heart failure and the intervention of traditional Chinese medicine

Heart failure(HF)represents one of the leading causes of morbidity and mortality in the modern world,which threatened approximately 1%~2%of adults’lives.HF is the end stage of multiple cardiovascular diseases characterized by cardiac hypertrophy and myocardial remodeling,and the pathophysiological processes of which include oxidative stress,endoplasmic reticulum homeostasis,apoptosis,autophagy,energy metabolism disorder,etc.The regulation of protein homeostasis intrinsically interrelates the above pathophysiological processes.Therefore,it is imperative to elucidate the molecular mechanism from the perspective of protein homeostasis to find new therapeutic targets for HF treatment.The dynamic regulation and post-translational modification of protein synthesis and degradation play a vital role in response of living organisms to physiological changes.The ubiquitin-proteasome system(UPS),which degrades 70-90%of endogenous proteins,plays an integral part in the pathophysiological processes of HF.The UPS can regulate oxidative stress,endoplasmic reticulum homeostasis,apoptosis and autophagy of cardiomyocytes(CMs),energy metabolism,targeting degradation signals and structural proteins,thus modulating cardiac hypertrophy,fibrosis and remodeling,finally contributing to the occurrence and progression of HF.Thus,regulating UPS is a promising effective strategy to treat HF.Increasing evidence indicates that traditional Chinese medicine(TCM)targeting the UPS is potential to ameliorate HF.This review will summarize the current knowledge focusing on the underlying mechanism and the important research advances related to UPS in treating HF,and the traditional Chinese medicine targeting UPS.

Prospects for the future of clinical efficacy evaluation of traditional Chinese medicine——Emphasis on original theory and clinical practice

Traditional Chinese medicine(TCM)clinical efficacy evaluation runs through the development of TCM and has been progressing so far.With the introduction of evidence-based medicine(EBM)in recent 20 years,TCM clinical efficacy evaluation has developed rapidly,accumulated research and experience,improved the quality and standardization of research,but also gradually found deep-seated deficiencies.In 2019,the China Center for Evidence-based Traditional Chinese Medicine(CCEBTCM)was established,and TCM was included in the 11th revision of the International Statistical Classification of Diseases(ICD-11).In above opportunities for TCM clinical efficacy evaluation,it is necessary to face up to the previous deficiencies,so that the TCM clinical efficacy evaluation can truly reflect the actual clinical practice characteristics,including TCM clinical problems,TCM thinking and TCM diagnosis&treatment mode.Based on the summary and analysis of past research,development concepts are proposed in this article.On the one hand,original concepts of TCM should be confidently paid more attention to the design and implementation of TCM clinical efficacy evaluation to be close to TCM clinical practice.On the other hand,it is necessary to consolidate the foundation of TCM clinical practice before evaluating efficacy.Evaluated object built on TCM ontology knowledge should be demonstrated based on clinical practice,and unknown evaluated object combined with new methods,technologies and concepts should be maturely integrated in clinical practice firstly.

Clinical research of traditional Chinese medicine under the influence of ICD-11: a new bridge and a new balance

On May 25,2019,the 72nd World Health Organization Assembly reviewed and approved the 11th revision of the International Classification of Diseases(ICD-11).ICD-11 features a new chapter of traditional medicine,incorporating 150 traditional Chinese medicine(TCM)diseases and 196 TCM syndromes.This is the first time that the TCM's understandings of diseases and syndromes were introduced into the authoritative international medical classification system and were presented to medical researchers and clinicians from different cultures and with various knowledge backgrounds.It is a landmark achievement for the TCM's move to go global.

Wenxin granule for cardiac arrhythmia: an overview of systematic reviews

Objectives: Evaluating the quality of systematic reviews/meta-analysis of Wenxin granule in treating cardiac arrhythmia to provide evidence for clinical practice, and analyzing the problems in the research to identify potential research priorities for researchers. Method: The systematic reviews of Wenxin granule in treating cardiac arrhythmia were searched from 8 databases. The methodological quality and evidence quality were assessed by AMSTAR and GRADE respectively. Results: Nineteen eligible systematic reviews with 52,905 participants were included. The overall scores of AMSTAR ranged from 3 to 10 with a mean score of 6.5, the median score was 6. There were 9 (9/19, 47.37%) systematic reviews had the score of 7 or more. 6 of them with appropriate information were assessed the quality of evidence by GRADE. The results showed that the overall quality of evidence was limited (range from “very low” to “low”), no “moderate” or “high” quality of evidence existed. For the outcome reporting, no systematic reviews reported endpoints and limited evidence showed that there is causality between Wenxin granule and adverse effects/events. The outcome matrix showed that there are obvious heterogeneity and incompleteness for the outcome reporting in included systematic reviews, so that some included studies cannot be conducted meta-analysis. Meanwhile, there were studies excluded because of inappropriate outcome measures, such as outcome measures did not meet inclusion criteria, treatment time did not meet inclusion criteria, treatment time was unclear, incomplete data or the data cannot be extracted. Conclusions: Wenxin granule have limited efficacy and safety for treating arrhythmia. In the future, high quality of RCTs and systematic reviews should be conducted. Core outcome set for cardiac arrhythmia is needed to improve outcome reporting and decrease waste.

ICD和免疫激动剂协作的树形高分子纳米平台作为极简“原位”肿瘤疫苗用于高效化学免疫治疗

作为一种新兴的联合治疗策略,肿瘤化学免疫治疗拓展了传统化疗药物的潜在可能性,利用某些化疗药物诱发免疫原性细胞死亡(ICD)激活抗肿瘤免疫应答,提升肿瘤治疗效率.本文设计了一种ICD和免疫激动剂协作的树形高分子纳米平台作为极简“原位”肿瘤疫苗用于高效的化学免疫治疗.利用树状高分子PAMAM担载ICD引发药物DOX以及免疫激动剂CpG,该DOX@PAMAM/CpG(简称DPC)纳米粒子物理性能适宜,通过便捷的瘤内注射可在肿瘤组织良好蓄积和内化,并最大限度地降低全身毒性.在CpG的协助下该纳米粒子可引发强劲的ICD并激活全面的抗肿瘤免疫反应,体内动物实验证实该DPC纳米粒子对侵袭性黑色素瘤具有显著的抑制.本研究为肿瘤化学免疫治疗纳米递药平台的构建提供了一种切实可行的策略.

Single-cell spatial transcriptomics in cardiovascular development,disease,and medicine

Cardiovascular diseases(CVDs)impose a significant burden worldwide.Despite the elucidation of the etiology and underlying molecular mechanisms of cvDs by numerous studies and recent discovery of effective drugs,their morbidity,disability,and mortality are still high.Therefore,precise risk stratification and effective targeted therapies for CvDs are warranted.Recent improvements in single-cell RNA sequencing and spatial transcriptomics have improved our understanding of the mechanisms and cells involved in cardiovascular phylogeny and CvDs.Single-cell RNA sequencing can facilitate the study of the human heart at remarkably high res-olution and cellular and molecular heterogeneity.However,this technique does not provide spatial information,which is essential for understanding homeostasis and disease.Spatial tran-scriptomics can elucidate intracellular interactions,transcription factor distribution,cell spatial localization,and molecular profiles of mRNA and identify cell populations causing the disease and their underlying mechanisms,including cell crosstalk.Herein,we introduce the main methods of RNA-seq and spatial transcriptomics analysis and highlight the latest ad-vances in cardiovascular research.We conclude that single-cell RNA sequencing interprets dis-ease progression in multiple dimensions,levels,perspectives,and dynamics by combining spatial and temporal characterization of the clinical phenome with multidisciplinary tech-niques such as spatial transcriptomics.This aligns with the dynamic evolution of CVDs(e.g.,"angina-myocardial infarction-heart failure"in coronary artery disease).The study of pathways for disease onset and mechanisms(e.g.,age,sex,comorbidities)in different patient subgroups should improve disease diagnosis and risk stratification.This can facilitate precise individualized treatment of CVDs.

The traditional Chinese medicines treat chronic heart failure and their main bioactive constituents and mechanisms

Chronic heart failure(CHF)is a severe public health problem with increasing morbidity and mortality,any treatment targeting a single session is insufficient to tackle this.CHF is characterized by reduced cardiac output resulting from neurohumoral dysregulation and cardiac remodeling,which might be related to oxidative stress,inflammation,endoplasmic reticulum stress,apoptosis,autophagy,mitochondrial function,and angiogenesis.These molecular mechanisms interact with each other through crosstalk.Historically,Chinese medicinal herbs have been widely applied in the treatment of CHF,and therapeutic effects of Chinese medicinal herbs and their ingredients have been scientifically confirmed over the past decades.Traditional Chinese medicine(TCM)with multiple components can confront the different pathogenesis of CHF through multiple targets.This review analyzes commonly used TCM patent drugs and TCM decoctions that are applicable to different stages of CHF based on clinical trials.Diverse bioactive ingredients in Chinese medicinal herbs have been found to treat CHF via multiple molecular mechanisms.This review comprehensively covers the key works on the effects and underlying mechanisms of TCM,herbal ingredients and synergistic effects of constituent compatibility in treating CHF,providing additional ideas to address this threat.

(+)/(-)-Yanhusuosines A and B, two dimeric benzylisoquinoline-protoberberine alkaloid atropo-enantiomers featuring polycyclic skeletons from Corydalis yanhusuo

(+)/(-)-Yanhusuosines A(1) and B(2), two pairs of trace benzylisoquinoline-protoberberine atropoenantiomeric homodimers featuring an unprecedented 6/7/6/6/6/6 hexacyclic skeleton, were isolated from the tubers of Corydalis yanhusuo. The structures of(+)/(-)-1 and(+)/(-)-2 were elucidated using spectroscopic and quantum-chemical calculation approaches.(+)/(-)-Yanhusuosines A(1) and B(2)represent a new class of alkaloid dimers biogenetically constructed by a molecule of benzylisoquinoline with a unit of protoberberine via an intermolecular [4 + 3] cycloaddition. Their plausible biosynthetic pathways are discussed, and compound 2 exerted moderate inhibitory activity of NO formation in LPS induced RAW264.7 macrophages.