Annual advances of integrative pharmacology in 2019

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 51801,China.

Abstract

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

Background

In the almanac for 2019,the representative research regarding the pharmacology of traditional medicine over the past 12 months has been systematically summarized.The results are divided into two sections:research highlights and representative traditional medicine studies on different diseases.In the research highlights section for the pharmacology of traditional medicine,the antimalarial drugs artemisinin (ART)and quinine have attracted the most interest from the scientific community.The proven health benefits of traditional teas are also a hot topic.Studies of Alzheimer’s disease (AD) involving traditional medicine focused on gut microbiota regulation using

Ginseng Radix et Rhizomaand marine-derived oligosaccharide (GV-971) from brown algae are emerging treatments.The gut microbiota has recently been linked to AD,and the potential relationships between gut microbiota are already associated with a broad spectrum of human diseases.In representative traditional medicine studies of different diseases,reports involving anti-cancer studies still take the top spot.Moreover,reports on diabetes and metabolic diseases,or cardiovascular and cerebrovascular diseases are ongoing.Notably,research reports of traditional medicines used as therapy for immunological diseases and infectious diseases attracted attention during 2019,which likely occurred because of recent bacterial or influenza virus outbreaks and HIV or Ebola viral infections.Additionally,traditional medicine studies against neurodegenerative diseases,depression,and mental disorders are required in the future.Collectively,this work provides a broad annual overview of the trends affecting traditional medicine pharmacology studies during 2019.

Research highlights involving traditional medicine pharmacology during 2019

Antimalarial drugs artemisinin and quinine

ART from the herbArtemisia annuaLinn.is a famous antimalarial drug derived from the traditional medicinal plantArtemisia annua.In addition to the treatment of malaria,ART has also been reported to exert multiple pharmacological activities.In this study,ART,as well as its derivate,were reported to promote sensibility to ferroptosis in cancer cells,a new form of programmed cell death.This finding may have helped to enhance the potential therapeutic effects of anti-cancer agents involved in ferroptosis-inducing potency during clinical treatment.Studies concerning the mechanism of action reveal that an ART derivative can promote lysosomal degradation of ferritin and up-regulated cellular free iron levels,resulting in the cancer cell sensibility to ferroptosis [1].Moreover,quinine is a natural antimalarial drug from the bark of the cinchona tree;however,the underlying antimalarial mechanism is still controversial.Here,the mechanisms of action for quinine and a derivative mefloquine were investigated in depth.The cellular thermal shift assay was coupled with a mass spectrometry strategy and applied as a direct cellular target identification for these two agents in human malaria cases caused byPlasmodium falciparum(P.falciparum).The results reveal thatP.falciparumpurine nucleoside phosphorylase is a crucial binding target for quinoline and mefloquine,which provides a potential molecular explanation for their antimalarial effects and potential for resistance improvement [2].Notably,ART-based combination therapy was also conducted.Furthermore,an interesting study involving ART-based hybrids reportedly found that they could overcome drug resistance to chloroquine in malaria parasites.In this study,ART-based hybrids were synthetized,including ART-isoquinoline and ART-quinolone hybrids.These ART-based hybrids significantly improved chloroquine resistance and multidrug-resistance inP.falciparum.Further investigation has suggested that ART-based hybrids interacted with several cellular target proteins,including plasmodium falciparumcalcium ATPase 6 and the 40S ribosomal protein,in order to overcome resistance,suggesting that these hybrids could affectP.falciparumdevelopment[3].

Effects of the flavonoid rutin on neuroinflammation

Rutin is a natural glycoside of flavonoid quercetin fromHerba HypericiandRuta graveolensL.,which is involved in multiple biological activities.Recent studies have revealed that sodium rutin (NaR) is a promising therapeutic agent for the treatment of neurodegenerative diseases,including AD,as it can regulate the microglia-mediated neuroinflammation.Their results also show that NaR activated microglia to clean A β by inducing the expression of phagocytosis-related receptors.NaR also promotes ATP production for the Aβ clearance energy supply in the microglia.Since A β clearance is a crucial AD therapy strategy,NaR may act as a novel agent for AD by modulating microglia-dependent Aβ clearance and thereby ameliorating memory deficits[4].

Analgesic effect of scorpion toxin

Scorpion venom fromScorpiohas been used in traditional medicine for many years and has recently become a research focus.Scorpion venom contains several types of toxins that regulate ion channel function.In this study,scorpion toxin (WaTx) was reported to activate the transient receptor potential ankyrin 1 (TRPA1) ion channel for the alleviation of acute and persistent pain.When the mechanism involved was investigated,it suggested that WaTx stabilized TRPA1 (responsible for pain hypersensitivity).These findings indicate that WaTx can act as a promising therapeutic agent targeting TRPA1 to treat clinical-pathological pain[5].

Proven health benefits of traditional tea

Green tea,as a globally popular beverage,contains various tea polyphenols.Tea catechins and phenolic acids are metabolized into antioxidant protocatechuic acid (PCA).In this study,PCA from green tea was investigated,and a PCA-controlled switch system was constructed for epigenetic remodeling.By using this switch system,glucose homeostasis in diabetic mice and monkeys was restored following oral administration of the PCA or green tea.This system was also successfully used for type 1 and type 2 diabetes in the mice and the cynomolgus monkey’s model,providing a novel therapy strategy for metabolic disorders [6].In addition,Pu-erh tea,which is also known as “black tea,” and originates from China.Pu-erh tea is post-fermented through a microbial fermentation process following drying.Pu-erh tea is reported to exhibit an anti-obesity function as it lowers the cholesterol level,but the underlying mechanism has not yet been explicated.As a key active pigment in Pu-erh tea,theabrownin is found to alter gut microbiota and increase the ileal conjugated bile acids,directly resulting in inhibition of the intestinal farnesoid X receptor-fibroblast growth factor 15 signaling pathway and reduced hepatic cholesterol levels.These findings indicate that intestinal bile-salt hydrolase microbes and farnesoid X receptor-fibroblast growth factor 15 signaling can act as crucial therapeutic targets of Pu-erh tea.Thus,ingestion of this tea can potentially improve metabolic syndrome[7].

TCM impacts on gut microbiota

Panax ginsengC.A.Mey.has been used in TCM for centuries,asGinseng Radix et Rhizomainfluences body weight.However,the precise molecular mechanism associated withGinseng Radix et Rhizomaand obesity is still largely unexplored.In this study,the effect ofGinseng Radix et Rhizomaextract on the gut microbiota was investigated to explore the possible mechanism of action.The results suggest thatGinseng Radix et Rhizomaextract inducesEnterococcus faecalis(E.faecalis) to produce myristoleic acid,which activates brown adipose tissue(BAT).Moreover,acyl-coa thioesterases inE.faecalisare found to exert biosynthesis to myristoleic acid.These observations indicate thatGinseng Radix et Rhizomaextract can markedly promote energy expenditure and reduce adiposity via BAT activation for the treatment of obesity and metabolic syndrome [8].Moreover,GV-971,a marine brown algae-derived oligosaccharide with multitargeting mechanisms,shows cognitive benefit over 36 weeks in patients with mild to moderate AD.The study of the mechanism of action reveals that GV-971 returns a gut microbial profile to normal and lessens the brain immune cell infiltration and neuroinflammation.Also,an AD mouse model was administrated with GV-971 and shows obvious gut microbiota alterations together with a reduction in amyloid-beta (Aβ) plaques and Th1 cell numbers in the brain.This study suggests that microbiome modulation might be an important strategy for neuroinflammation regulation and AD pathogenesis[9].

Novel direction for traditional medicine study using supramolecular chemistry

Hydrogels are key materials used for biomedical applications.Recently,small-molecule self-assembling hydrogels have attracted much attention.Several self-assembly hydrogels derived from natural products have been synthetized for specific biological activities.Rhein,an anthraquinone isolated fromRheum palmatumL.,is investigated and reported to directly self-assemble into hydrogels with three-dimensional nanofiber networks through noncovalent interactions.Moreover,rhein hydrogels exert significant anti-inflammation activity by dephosphorylating IκBα and inhibiting NF-κB p65 nuclear translocation against lipopolysaccharide stimulation.These findings suggest a new direction for a modern medical transformation of TCM in the supramolecular chemistry field as well as a new clinical therapy strategy for human inflammatory diseases[10].

Representative traditional medicine studies on different human diseases

Cancers

Cancer remains one of the most serious diseases that threaten human health globally.Therefore,during 2019,a large number of cancer studies using traditional medicine as treatments were reported.Withaferin A fromAcnistus arborescenshas been found to covalently bond to cysteine 239 of β-tubulin and promote degradation,which might inhibit tumor cell growth by suppressing the cell division[11].Chaetocin from theChaetomiumspecies of fungi inhibits thioredoxin reductase 1 and subsequently induces excessive ROS accumulation via inactivation of the PI3K/AKT pathway,ultimately leading to gastric cancer cell death [12].Parthenolide,a kind of sesquiterpene lactone from the feverfew plant(Tanacetum parthenium),that covalently modifies cysteine 427 of the focal adhesion kinase 1,eventually inhibiting breast cancer cell proliferation,survival,and motility.Meanwhile,other exocyclic methylene lactone-containing sesquiterpenes have exhibited similar activities[13].

A natural product nimbolide derived from the Neem tree (Azadirachta indica),impairs breast cancer cell proliferation partly by disrupting ring finger protein 114 substrate recognition,leading to the inhibition of ubiquitination-dependent degradation of tumor suppressors such as p21 [14].Moreover,microRNAs have been found to be involved in cancer progression,and targeting microRNAs by natural agents has opened avenues for cancer treatment and drug development.Sanguinarine,one of the most abundant active ingredients inSophora alopecuroidesL.,has been identified to up-regulate miR-16 expression in hepatocellular carcinoma cells that suppress tumor growth via induction of the G0/G1 cell cycle arrest and apoptosis in a p53-dependent manner [15].Butylcycloheptyl prodiginine binds to pre-miR-21 and inhibits dicer-mediated processing,which results in inhibition of cell proliferation[16].

Significant amounts of research have produced the synthesis of natural product analogs with the goal of improving their drug ability while maintaining or enhancing their biological function.Rapaglutin A is inspired by the natural products rapamycin and FK506.Rapaglutin A inhibits glycolysis and ATP biogenesis to promote AMPK activation,mammalian target of rapamycin (mTOR) inhibition,and induction of the cell cycle arrest and apoptosis,eventually blocking cancer cell growth[17].Pateamine A(PatA)is isolated from the New Zealand marine spongeMycalespp.,which disturbs eIF4A formation and inhibits translation initiation.A synthetic derivative of PatA,des-methyl des-amino PatA blocks mRNA translation,reduces Mcl-1 protein,and initiated apoptosis in chronic lymphocytic leukemia cells [18].Dihydroartemisinin is one of the semi-synthetic derivatives of artemisinin (fromArtemisia annua).Dihydroartemisinin induces autophagy by regulating the AMPK/mTOR/p70S6k signaling pathway to accelerate ferritin degradation for ferroptotic cell death[19].Human farnesyl pyrophosphate synthase(HsFPPS) is a target for bone resorption diseases and some cancers.HsFPPS is potently inhibited by bisphosphonates,but due to poor cell penetration and distribution in the soft tissues.Phenolic diterpene carnosic acid shows enhanced anti-cancer activities over the bisphosphonate drug zoledronate using pancreatic cancer cell lines,and a HsFPPS-dependent mechanism.Therefore,a series of compounds based on the carnosic acid are synthesized for pancreatic cancer by inhibiting HsFPPS[20].

A lot of natural products exude positive therapeutic effects in cancer therapy; however,the exact mechanism of action or potential targets require further investigation.Gambogic acid,with a polyprenylated xanthone structure,is derived from gamboge resin,which is exuded fromGarcinia hanburyiandGarcinia morellatrees.The anti-cancer mechanism of Gambogic acid reportedly increases E-cadherin in non-small cell lung cancer cells by targeting liver kinase B1 to block the mTOR signaling pathway [21].Neohesperidin,a flavonoid derived from citrus fruits,markedly inhibits colorectal tumorigenesis,which may be mediated by alteration of the gut microbiota.Furthermore,other citrus flavonoids may share similar pharmacological properties,indicating a new direction to develop chemopreventive agents for colorectal cancer therapy [22].Neocarzilin A fromStreptomyces carzinostaticusreportedly inhibits cancer cell migration via irreversible binding to the synaptic vesicle membrane protein VAT-1,which is a promising target for the development of anti-cancer drugs via preventing metastasis [23].Vioprolides A fromCystobacter violaceustargets nucleolar protein 14 to inhibit ribosome biogenesis in the acute lymphoblastic leukemia cell line,suggesting that Vioprolides A is a novel chemical tool to be used in the study of ribosomal processes and drug development[24].

Some natural products have been reported to elicit synergistic effects in combination with anti-cancer drugs,which improve the anti-tumor activity or reduced side effects.Gefitinib (Gef) has been used clinically due to efficacy against certain cancer cell types,including non-small cell lung cancer and esophageal carcinoma.Curcumin (Cur) fromCurcuma longaexerts a broad range of pharmacological activities.Gef and Cur co-treatment exhibits synergistic effects on cell viability in oral cancer.Moreover,γ-polyglutamic acid-coated nanoparticles loaded with Gef and Cur exhibit higher apoptotic effects [25].AlbA-DCA,a conjugate of natural oleanane triterpenoid saponin albiziabioside A fromAlbizia inundata,with PDK inhibitor dichloroacetate acid,exhibits an excellent synergistic effect for endometrial,metastatic breast and colorectal cancer cells [26].Taken together,these studies demonstrate evidence that natural products from traditional medicine used as anti-cancer candidates can potentially be used as drug targets for future cancer treatments.

Cardiovascular and cerebrovascular diseases

Although the number of studies of cardiovascular and cerebrovascular diseases in 2019 was limited,there were some inspiring studies on cerebrovascular diseases that should be addressed.2,7,2′-Trihydroxy4,4′7′-trimethoxy-1,1′-biphenanthren e is a natural product isolated fromCremastra appendiculataandLiparisnervosa.2,7,2′-Trihydroxy4,4′7′-trimethoxy-1,1′-biphenanthren e inhibits the oxygen-glucose deprivation reoxygenation-induced astrocyte oxidative stress partially through regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway [27].Moreover,geniposide is a natural product extracted fromGardenia jasminoidesand protected against hypoxic-ischemia-induced brain injury through the activation of the PI3K/Akt signaling pathway [28].These two compounds also exhibit various activities in other diseases,including neuroprotective and anti-cancer effects,suggesting a great opportunity for cardiovascular and cerebrovascular disease and drug development.

Inflammation-related diseases

Traditional medicine is an important source for the treatment of inflammation-related diseases.Nowadays,there are a lot of natural compounds isolated from traditional herbs with anti-inflammation effects.For example,isosibiricin fromMurraya exoticaL.inhibites the expression of TNF-α,IL-6,IL-1β,and IL-18 via up-regulating dopamine D1/2 receptors in LPS-activated microglial cells [29].Cymopol and related natural products from the marine green algaeCymopolia barbatamodulate the host inflammatory response via activating the anti-oxidative signaling pathway of nuclear factor erythroid 2-related factor 2[30].Moreover,shikonin fromLithospermum erythrorhizonprotects APAP-induced acute liver injury via modulating the inflammatory response and oxidative stress [31].7-Deoxy-transdihydronarciclasine fromLycoris chejuensisinhibits the pro-inflammatory factor production and microglial activation in the LPS-induced models and swedish mutation amyloid precursor protein transgenic mice T2576 [32].Furthermore,gracilin A and derivatives fromSpongionella gracilisexhibits anti-oxidative and anti-neuroinflammatory properties [33],and gracilin A congeners are also developed to retain neuroprotective and immunosuppressive effects at a much earlier synthetic stage by a simplified method“pharmacophore-directed retrosynthesis” [34].These studies indicate that natural products are a promising source for the discovery of novel anti-inflammatory agents and provide pharmacophore data for novel drug design.

Neurodegenerative diseases

AD is characterized by dementia and cognitive decline,which threatens human health.Thus,natural products have been widely investigated for AD.Mangiferin is extensively distributed in plants and fruits,including the mango tree,Anemarrhena asphodeloides,Iris domestica,Gentianascabra,andZizyphus cambodiana[35].Mangiferin significantly inhibits lipid peroxidation and decreases Aβ expression to protect the neurons,resulting in improvements in learning and memory behaviors [36].Traditional Chinese herbGlycyrrhiza uralensis Fischhas been widely studied in neurodegenerative diseases.Recently,licoflavonol fromGlycyrrhiza uralensis Fischis found to prevent the secretion of Aβ,soluble amyloid precursor protein α and β via increasing BACE1 phosphorylation and degradation [37].Natural products macaflavanone C and monachosorin B also inhibit the γ-secretase activating protein as a potential therapeutic target of AD [38].Until now,AD is considered incurable; thus,taking natural herbs orally as a preventive measure may protect or delay the onset of these neurodegenerative diseases.

Diabetes and metabolic diseases

Diabetes mellitus,caused by inadequate insulin secretion and insulin resistance,is one of the largest risk factors affecting human health.Natural products are widely investigated to prevent type 2 diabetes mellitus.Red algaRhodomela confervoides-derived compound 2,2′,3,3′-tetrabromo-4,4′,5,5′-tetrahydroxydiphenylmethane is reported to directly bind to the catalytic pocket of protein tyrosine phosphatase with an IC50value of 2.4 μM [39].Based on a natural dipetidyl peptidase-4 inhibitor iso-daphnetin,a series of novel compounds are discovered that potently inhibit dipetidyl peptidase-4 achieving a more favorable and extended anti-diabetic efficacy than validated drugs [40].As for other metabolic diseases,colletoic acid fromColletotrichum gloeosporioidesis a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor and used to block preadipocyte differentiation for a potential therapeutic effect on obesity [41].Another novel natural compound,antroalbol H fromAntrodiella albocinnamomea,increases glucose uptake in myotubes and adipocytes through activation of the LKB1-AMPK pathway at threonine 189 for hyperglycemia treatment [42].These studies indicate that novel metabolism regulation drugs could potentially be developed from natural compounds in the future.

Infectious diseases

Natural products have played fundamental roles in anti-infectious diseases for centuries.Traditional medicine plant-derived natural products provide a vast number of effective compounds,particularly antimicrobial agents,which have shown promising in vivo and in vitro efficacy against drug-resistant bacteria [43].For instance,phytochemical bergenin fromShorea robustainhibited mycobacterial growth in a murine model ofMycobacterium tuberculosisinfection via inducing pro-inflammatory mediators,including TNF-α,NO,IL-12 [44].The natural product agrimophol derivatives fromAgrimonia pilosaare reported to reduce intrabacterial pH with higher metabolic stability and lower cytotoxicity forMycobacterium tuberculosisinfection [45].Moreover,the natural product eugenol recently has been found to show anti-Ebola virus effects with EC50of 1.3µM[46].In addition to phytochemicals,there are some antibiotics derived fromPseudomonas fluorescensATCC 39502 and fungus,including β-lactone antibiotic obafluorin against Gram-positive and-negative pathogens,as well as the fungal metabolite apicidin that is biosynthesized by terrestrial strains against methicillin-resistant Staphylococcus aureus virulence [47,48].Furthermore,the biophenolic compound C2,a honokiol analog,has been reported to inhibit bacterial growth via disruption of the bacterial membrane [49].Analogs of the natural product gallinamide A exhibits potent inhibitory activity againstPlasmodium falciparumcysteine falcipain 2 and 3[50].

Depression and mental disorders

Mental illness has been investigated utilizing traditional medicine as treatments; however,further research is required.The natural product Andrographolide fromAndrographis paniculataeffectively relieves depressive-like behaviors in mice with chronic unpredictable mild stress,via inducing autophagy [51].Moreover,one review concentrates on the active constituents from TCM antidepressants and potential mechanisms of action.Chemical structures of the active ingredients with antidepressant activities in TCM have been classified and listed in this previous review.Thus,this review can be considered as a repository for future investigation[52].

Other diseases

Beyond the above-mentioned diseases,bioactive compounds from herbal medicine have been reported to potentially exert therapeutic effects on human acute or chronic diseases.The tetrapeptides isolated from the AustralianPenicilliumfungus have been developed as bilorphin,which is a potential novel analgesic via targeting the μ-opioid receptor [53].Interestingly,hydrogel combined with carbon dot nanoparticles is reported to generate ROS,which contributes to chondrogenic differentiation by regulating the TGF-β/SMAD and mTOR signaling pathways [54].Several natural products,such as 25-O-methylalisol F fromAlismaorientale,poricoic acid ZA fromPoria cocos,and salvianolic acid A fromsalvia miltiorrhiza,have been investigated to target redox signaling mediators against kidney diseases [55].Moreover,the oleanolic acid derivative HA-19 fromAchyranthes bidentataBlume shows a potential therapeutic effect in ameliorating muscle atrophy via promoting myoblast proliferation and terminal differentiation and down-regulation of the negative growth factor MuRF1 and Atrogin-1 [56].Licorice isoliquiritigeninencapsulated mesoporous silica nanoparticles have been found to have anti-osteoclast genetic effects by protecting against inflammatory bone destruction [57].Furthermore,quercetin alleviates cellular senescence in Werner syndrome and Hutchinson-Gilford progeria syndrome by regulating cell proliferation and restoration of heterochromatin architecture [58].Loganetin fromLoganin enzymaticallyhas been reported to possess a protective effect in acute kidney injury by inhibiting TLR4 activity and blocking the JNK/p38 pathway [59].Also,curcumin fromCurcuma longaattenuates ischemia-reperfusion injury in the liver via antioxidant enzymes and decreasing ROS in the oxidative stress pathway [60].Natural products also play an important role in novel drug discovery for other diseases,and additional efforts will be required to build a comprehensive database of these natural compounds.

Conclusion

During the year 2019,several rising star molecules from traditional medicine,including artemisinin,rutin,Ginseng Radix et Rhizoma,green tea,Pu-erh tea,and GV-971,exhibited efficacy as preventive,therapeutic,or potential treatments for serious illnesses.The merits of these herbal remedies were highlighted by other studies,and some of the pharmacological mechanisms and targets of these TCM bioactive molecules and extracts were elucidated.Thus,the authors of this review speculate that the trend toward herbal medicine will continue in the near future.Importantly,representative studies of infectious diseases using traditional medicine as treatments have become more numerous; this might be due to the rapidly increasing outbreak of coronavirus pneumonia that began at the end of 2019.However,studies on neurodegenerative diseases,depression,and mental disorders are limited during this study period and require more investigation.Identification of the pharmacological targets of traditional medicine also requires further research in the future.