Preparation of Ephedra houttuynia Granule and Its Therapeutic Mechanism of Anti-Mycoplasma gallisepticum Infection Based on Network Pharmacology

The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra houttuynia granule for the treatment of Mycoplasma galliscepticum(MG)infection was prepared.Furthermore,its action mechanism was explored through network pharmacology.The optimal extraction and granulation processes of the compound were determined by high performance liquid chromatography(HPLC)method and L9 orthogonal test,and in the treatment experiment,Ephedra houttuynia granule showed a significant therapeutic effect on MG infection.In the study of network pharmacology,the results showed that the core targets of Ephedra houttuynia granule against MG infection were vascular endothelial growth factor(VEGFA),fos proto-oncogene(FOS),prepro-coagulation factor II(F2),etc.,the gene ontology/kyoto encyclopedia of genes and genomes(GO/KEGG)analysis results indicated that the signaling pathways of neuroactive ligand receptor interaction,cAMP,IL-17,T cell receptor,and tumor necrosis factor(TNF)might involve in anti-MG infection.In conclusion,this study would provide a new idea for elucidating the action mechanism of other diseases in veterinary clinic,which had a certain guiding significance.

Study of molecular mechanisms underlying the medicinal plant Tripterygium wilfordii-derived compound celastrol in treating diabetic nephropathy based on network pharmacology and molecular docking

Background:Diabetic nephropathy(DN)is a serious complication of diabetes with rising prevalence worldwide.We aimed to explore the anti-DN mechanisms of the compound celastrol derived from the medicinal plant Tripterygium wilfordii.Methods:Celastrol-related targets were obtained from Herbal Ingredients’Targets(HIT)and GeneCards databases.DN-related targets were retrieved from GeneCards,DisGeNET,and Therapeutic Targets Database(TTD).A Protein-protein interaction(PPI)network was established using the Search Tool for the Retrieval of Interacting Genes(STRING)database.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed using ClusterProfiler.The cytoHubba plugin was used to select the top 10 hub targets.Molecular docking was performed employing PyMOL and AutoDock software.Cell counting kit-8(CCK-8)and flow cytometry assays were used to detect the viability and apoptosis of NRK-52E cells,respectively.The mRNA expression levels of mitogen-activated protein kinase 3(MAPK3),tumor necrosis factor(TNF),and AKT serine/threonine kinase 1(AKT1)in NRK-52E cells were assessed using quantitative real-time polymerase chain reaction(qRT-PCR).Results:We obtained sixty-six overlapping targets of celastrol and DN.GO and KEGG analyses demonstrated that the core targets of celastrol and DN were mainly involved in the inflammatory and immune response,oxidative stress,advanced glycation end products(AGEs)and their receptors(RAGEs)(AGE-RAGE),TNF,interleukin 17(IL-17),and MAPK signaling pathways.Finally,based on the good binding activity with celastrol,MAPK3,TNF,and AKT1 were identified as the foremost targets of celastrol.We observed that celastrol enhanced the viability of high glucose(HG)-treated NRK-52E cells and inhibited apoptosis in the in vitro assays.Moreover,celastrol decreased the mRNA expression levels of MAPK3,TNF,and AKT1 in high glucose(HG)-treated NRK-52E cells.Conclusion:Celastrol may treat DN by targeting APK3,TNF,and AKT1 and regulating inflammatory responses and oxidative stress through the AGE-RAGE,TNF,IL-17,and MAPK signaling pathways.

Mechanism, current status, and prospects of MSC and its extracellular vesicles in the treatment of IBD

The etiology of inflammatory bowel disease(IBD)is multifaceted,involving genetic susceptibility,immune dysregulation,alterations in the gut microbiota,and environmental factors.Both intrinsic and extrinsic factors can disrupt the intestinal mucosal barrier,leading to chronic nonspecific inflammation,local structural changes,and gastrointestinal dysfunction.Historically,due to a lack of effective treatments,recurrent inflammation and microcirculatory disturbances could result in complications such as intestinal fistulas,strictures,obstructions,perforations,gastrointestinal bleeding,sepsis,etc.,thereby increasing the risk of intestinal cell carcinoma and mortality.While the overall incidence of IBD remains at 0.5%in North America and Europe,its annual incidence is increasing in Asia,Africa,and South America,resulting in a growing number of patients and warning significant attention.Recent research has highlighted mesenchymal stem cell(MSC)therapy as an innovative treatment option for IBD due to its capacity to modulate inflammatory immune responses and promote tissue regeneration.A current preclinical study has shown a promising result,with systemic administration of MSCs in patients with reduced intestinal inflammation and no intestinal inflammation.In addition,in a new study,the use of mesenchymal stem cell-derived exosomes(MSC-EXOs)was successful,a type derived from mesenchymal stem cells,was successful,especially in patients with refractory anal fistula.Consequently,MSC therapy has become a preferred approach in IBD treatment,showcasing the potential application prospects for stem cell-based therapy in IBD.However,clinical research in this field still needs to refine strategies and further explore to lay a solid foundation.

Mechanisms of retinal neuroprotection of calcium dobesilate：therapeutic implications

Current treatments for diabetic retinopathy （DR） are based on laser photocoagulation and intravitreal injections of corti- costeroids or anti-vascular endothelial growth factor （VEGF） agents. These treatments are applicable only at advanced stages of the disease. In addition, they are expensive, require a vitreo- retinal specialist and are associated with significant adverse ef- fects. Therefore, new pharmacological treatments for the early stages of the disease are needed.

Melastatin-related transient receptor potential 2 channel in Aβ_(42)-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics

Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.

Research progress of traditional Chinese medicine in the treatment of endocrine metabolic diseases in 2023

This study aimed to provide a comprehensive review of the research progress in Chinese medicine in the treatment of endocrine metabolic diseases in 2023,covering traditional Chinese medicine(TCM)monomers,TCM extracts,and TCM combinations,including non-alcoholic fatty liver disease,type 2 diabetes mellitus and its complications,obesity,hyperuricaemia,and thyroid disorders.After systematic sorting and summary,we found that in 2023,the research focusing on the application of TCM for endocrine metabolic diseases was still on the mechanism of action at the cellular and molecular levels,which not only influenced the classical pathways of lipid metabolism,but also delved into the key mechanisms of anti-inflammation,anti-oxidation,anti-insulin resistance,and so on.Additionally,TCM has shown remarkable results in the treatment of endocrine metabolic diseases by improving intestinal flora disorders and abnormal cellular iron death.These research results provide valuable ideas,methods,and tools for TCM in the prevention and treatment of endocrine metabolic diseases,and provide important references and guidance for future research and practice.

Nanomedicine-based multimodal therapies:Recent progress and perspectives in colon cancer

Colon cancer has attracted much attention due to its annually increasing incidence.Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects.In the past decade,nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention,high accumulation at tumor sites,co-loading with different drugs,and combination of various therapies.This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy,radiotherapy,phototherapy(photothermal therapy and photodynamic therapy),chemodynamic therapy,gas therapy,and immunotherapy.Additionally,the therapeutic mechanisms,limitations,improvements,and future of the above therapies are discussed.

Mechanisms of Dangua Fang(丹瓜方)in multi-target and multi-method regulation of glycolipid metabolism based on phosphoproteomics

OBJECTIVE:To explore the mechanism of Dangua Fang(丹瓜方,DGR)in multi-target and multi-method regulation of glycolipid metabolism based on phosphoproteomics.METHODS:Sprague-Dawley rats with normal glucose levels were randomly divided into three groups,including a conventional diet control group(Group A),high-fat-highsugar diet model group(Group B),and DGR group(Group C,high-fat-high-sugar diet containing 20.5 g DGR).After 10 weeks of intervention,the fasting blood glucose(FBG),2 h blood glucose[PBG;using the oral glucose tolerance test(OGTT)],hemoglobin A1c(HbA1c),plasma total cholesterol(TC),and triglycerides(TG)were tested,and the livers of rats were removed to calculate the liver index.Then,hepatic portal TG were tested using the Gross permanent optimization-participatiory action planning enzymatic method and phosphoproteomics was performed using liquid chromatography with tandem mass spectrometry(LC-MS/MS)analysis followed by database search and bioinformatics analysis.Finally,cell experiments were used to verify the results of phosphoproteomics.Phosphorylated mitogen-activated protein kinase kinase kinase kinase 4(MAP4k4)and phosphorylated adducin 1(ADD1)were detected using western blotting.RESULTS:DGR effectively reduced PBG,TG,and the liver index(P<0.05),and significantly decreased HbA1c,TC,and hepatic portal TG(P<0.01),showed significant hematoxylin and eosin(HE)staining,red oil O staining,and Masson staining of liver tissue.The total spectrum was 805334,matched spectrum was 260471,accounting for accounting 32.3%,peptides were 19995,modified peptides were 14671,identified proteins were 4601,quantifiable proteins were 4417,identified sites were 15749,and quantified sites were 14659.Based on the threshold of expression fold change(>1.2),DGR upregulated the modification of 228 phosphorylation sites involving 204 corresponding function proteins,and downregulated the modification of 358 phosphorylation sites involving 358 corresponding function proteins,which included correcting 75 phosphorylation sites involving 64 corresponding function proteins relating to glycolipid metabolism.Therefore,DGR improved biological tissue processes,including information storage and processing,cellular processes and signaling,and metabolism.The metabolic functions regulated by DGR mainly include energy production and conversion,carbohydrate transport and metabolism,lipid transport and metabolism,inorganic ion transport and metabolism,secondary metabolite biosynthesis,transport,and catabolism.In vitro phosphorylation validation based on cell experiments showed that the change trends in the phosphorylation level of MAP4k4 and ADD1 were consistent with that of previous phosphoproteomics studies.CONCLUSION:DGR extensively corrects the modification of phosphorylation sites to improve corresponding glycolipid metabolism-related protein expression in rats with glycolipid metabolism disorders,thereby regulating glycolipid metabolism through a multi-target and multi-method process.

Advances in traditional Chinese medicine for liver disease therapy in 2021

Liver diseases and their co-morbidities represent a major public health problem.Owing to its progressive pathogenesis and lack of effective treatment,liver disease has become one of the most important causes of death worldwide.Traditional Chinese medicine(TCM)has potential advantages in the prevention and treatment of liver diseases,including high safety,remarkable curative effects,and low toxicity and side effects.In 2021,TCM extracts and their derivatives,TCM compounds,and ethnic medicines showed good efficacy in the treatment of liver diseases.The main mechanisms and representative drugs of TCM can be summarized by the use of amygdalin,dicoumarol,quercetin,and ancient ephedrine decoction to treat hepatitis by inhibiting viral replication,as well as the use of Gentianae Radix,lupeol,Zornia diphylla(L.)Pers.,and Chinese patent medicine Liuwei Wuling tablet to alleviate acute liver injury by improving oxidative stress and inflammatory responses in the body.In the treatment of alcoholic liver disease and metabolic-associated fatty liver disease,the mechanism of TCM is the inhibition of oxidative stress,improving metabolism,regulating intestinal microflora,and enhancing intestinal barrier function.The representative TCM for alcoholic liver disease includes astragaloside,puerarin,patchouli alcohol,and Mori Fructus polysaccharide,while those for metabolic-associated fatty liver disease include saikosaponin,dehydroabietic acid,hesperetin,berberine,and Panax Notoginseng saponins.Additionally,germacrone,forsythin,geniposide,and protocatechuic acid can inhibit the activation or migration of stellate cells and improve liver fibrosis.Toosendanin,paeoniflorin,chrysin,and the classical prescription Huanglian decoction can significantly inhibit the proliferation of liver cancer cells and promote their apoptosis for the treatment of hepatocellular carcinoma.The activation of the farnesol X receptor pathway can improve bile metabolism in the liver,thus,significantly alleviating cholestatic liver disease.Its representative drugs include the TCM extracts pterostilbene and arbutin.In this review,we summarize the advances made in research on TCM used in the treatment of liver diseases in 2021,providing a reference for further development of TCM for the prevention and treatment of liver diseases.

Advances in Chinese medicine treatment and research on endocrine diseases in 2021

This paper reviews the progress in treatment regimens involving traditional Chinese medicine and research on common clinical endocrine diseases in 2021,to provide a reliable basis for the traditional Chinese medicine treatment of endocrine diseases.In 2021-2022,research on traditional Chinese medicine for endocrine diseases has been focused on pathogenesis.We have summarized the results of the use of traditional Chinese medicine and herbal extracts for treating common endocrine system diseases in 2021,focusing on the following aspects.(1)Chinese herbal extracts or active ingredients,such as echinatin,breviscapine,and puerarin,can treat metabolic-associated fatty liver disease by inhibiting inflammation and oxidative stress,improving lipid metabolism,and regulating intestinal flora.(2)Chinese herbal extracts or active ingredients,such as Juglandis Semen extracts,Momordica charantia saponins,and Anemarrhenae Rhizoma extracts can treat type 2 diabetes by reducing insulin resistance,improving pancreatic beta cell function,and regulating intestinal microbial disorders.(3)Chinese herbal extracts or active ingredients,such as berberine,astragaloside IV,and Scutellariae Barbatae Herba polysaccharides,can treat diabetes-related complications by improving mitochondrial function,regulating autophagy,and inhibiting apoptosis and pyroptosis.(4)Chinese herbal medicines and herbal extracts or active ingredients,such as berberrubine and Resedaodorata,can treat hyperuricemia by activating the Janus kinase 2/signal transducers and activators of transcription 3 signaling pathway and inhibiting toll-like receptor 4/NOD-like receptor family,pyrin domain-containing protein 3 signaling to increase urate excretion.(5)Herbal extracts or active ingredients,such as ginsenoside Rb1,corylin,and Scutellariae Radix polysaccharides,can exert anti-obesity effects by promoting the browning of white adipocytes,activation of brown adipose tissue,and regulation of intestinal flora.(6)Chinese herbal extracts or active ingredients,such as diosgenin and Prunellae Spica extract,are able to treat thyroid-related diseases by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory vesicle activation,regulating the expression of proliferating cell nuclear antigen,and cadherin 1,and upregulating the ubiquitination of interferon regulatory factor 4.

COVID-19 Infection: The Virus and Its Origin, the Variants, the Immune Defense, the Multiorgan Autoimmune Reactions, and the Targeted Treatments

Background: SARS-CoV-2, the virus responsible for the current COVID-19 infection pandemic, has caused substantial damage and negative impacts in the world, including physical sickness, mental illness, death, society lock down, work interruption, and productivity reduction. From the onset in early 2020, the pandemic has not yet totally subsided as of July 2022. Although great efforts have been made to understand the nature of this pandemic by the medical and scientific communities, a comprehensive review of this pandemic has not been reported. Purpose: We aimed to perform a thorough review of the subject in order to come to a better understanding of the origin of the virus, its mutations and their corresponding health effects, its pathophysiology, and its responses to therapeutic intervention. A more comprehensive set of data on these subject matters, if available, would give healthcare providers a valuable tool in formulating the best methods to respond to the current disease and prevent the disease from spreading in the future. Method: An extensive literature search on the subjects of COVID-19 was conducted regarding the possible origin of the viral pathogen, its evolutionary changes and health impacts, the world’s responses to COVID-19 and outcomes of their responses, and healthcare professional’s actions to understand and manage the disease and the results of their actions. To gather these data, websites of PubMed and Google Scholar were utilized for the search with the following keywords: Pandemic, COVID-19, coronavirus, SARS, SARS-CoV, SARS-CoV-2, origin, pathogenesis, and treatment. Results: Our review revealed data that points to an interesting autoimmune phenomenon where most seriously sick patients affected by COVID-19 were documented by an IgA-dominant immune response to the pathogen, along with a neutrophil-directed infiltration to the vital organ in the lung aveola, resulting in critical lung injury, leading to respiratory failure, multi-organ failure, and death. Surprisingly, this IgA-mediated and neutrophil-directed disease pattern is nearly identical to a group of IgA-mediated autoimmune skin diseases, such as dermatitis herpetiformis, IgA bullous dermatosis, and IgA pemphigus, which respond well to treatment by dapsone, a sulfone class of antibiotic/anti-inflammatory drug. Moreover, the usefulness of dapsone was supported by a small clinical study. In addition, systemic corticosteroid, a trusted anti-inflammatory medication, has been used in this pandemic with variable degrees of success. Conclusion: The data collected from our review of the subject, together with our prior search knowledge, compel us to conclude that the underlying pathophysiology that causes serious respiratory distress and multi-organ failure is most likely to be autoimmune in nature and that strategies to counter these multifacet autoimmune disorders would be the most valuable in life-saving. Specifically, we identified clinical and laboratory evidence pointing to IgA autoimmune reaction as a key factor that causes significant mortality in many patients. Accordingly, we proposed the utilization of a combination of dapsone, corticosteroid, and anti-thrombotic drugs in severely ill patients at the earliest point of the disease process. The autoimmune multi-organ syndrome may explain the pathogenesis of COVID-19 as well as Post-COVID conditions and may guide healthcare professionals in a better direction to manage the disease. The possible origin of the viral pathogen may shed light on a better understanding of the pathogenesis of the disease.

Research progress of traditional medicine to improve colorectal tumor from the perspective of intestinal flora

Colorectal cancer(CRC)is one of the cancers with a high mortality rate.More and more scientific researches have found that intestinal flora can directly interact with organisms.It can also be involved in the development of CRC by regulating metabolites such as bile acids,short-chain fatty acid and amino acids.Chinese traditional medicine has unique advantages in the treatment of CRC by correcting microbiome,restoring intestinal microecology,improving intestinal immune function and enhancing intestinal barrier stability.The author combines the global scientific research in this direction for analysis and report,to make a summary.

Transforming growth factor-β signaling in systemic sclerosis

Systemic sclerosis（SSc） is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific Immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β（TGF-β） has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β,a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.

Molecular mechanism revealing therapeutic opportunities of histone deacetylases inhibitors in triple-negative breast cancer

Subject Code:H31With the support by the National Natural Science Foundation of China,Ministry of Science and Technology of China and Chinese Academy of Sciences,the research team led by Prof.Geng Meiyu(耿美玉)and Ding Jian(丁健)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences,demonstrated the therapeutic opportunities of histone deacetylases(HDACs)inhibitors in

Recent advances in nanotherapeutics for the treatment of burn wounds

Moderate or severe burns are potentially devastating injuries that can even cause death,and many of them occur every year.Infection prevention,anti-inflammation,pain management and administration of growth factors play key roles in the treatment of burn wounds.Novel therapeutic strategies under development,such as nanotherapeutics,are promising prospects for burn wound treatment.Nanotherapeutics,including metallic and polymeric nanoformulations,have been extensively developed to manage various types of burns.Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application.Herein,we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds.

Peptide or Protein-Protected Metal Nanoclusters for Therapeutic Application

What is the most favorite and original chemistry developed in your research group?The most favorite and original work we have done is the development of gold nano clusters for diagnostic and therapeutic application.How do you get into this specific field?Could you please share some experiences with our readers?I have a great passion for research on bioanalytical imaging and the biomedical effects of nanomaterials,which may contribute to early diagnosis and treatment of diseases.My research is focused on exploring the mechanism of protein or peptide-protected metal nanoclusters in disease diagnosis and treatment with the expectation of leading to superior therapeutic outcomes.

Molecular Insight into the Therapeutic Promise of Xuebijing Injection against Coronavirus Disease 2019

Background:The potential human-to-human transmission of the coronavirus pneumonia(coronavirus disease 2019[COVID-19])has caused an outbreak of acute respiratory illness.Xuebijing injection is recommended as first-line treatment for the severe and critical patients with COVID-19.The aim of present study is to interpret the pharmacological mechanisms and molecular connections of Xuebijing injection against COVID-19 by utilizing the approaches of network pharmacology and molecular docking.Materials and Methods:Active ingredients of Xuebijing injection were collected by Traditional Chinese Medicine Systems Pharmacology(TCMSP)database,and putative therapeutic targets were screened from TCMSP,Swiss Target Prediction,and STITCH databases.Moreover,the protein–protein interactions,topological analysis,and pathway enrichment were established to distinguish the hub targets and pathways by employing STRING database,Cytoscape software,DAVID database,respectively.In addition,the potential interaction and binding activity of candidate ingredients in Xuebijing injection with core targets were revealed by molecular docking simulation(Auto Dock software).Results:A total of 115 bioactive components in Xuebijing injection were collected,and416 targets including AKT1,TP53,VEGFA,ALB,TNF and so on were responsible for treating COVID-19.Bioinformatics analysis revealed that matching core targets were closely associated with the inhibition of cytokine storm for its clinical beneficial effects in severe cases.The results of enrichment analysis indicated that PI3 K-Akt signaling pathway,human T-cell leukemia virus type 1 infection,mitogen-activated protein kinase signaling pathway,tuberculosis,focal adhesion,TNF signaling pathway,and small-cell lung cancer were represented pathways of Xuebijing injection against COVID-19 in terms of lung inflammation,virus infection,and lung injury.Meanwhile,the active ingredients of Xuebijing injection exerted superior binding activities with 3 CLpro and angiotensin-converting enzyme 2 as observed via molecular docking simulation.Conclusions:Through the comprehensive analysis of network pharmacology,the current research preliminarily elaborated the molecular regulation of therapeutic mechanisms for Xuebijing injection against COVID-19 and binding activity between active components and core targets,which provided scientific evidence to facilitate the development of Xuebijing injection and clinical treatment for COVID-19.

Osthole attenuates pulmonary arterial hypertension by the regulation of sphingosine 1-phosphate in rats

Osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1 P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1 P via microRNA-21-PI3 K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.

Chinese Medicine Meets Conventional Medicine in Targeting COVID-19 Pathophysiology,Complications and Comorbidities

Objective: To investigate how the National Health Commission of China(NHCC)-recommended Chinese medicines(CMs) modulate the major maladjustments of coronavirus disease 2019(COVID-19),particularly the clinically observed complications and comorbidities. Methods: By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology(hyperinflammations, viral replication), complications(pain, headache) and comorbidities(hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database. The experimentally-determined targets and the activity values of the chemical ingredients of these CMs were from the Natural Product Activity and Species Source Database. The approved and clinical trial drugs against these targets were searched from the Therapeutic Target Database and DrugBank Database. Pathways of the targets was obtained from Kyoto Encyclopedia of Genes and Genomes and additional literature search. Results: Overall,9 CMs modulated 6 targets discovered by the COVID-19 target discovery studies, 8 and 11 CMs modulated 8and 6 targets of the approved or clinical trial drugs for the treatment of the major COVID-19 complications and comorbidities, respectively. Conclusion: The coordinated actions of each NHCC-recommended CM against a few targets of the major COVID-19 pathophysiology, complications and comorbidities, partly have common mechanisms with the conventional medicines.