Annual advances of integrative pharmacology in 2020

Ke-Wu Zeng,Ming-Yao Gu

1State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;2Department of Cell Biology and Medical Genetics,School of Basic Medical Sciences,Shenzhen University Health Science Center,Shenzhen 518061,China.

Abstract Major studies on the pharmacology of traditional herbs as well as active compounds have been introduced in this review over the previous 12 months.This annual integrative pharmacology review includes the reports published in 2020 on bioactive herbal extracts and novel compounds in traditional medicine.Pharmacological reports on traditional herbs as well as their active compounds for anticancer,inflammation,and metabolic diseases occupy dominant positions.Traditional medicines are still widely reported as a crucial treatment to exhibit anticancer efficacy in numerous human cancer cells.Moreover,the focus on the discovery of bioactive compounds from traditional medicines against mental disorders and neurodegenerative diseases seems to increase.The reports on bone loss and organ fibrosis treatments have notably gradually increased.Furthermore,studies of traditional herbs on cardiovascular and cerebrovascular diseases show a declining trend.These pharmacological reports in 2020 collectively show several crucial therapeutic targets and promising candidate compounds from traditional medicines for human diseases.

Keywords:Traditional medicine,Natural product,Pharmacology,Cancer,Inflammation,Infectious diseases

Background

The representative studies on the pharmacology of traditional herbs over the previous 12 months have been summarized in the almanac for 2020 to build a comprehensive understanding of the progress of traditional medicines for human disease treatments.The total number of pharmacological studies on traditional medicines has not changed much compared with previous years.The studies of the active ingredients from traditional medicines in anticancer research still occupy a dominant position.In particular,some famous natural products(e.g.,berberine,tanshinol A,lycorine,and emodin)are major topics of concern.Moreover,research reports of traditional medicines used as therapy for metabolic diseases maintained strong upwards momentum in 2020.Pharmacological studies of active compounds including isoliquiritigenin, hypericin, and protocatechuic acid on diabetes have obtained more attention.Interestingly,the bioactive compounds from traditional herbs against inflammation-associated diseases including artesunate,ginsenoside,and celastrol arouse people’s interest again.Meanwhile,pharmacological studies have shown a diversification trend.For example,increasing number of studies reported the protective effects of traditional herbs on bone loss and organ fibrosis.Unexpectedly,the studies on cardiovascular and cerebrovascular diseases have decreased,which is different from previous years.Thus,this review provides a broad annual summary of the pharmacological study progress on traditional medicine during the year 2020(Figure 1).

Cancers

Cancer is still one of the greatest threats to human health.Thus,researchers worldwide are exerting a lot of effort into looking for natural compounds from traditional medicinal plants to treat various cancers.A great number of studies on cancer study exist in the year 2020,similar to previous years.Some reports about the natural compounds targeting colorectal cancer mainly through inhibiting cell proliferation-related cell signaling pathways were found.Delicaflavone,isolated fromSelaginella doederleinii,inhibits the viability of colorectal cancer cells by blocking both Ras/MEK/Erk and PI3K/AKT/mTOR pathways[1].Acetylshikonin,a diterpenoid compound from the root ofLithospermum erythrorhizon, has been identified as a T-lymphokine-activated killer cell-originated protein kinase inhibitor to attenuate the proliferation of colorectal cancer cells[2].Moreover,berberine serves as a potential therapeutic agent against colon cancer by targeting the cleavage activating protein/sterol regulatory element binding protein-1 pathway[3].The natural product β-elemene,fromCurcumae rhizoma,is a novel ferroptosis inducer.In addition,β-elemene co-treatment with cetuximab suppresses KRAS mutant tumor cell proliferation as well as metastases by inducing iron-dependent reactive oxygen species(ROS)accumulation,lipid peroxidation,and downregulation of negative regulatory proteins[4].Palmatine is an isoquinoline alkaloid fromRhizoma coptidis,which shows significant anticolon cancer effects by promoting ROS production[5].Furthermore,triterpenoid saponin extracted fromMelia toosendanSieb et Zucc suppresses Wnt/β-catenin signaling to reduce the proliferation of colorectal cancer cells[6].

Lung cancer is well-known as the most common type of malignant tumor in the respiratory system.Many natural products are to be studied to treat lung cancer mainly via targeting tumor angiogenesis with the increasing number of lung cancer patients and the related treatment research.Tanshinol A,a natural compound fromSalvia miltiorrhiza,exerts its anticancer effect in the lung by inducing intracellular adenosine triphosphate depletion and ROS generation[7].Deguelin,a natural product isolated fromDerris elliptica,decreases the Mcl-1 protein level in an ubiquitination-dependent fashion against non-small cell lung cancer cells[8].Pristimerin,isolated fromCelastrus aculeatusMerr,inhibits vessel sprouts formation by targeting Shh/Gli1 signaling pathway to suppress tumor angiogenesis in NCI-H1299 xenografts[9].Arctigenin fromArctium lappasuppresses lung adenocarcinoma growth via the mitogen-activated protein kinases(MAPK)pathway[10].Erianin,a novel dibenzyl compound inDendrobium chrysotoxumLindl,induces Ca2+/CaM-dependent ferroptosis in lung cancer cells[11].Lycorine,a natural small molecule fromLycoris radiate,suppresses tumorigenicity,angiogenesis,and invasion of lung cancer cells by inducing the accumulation of tumor suppressor Salvador homolog 1[12].Hederagenin,a triterpenoid derived from theHedera helix,may be used as an adjuvant to promote the antineoplastic effects of conventional chemotherapeutics[13].Moreover,thevebioside,fromThevetia peruviana,is a potent antitumor drug degrading the steroid receptor coactivator 3 in an ubiquitin-proteasome-dependent manner[14].Furthermore,daurisoline fromRhizoma menispermirepresses lung tumorigenesis by targeting HSP90 to destabilize β-catenin[15].

In addition,some natural compounds targeting breast cancer also exist.For example,glidobactin C from aBurkholderialesdisplays a β2/β5 coinhibition profile with single-digit nanomolar potency[16].In addition,1,3-dicaffeoylquinic acid fromEucommia ulmoidescan be used as a lead compound for treating triple-negative breast cancer (TNBC) [17].Oxyresveratrol from the shell ofCocus nuciferasignificantly inhibits TNBC proliferation by promoting chromatin condensation and DNA fragmentation[18].Curcumol,a natural compound from the herbal plantRhizoma curcumae,enhances doxorubicin sensitivity in TNBC breast cancer[19].Emodin,aRheum palmatum-derived small molecule has potential therapy for TNBC by targeting nuclear receptor corepressor 2 to suppress vascular endothelial growth factor A transcription[20].In addition,crocin fromCrocus sativusinduces apoptosis in human breast cancer MDA-MB-231 and MCF-7 cells via inhibiting the Akt/FOXO3a pathway[21].AcetyltanshinoneⅡA,obtained from the chemical modifications of Tanshinone IIA,has the potential to treat breast cancers via inducing human epidermal growth factor receptor 2 degradation[22].

Moreover,some natural compounds are discovered to treat other cancers.For example,berberine exerts antimultiple myeloma activity[23].Pyroptosis is a form of programmed cell death,involves pro-and antiapoptotic proteins in various cancer cells,promotes their death,and inhibits their proliferation and migration.Thus,some researchers focus on the natural products that can activate pyroptosis in some cancers.Pyridoxine induces pyroptosis in human leukemic THP-1 cells[24].Geniposide attenuates the invasion,proliferation,and lung metastasis of hepatocellular carcinoma(HCC)[25].Moreover,miltirone significantly suppresses HCC by inducing pyroptosis[26].Proanthocyanidin-B2 from peanut skin also has strong antitumor effects in HCC by inhibiting AKT activity[27].In addition,echinatin fromGlycyrrhiza uralensissuppresses the proliferation and migration of esophageal squamous cell carcinoma through the regulation of AKT/mTOR signaling pathway[28].Cordycepin synergistically induces cell apoptosis of esophageal cancer cells[29].Schisantherin A fromSchisandra chinensishas an antiproliferation effect on gastric cancer cell lines by inducing cell cycle arrest at the G2/M phase and cell apoptosis[30].Imperatorin,a natural active compound fromAngelica dahurica,is reported to treat muscle wasting in cancer cachexia by inhibiting the signal transducer and activator of transcription 3 pathway[31].Fisetin fromRhus succedaneaL.inhibits cell proliferation and induces DNA damage and S-phase arrest in pancreatic adenocarcinoma[32].Cardenolides ouabain fromStrophanthus gratusand reevesioside A fromS.gratusshow angiogenesis effect by promoting fibroblast growth factor 2 secretion[33].

Cardiovascular and cerebrovascular diseases

An increasing number of current studies tried to use natural products to treat cardiovascular and cerebrovascular diseases.Among them,hypertension is the most common chronic disease and the most important risk factor.Tetramethylpyrazine,isolated from the traditional Chinese herbLigusticum chuanxiong,shows a potential therapeutic role in pulmonary hypertension[34].Triptolide,a bioactive component fromTripterygium wilfordii,shows protective effects on renal injury in salt-sensitive hypertension[35].Some compounds that show a protective effect in cardiovascular disease have been reported.Cannabidiol,a natural bioactive compound fromCannabis sativa,protects against high glucose-elicited oxidative stress through inhibiting cardiac voltage-gated sodium channels[36].Moreover,dihydromyricetin is a flavonoid compound extracted fromHovenia dulcis,and has a cardioprotective effect in patients with heart failure[37].Liensinine,an isoquinoline alkaloid fromNelumbo nuciferaGaevth,shows a protective effect on doxorubicin-induced cardiotoxicity[38].Isorhapontigenin fromGnetum parvifoliumreverses cardiotoxicity by targeting Yes-associated protein[39].Two compounds show an anticardiac hypertrophy effect,including delphinidin(a natural flavonoid compound from fruits)that shows antioxidant,antiapoptotic,and anticancer activities.It represses pathological cardiac hypertrophy by regulating oxidative stress through the adenosine monophosphate-activated protein kinase/NADPH oxidase/MAPK signaling pathway[40].Celastrol,derived fromT.wilfordii,attenuates Ang II-induced cellular and TAC-challenged in vivo cardiac hypertrophy and fibrotic responses[41].

Inflammation-related diseases

Inflammation-related diseases could be treated with various traditional medicines that contain a many active natural compounds.For example,luteolin attenuates intestinal mucositis by decreasing and increasing the proinflammatory and antiinflammatory cytokines,respectively[42].Berberine fromCoptis chinensisshows a therapeutic effect on chronic colitis by targeting REV-ERBα[43].Parthenolide,a sesquiterpene lactone fromTanacetum balsamita,ameliorates colon inflammation in a gut microbiota-dependent manner in vivo[44].Berberine guides gut microbiota to coordinate the bacterial metabolites to mediate the gut barrier functions in inflammatory bowel diseases[45].Ginsenoside Rb1 targets Hrd1 to alleviate the ER stress response in colitis symptoms[46].β-PAE,a tricyclic sesquiterpene isolated fromPogostemon cablin,may be a potential therapeutic agent for ulcerative colitis by suppressing colic leakage and bacterial imbalance[47].All of the aforementioned natural compounds show therapeutic effects in colitis.Δ9-THCA-A,a phytocannabinoid fromC.sativa,and cannabidiol,a phytocannabinoid fromC.sativahas the effect of resisting arthritis.Δ9-THCA-A activates the CB1 receptor,inhibits the CB2 receptor,and regulates the peroxisome proliferator-activated receptor gamma(PPAR-γ)signaling pathway[48],and cannabidiol targeted synovial fibroblasts[49].Moreover,some compounds also ameliorate inflammation in the respiratory system.Tetrahydrocannabinol,a compound fromC.sativaL.,acts as a palliative for enterotoxin-B-induced acute respiratory distress syndrome[50].Lycorine fromAmaryllidaceaeshows a protective effect in pulmonary fibrosis and acute lung injury by suppressing collagen deposition and ameliorating inflammasome activation[51].Scutellarin fromErigeron breviacapus,ameliorates pulmonary fibrosis via NF-κB/NLRP3-associated inflammatory response[52].Furthermore,imperatorin fromRadix angelicaeDahuricae,treats allergic asthma by reducing calcium flux[53].Apocynin fromPicrorhiza kurroa,exerts an antiinflammatory effect by inhibiting the granulocyte-macrophage colony-stimulating factor-induced AKT-MEK1/2-ERK1/2 pathway and granulocyte-macrophage colony-stimulating factor-prosurvival effect[54].Nardosinanone N,fromNardostachys chinensis,is a potential new antiinflammatory drug inhibiting M1 phenotype and increasing M2 phenotype[55].Artesunate from the medicinal plantArtemisia annuaLinn affects sepsis-induced immunosuppression by interacting with vitamin D receptor[56].Arctigenin,fromA.lappa,has a protective effect in acute peritonitis by reducing inflammatory cell infiltration[57].6BIGOE,isolated fromAngelicasinensis, inhibits lipopolysaccharide-induced cytokine release by targeting glycogen synthase kinase 3 in monocytes[58].AEDC,isolated fromActaea vaginata,modulates macrophage-adipocyte crosstalk to alleviate adipose tissue inflammation[59].

Neurodegenerative diseases

Maslinic acid,a triterpenoid isolated fromCrataegus pinnatida,reverses the scopolamine-induced memory impairment of mice[60].Tanshinone IIA prevents spatial learning and memory deficits in APP/PS1 mice[61].Ginsenoside Rg1 alleviates behavioral defects in a mouse model of Huntington’s disease[62].Moreover,(+)-(S)-scocycamide and(-)-(R)-scocycamide fromScopolia tanguticashows potential therapeutic effect against Alzheimer’s disease by inhibiting butyryl cholinesterase and exhibiting antioxidant capacity[63].Scopoletin fromConvolvulus pluricaulis,restores the redox balance through efficient recycling of glutathione to recover dopaminergic neural networks and motor coordination abilities in theDrosophilagenetic model of Parkinson’s disease[64].LFP-1,a natural compound fromLycii fructus,effectively protected against 1-methyl-4-phenylpyridiniuminduced neurotoxicity in the Parkinson’s disease model by promoting neuronal differentiation and neurite outgrowth[65].In addition,ursolic acid fromArctostaphylos uva-ursipromotes oligodendrocyte maturation,and central nervous system myelin repair decreases in an animal model of multiple sclerosis[66].Furthermore,cariside II fromHerba epimediisignificantly ameliorates ischemia/reperfusion-induced blood-brain barrier disruption and neuronal apoptosis in middle cerebral artery occlusion rats through modulating the matrix metalloproteinase 9/tissue inhibitor of metalloproteinase-1 balance[67].

Diabetes and metabolic diseases

Metabolic diseases are a cluster of diseases(e.g.,type 2 diabetes and fatty liver),which affect human health.In 2020,plenty of natural products were found that may be used to prevent diabetes.For example,GdTI fromGeoffroea decorticansmay be a potential natural antithrombotic and antidiabetic drug [68].Sarsasapogenin,fromAnemarrhena asphodeloides,ameliorates the damaged vascular endothelium in high glucose-cultured human umbilical vein endothelial cells[69].Rographolide,fromAndrographis paniculata,facilitates PANC-1 cells differentiation into functional insulin-producing cells[70].Bromophenol 3-bromo-4, 5-bis (2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol fromRhodomela confervoidesserves as a protein tyrosine phosphatase 1B inhibitor against hyperglycaemia[71].Moreover,rosmarinic acid is a natural therapeutic agent for diabetic cardiovascular disease,which protects endothelial dysfunction in diabetic atherosclerosis[72].Isoliquiritigenin,a flavonoid natural compound fromG.uralensis,Sinofranchetia chinensis,andDalbergia odorifera,can be used to protect against diabetic nephropathy progression by ameliorating renal fibrosis,apoptosis,and the deterioration of the renal function in diabetic mice[73].Steatohepatitis is a common disease caused by the storage of extra fat in the liver.However,no medication has been approved and researchers are still trying to find natural drugs to treat fatty liver disease.In addition,tetrahydroxystilbene glucoside,isolated fromPolygonum multiflorum,regulates the crosstalk between macrophages and hepatocytes in alcoholic hepatosteatosis[74].Hypericin,one of the main active ingredients ofHypericum perforatumL.,is used for treating nonalcoholic fatty liver disease by regulating lipid metabolism [75].Cyanidin-3-O-glucoside isolated fromGlycine maxaffects in the nonalcoholic fatty liver disease[76].Roseotoxin B,a natural compound fromTrichothecium roseum,possesses a beneficial effect on cholestatic liver fibrosis[77].Protocatechuic acid attenuates high-fat diet-induced fatty acid metabolism disorder in nonalcoholic fatty liver disease[78].Furthermore,pristimerin fromCelastrus orbiculatusis a novel compound for the treatment of NLRP3-related metabolic disorder[79].Gypenosides,fromGynostemma yixingense,have therapeutic potential for metabolic syndrome[80].

Infectious diseases

Some infectious diseases have been conquered by the discovery of antibiotics agents.However,natural products still are needed to be widely studied as drugs against infectious diseases.Rosmarinic acid,a compound extracted fromRosmarinus officinali,exerts antiviral effects on EV-A71 by affecting the early stage of viral infection[81].Semiperfoliata,extracted fromEuphorbia amygdaloides,induces HIV transcription and reactivates HIV-1 in CD4+T cells[82].Baicalein,a natural compound fromScutellaria baicalensis,is an effective inhibitor of multidrug-resistantStaphylococcus aureusthat directly binds to vWbp and blocks its coagulase activity[83].In the previous 2 years,the new coronavirus has affected the whole world,and herbal medicine has played an important role in the treatment and prevention of the new coronavirus.Salvianolic acid C extracted fromS.miltiorrhizaBunge suppresses SARS-CoV-2 infection through regulating the hydrophobic pocket in the HR1 region of SARS-CoV-2 and blocking the six-helix bundle formation between HR1 and HR2[84].Cardenolides are expected to exert significant anticoronaviral activities for porcine TGEV and human HCoV-OC43[85].Perillaldehyde,a natural monoterpenoid agent extracted fromPerilla frutescence,affects the oropharyngeal candidiasis by resistingCandida albicans[86].

Depression and mental disorders

In 2020,only a few studies reported that traditional medicine can treat depression and mental disorders.Epidiole is reported to regulate the one-carbon cycle components,which are deregulated in a Dravet model[87].Oridonin,a diterpene compound,ameliorates the depressive symptoms of mice by increasing the level of PPAR-γ and GluA1 phosphorylation[88].

Other diseases

Many bioactive compounds from herbs also exist to treat other diseases in addition to the aforementioned summarized diseases.For example,catalpol,an active compound fromRehmannia glutinosa,can be developed as a promising potential therapy for osteoclast-related bone diseases[89].Corylin,a natural flavonoid fromPsoralea corylifoliaL.,has antiosteogenic activities[90].Aucubin fromE.ulmoideshas antiosteoporotic effects which promotes cytokines expression associated with osteoblast differentiation[91].Moreover,cardamonin fromAlpinia katsumadaihas been used to treat autosomal-dominant polycystic kidney disease by reducing the formation and enlargement of cyst in the Madin-Darby canine kidney cyst model[92].Chrysophanol fromR.palmatumL.has an inhibitory effect on renal interstitial fibrosis by suppressing the expressions of fibrotic markers including collagen I and alpha-smooth muscle actin[93].Furthermore,ethyl-p-methoxycinnamate,a natural compound from the medicinal herbKaempferia galangalmaintains self-renewal and pluripotency of stem cells[94].Myricetin,a flavonoid derived fromMyrica rubraSieb.et Zucc,inhibits the activation of lung fibroblasts by targeting the heat shock protein 90 to regulate transforming growth factor-beta/Smad and non-Smad signaling pathways[95].Clausenamide,an alkaloid isolated fromClausena lansium(Lour.)Skeels,shows a protective effect on acetaminophen-induced hepatocyte ferroptosis in vitro and in vivo[96].In addition,salidroside alleviates pain and joint swelling in the early acute osteoarthritis stage[97].Chrysophanol,an anthraquinone extracted fromR.palmatumL.,significantly ameliorates kidney damage and decreases the production of fibrotic markers[98].Quercetin protects bones and prevents unloading-caused bone loss in mice[99].Moreover,quercetin promotes the maturation and early embryonic development of oocytes in vitro from aged mice and humans[100].Furthermore,atractylenolide I,a sesquiterpenoid lactone derivative of the Chinese medicineAtractylodes macrocephala,may be a therapeutic biologic agent for renal fibrosis prevention[101].Osthole,the main active ingredient of the Chinese medicineCnidium monnieri,shows pharmacological effect in inhibiting airway hyperreactivity by enhancing autocrine PGE2-mediated airway dilation[102].

Conclusion

The number of pharmacological studies on traditional medicines and their bioactive compounds has maintained a momentum of rapid growth in the year 2020.Moreover,studies on traditional medicines for cancer,metabolic diseases,and inflammation are still in a leadership position,indicating a further cause for concern.Meanwhile,the current study noticed that the reports on cardiovascular and cerebrovascular diseases have decreased during the previous year.Particularly,an unexpected increase of the studied on traditional herbal treatments for bone loss and organ fibrosis has been observed(Table1).Therefore,the authors speculate that the trend toward herbal medicine will show a diversification trend in the future.