Traditional Medicine Research Doi: 10.12032/TMR20210616237

Traditional Medicine Research doi: 10.12032/TMR20210616237

Annual advances of integrative pharmacology in 2020

Ke-Wu Zeng1*, Ming-Yao Gu2*

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.

*Corresponding to: Ke-Wu Zeng, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, No.38 Xueyuan Road, Haidian District, Beijing 100191, China; E-mail: [email protected]. Ming-Yao Gu, Department of Cell Biology and Medical Genetics, School of Basic Medical Sciences, Shenzhen University Health Science Center, No.1066 Xueyuan Avenue, Nanshan District, Shenzhen 518061, China; E-mail: [email protected].

Highlights

This review covers the studies in the year 2020 for pharmacological reports on traditional medicine as well as herb-derived active natural products. Moreover, the pharmacological reports on active natural products against cancers, inflammation, and metabolic diseases were major topics.

Tradition

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.

Submit a manuscript: https://www.tmrjournals.com/tmr 1 doi: 10.12032/TMR20210616237 REVIEW

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

Author contributions: Ke-Wu Zeng and Ming-Yao Gu wrote the manuscript together, and also contributed to the manuscript editing. Additionally, Ke-Wu Zeng provided the original materials and Ming-Yao Gu prepared the figure and table. Competing interests: The authors declare no conflicts of interest. Acknowledgments: None. Abbreviations: ROS, reactive oxygen species; MAPK, mitogen-activated protein kinases; TNBC, triple-negative breast cancer; HCC, hepatocellular carcinoma; PPAR-γ, peroxisome proliferator-activated receptor gamma. Citation: Zeng KW, Gu MY. Annual advances of integrative pharmacology in 2020. Tradit Med Res. 2021;6(4):31. doi: 10.12032/TMR20210616237. Executive editor: Rui-Wang Zhao. Submitted: 02 June 2020, Accepted: 18 June 2021, Online: 21 June 2021.

2 Submit a manuscript: https://www.tmrjournals.com/tmr Traditional Medicine Research doi: 10.12032/TMR20210616237 Cancers Background Cancer is still one of the greatest threats to human The representative studies on the pharmacology of health. Thus, researchers worldwide are exerting a lot traditional herbs over the previous 12 months have of effort into looking for natural compounds from been summarized in the almanac for 2020 to build a traditional medicinal plants to treat various cancers. A comprehensive understanding of the progress of great number of studies on cancer study exist in the traditional medicines for human disease treatments. year 2020, similar to previous years. Some reports The total number of pharmacological studies on about the natural compounds targeting colorectal traditional medicines has not changed much compared cancer mainly through inhibiting cell with previous years. The studies of the active proliferation-related cell signaling pathways were ingredients from traditional medicines in anticancer found. Delicaflavone, isolated from Selaginella research still occupy a dominant position. In particular, doederleinii, inhibits the viability of colorectal cancer some famous natural products (e.g., berberine, cells by blocking both Ras/MEK/Erk and tanshinol A, lycorine, and emodin) are major topics of PI3K/AKT/mTOR pathways [1]. Acetylshikonin, a concern. Moreover, research reports of traditional diterpenoid compound from the root of Lithospermum medicines used as therapy for metabolic diseases erythrorhizon, has been identified as a maintained strong upwards momentum in 2020. T-lymphokine-activated killer cell-originated protein Pharmacological studies of active compounds kinase inhibitor to attenuate the proliferation of including isoliquiritigenin, hypericin, and colorectal cancer cells [2]. Moreover, berberine serves protocatechuic acid on diabetes have obtained more as a potential therapeutic agent against colon cancer by attention. Interestingly, the bioactive compounds from targeting the cleavage activating protein/sterol traditional herbs against inflammation-associated regulatory element binding protein-1 pathway [3]. The diseases including artesunate, ginsenoside, and natural product β-elemene, from Curcumae rhizoma, is celastrol arouse people’s interest again. Meanwhile, a novel ferroptosis inducer. In addition, β-elemene pharmacological studies have shown a diversification co-treatment with cetuximab suppresses KRAS mutant trend. For example, increasing number of studies tumor cell proliferation as well as metastases by reported the protective effects of traditional herbs on inducing iron-dependent reactive oxygen species (ROS) bone loss and organ fibrosis. Unexpectedly, the studies accumulation, lipid peroxidation, and downregulation on cardiovascular and cerebrovascular diseases have of negative regulatory proteins [4]. Palmatine is an decreased, which is different from previous years. isoquinoline alkaloid from Rhizoma coptidis, which Thus, this review provides a broad annual summary of shows significant anticolon cancer effects by the pharmacological study progress on traditional promoting ROS production [5]. Furthermore, medicine during the year 2020 (Figure 1). triterpenoid saponin extracted from Melia toosendan Sieb 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 from Salvia miltiorrhiza, exerts its anticancer effect in the lung by inducing intracellular adenosine triphosphate depletion and ROS generation [7]. Deguelin, a natural product isolated from Derris elliptica, decreases the Mcl-1 protein level in an ubiquitination-dependent fashion against non-small cell lung cancer cells [8]. Pristimerin, isolated from Figure 1 Comparison of published reports about 9 Celastrus aculeatus Merr, inhibits vessel sprouts diseases between 2019 and 2020. C, cancer; CCD, formation by targeting Shh/Gli1 signaling pathway to cardiovascular and cerebrovascular diseases; IRD, suppress tumor angiogenesis in NCI-H1299 xenografts inflammation-related diseases; ND, neurodegerative [9]. Arctigenin from Arctium lappa suppresses lung diseases; MD, diabetes and metabolic diseases; ID, adenocarcinoma growth via the mitogen-activated infectious diseases; DMD, depression and mental protein kinases (MAPK) pathway [10]. Erianin, a disorders; OD, other diseases; BL, bone loss; OF, novel dibenzyl compound in Dendrobium chrysotoxum organ fibrosis. Lindl, induces Ca2+/CaM-dependent ferroptosis in lung cancer cells [11]. Lycorine, a natural small molecule

Submit a manuscript: https://www.tmrjournals.com/tmr 3 doi: 10.12032/TMR20210616237 REVIEW from Lycoris radiate, suppresses tumorigenicity, Schisandra chinensis has an antiproliferation effect on angiogenesis, and invasion of lung cancer cells by gastric cancer cell lines by inducing cell cycle arrest at inducing the accumulation of tumor suppressor the G2/M phase and cell apoptosis [30]. Imperatorin, a Salvador homolog 1 [12]. Hederagenin, a triterpenoid natural active compound from Angelica dahurica, is derived from the Hedera helix, may be used as an reported to treat muscle wasting in cancer cachexia by adjuvant to promote the antineoplastic effects of inhibiting the signal transducer and activator of conventional chemotherapeutics [13]. Moreover, transcription 3 pathway [31]. Fisetin from Rhus thevebioside, from Thevetia peruviana, is a potent succedanea L. inhibits cell proliferation and induces antitumor drug degrading the steroid receptor DNA damage and S-phase arrest in pancreatic coactivator 3 in an ubiquitin-proteasome-dependent adenocarcinoma [32]. Cardenolides ouabain from manner [14]. Furthermore, daurisoline from Rhizoma Strophanthus gratus and reevesioside A from S. gratus menispermi represses lung tumorigenesis by targeting show angiogenesis effect by promoting fibroblast HSP90 to destabilize β-catenin [15]. growth factor 2 secretion [33]. In addition, some natural compounds targeting breast cancer also exist. For example, glidobactin C Cardiovascular and cerebrovascular diseases from a Burkholderiales displays a β2/β5 coinhibition profile with single-digit nanomolar potency [16]. In An increasing number of current studies tried to use addition, 1,3-dicaffeoylquinic acid from Eucommia natural products to treat cardiovascular and ulmoides can be used as a lead compound for treating cerebrovascular diseases. Among them, hypertension is triple-negative breast cancer (TNBC) [17]. the most common chronic disease and the most Oxyresveratrol from the shell of Cocus nucifera important risk factor. Tetramethylpyrazine, isolated significantly inhibits TNBC proliferation by promoting from the traditional Chinese herb Ligusticum chromatin condensation and DNA fragmentation [18]. chuanxiong, shows a potential therapeutic role in Curcumol, a natural compound from the herbal plant pulmonary hypertension [34]. Triptolide, a bioactive Rhizoma curcumae, enhances doxorubicin sensitivity component from Tripterygium wilfordii, shows in TNBC breast cancer [19]. Emodin, a Rheum protective effects on renal injury in salt-sensitive palmatum-derived small molecule has potential hypertension [35]. Some compounds that show a therapy for TNBC by targeting nuclear receptor protective effect in cardiovascular disease have been corepressor 2 to suppress vascular endothelial growth reported. Cannabidiol, a natural bioactive compound factor A transcription [20]. In addition, crocin from from Cannabis sativa, protects against high Crocus sativus induces apoptosis in human breast glucose-elicited oxidative stress through inhibiting cancer MDA-MB-231 and MCF-7 cells via inhibiting cardiac voltage-gated sodium channels [36]. Moreover, the Akt/FOXO3a pathway [21]. Acetyltanshinone ⅡA, dihydromyricetin is a flavonoid compound extracted obtained from the chemical modifications of from Hovenia dulcis, and has a cardioprotective effect Tanshinone IIA, has the potential to treat breast in patients with heart failure [37]. Liensinine, an cancers via inducing human epidermal growth factor isoquinoline alkaloid from Nelumbo nucifera Gaevth, receptor 2 degradation [22]. shows a protective effect on doxorubicin-induced Moreover, some natural compounds are discovered cardiotoxicity [38]. Isorhapontigenin from Gnetum to treat other cancers. For example, berberine exerts parvifolium reverses cardiotoxicity by targeting antimultiple myeloma activity [23]. Pyroptosis is a Yes-associated protein [39]. Two compounds show an form of programmed cell death, involves pro- and anticardiac hypertrophy effect, including delphinidin (a antiapoptotic proteins in various cancer cells, promotes natural flavonoid compound from fruits) that shows their death, and inhibits their proliferation and antioxidant, antiapoptotic, and anticancer activities. It migration. Thus, some researchers focus on the natural represses pathological cardiac hypertrophy by products that can activate pyroptosis in some cancers. regulating oxidative stress through the adenosine Pyridoxine induces pyroptosis in human leukemic monophosphate-activated protein kinase/NADPH THP-1 cells [24]. Geniposide attenuates the invasion, oxidase/MAPK signaling pathway [40]. Celastrol, proliferation, and lung metastasis of hepatocellular derived from T. wilfordii, attenuates Ang II-induced carcinoma (HCC) [25]. Moreover, miltirone cellular and TAC-challenged in vivo cardiac significantly suppresses HCC by inducing pyroptosis hypertrophy and fibrotic responses [41]. [26]. Proanthocyanidin-B2 from peanut skin also has strong antitumor effects in HCC by inhibiting AKT Inflammation-related diseases activity [27]. In addition, echinatin from Glycyrrhiza uralensis suppresses the proliferation and migration of Inflammation-related diseases could be treated with esophageal squamous cell carcinoma through the various traditional medicines that contain a many regulation of AKT/mTOR signaling pathway [28]. active natural compounds. For example, luteolin Cordycepin synergistically induces cell apoptosis of attenuates intestinal mucositis by decreasing and esophageal cancer cells [29]. Schisantherin A from increasing the proinflammatory and antiinflammatory 4 Submit a manuscript: https://www.tmrjournals.com/tmr Traditional Medicine Research doi: 10.12032/TMR20210616237 cytokines, respectively [42]. Berberine from Coptis Maslinic acid, a triterpenoid isolated from Crataegus chinensis shows a therapeutic effect on chronic colitis pinnatida, reverses the scopolamine-induced memory by targeting REV-ERBα [43]. Parthenolide, a impairment of mice [60]. Tanshinone IIA prevents sesquiterpene lactone from Tanacetum balsamita, spatial learning and memory deficits in APP/PS1 mice ameliorates colon inflammation in a gut [61]. Ginsenoside Rg1 alleviates behavioral defects in microbiota-dependent manner in vivo [44]. Berberine a mouse model of Huntington’s disease [62]. Moreover, guides gut microbiota to coordinate the bacterial (+)-(S)-scocycamide and (−)-(R)-scocycamide from metabolites to mediate the gut barrier functions in Scopolia tangutica shows potential therapeutic effect inflammatory bowel diseases [45]. Ginsenoside Rb1 against Alzheimer’s disease by inhibiting butyryl targets Hrd1 to alleviate the ER stress response in cholinesterase and exhibiting antioxidant capacity [63]. colitis symptoms [46]. β-PAE, a tricyclic sesquiterpene Scopoletin from Convolvulus pluricaulis, restores the isolated from Pogostemon cablin, may be a potential redox balance through efficient recycling of therapeutic agent for ulcerative colitis by suppressing glutathione to recover dopaminergic neural networks colic leakage and bacterial imbalance [47]. All of the and motor coordination abilities in the Drosophila aforementioned natural compounds show therapeutic genetic model of Parkinson’s disease [64]. LFP-1, a effects in colitis. Δ9-THCA-A, a phytocannabinoid natural compound from Lycii fructus, effectively from C. sativa, and cannabidiol, a phytocannabinoid protected against 1-methyl-4-phenylpyridinium- from C. sativa has the effect of resisting arthritis. induced neurotoxicity in the Parkinson’s disease model Δ9-THCA-A activates the CB1 receptor, inhibits the by promoting neuronal differentiation and neurite CB2 receptor, and regulates the peroxisome outgrowth [65]. In addition, ursolic acid from proliferator-activated receptor gamma (PPAR-γ) Arctostaphylos uva-ursi promotes oligodendrocyte signaling pathway [48], and cannabidiol targeted maturation, and central nervous system myelin repair synovial fibroblasts [49]. Moreover, some compounds decreases in an animal model of multiple sclerosis [66]. also ameliorate inflammation in the respiratory system. Furthermore, cariside II from Herba epimedii Tetrahydrocannabinol, a compound from C. sativa L., significantly ameliorates ischemia/reperfusion-induced acts as a palliative for enterotoxin-B-induced acute blood-brain barrier disruption and neuronal apoptosis respiratory distress syndrome [50]. Lycorine from in middle cerebral artery occlusion rats through Amaryllidaceae shows a protective effect in pulmonary modulating the matrix metalloproteinase 9/tissue fibrosis and acute lung injury by suppressing collagen inhibitor of metalloproteinase-1 balance [67]. deposition and ameliorating inflammasome activation [51]. Scutellarin from Erigeron breviacapus, Diabetes and metabolic diseases ameliorates pulmonary fibrosis via NF-κB/NLRP3-associated inflammatory response [52]. Metabolic diseases are a cluster of diseases (e.g., type Furthermore, imperatorin from Radix angelicae 2 diabetes and fatty liver), which affect human health. Dahuricae, treats allergic asthma by reducing calcium In 2020, plenty of natural products were found that flux [53]. Apocynin from Picrorhiza kurroa, exerts an may be used to prevent diabetes. For example, GdTI antiinflammatory effect by inhibiting the from Geoffroea decorticans may be a potential natural granulocyte-macrophage colony-stimulating antithrombotic and antidiabetic drug [68]. factor-induced AKT-MEK1/2-ERK1/2 pathway and Sarsasapogenin, from Anemarrhena asphodeloides, granulocyte-macrophage colony-stimulating ameliorates the damaged vascular endothelium in high factor-prosurvival effect [54]. Nardosinanone N, from glucose-cultured human umbilical vein endothelial Nardostachys chinensis, is a potential new cells [69]. Rographolide, from Andrographis antiinflammatory drug inhibiting M1 phenotype and paniculata, facilitates PANC-1 cells differentiation into increasing M2 phenotype [55]. Artesunate from the functional insulin-producing cells [70]. Bromophenol medicinal plant Artemisia annua Linn affects 3-bromo-4, 5-bis (2,3-dibromo-4,5- sepsis-induced immunosuppression by interacting with dihydroxybenzyl)-1, 2-benzenediol from Rhodomela vitamin D receptor [56]. Arctigenin, from A. lappa, has confervoides serves as a protein tyrosine phosphatase a protective effect in acute peritonitis by reducing 1B inhibitor against hyperglycaemia [71]. Moreover, inflammatory cell infiltration [57]. 6BIGOE, isolated rosmarinic acid is a natural therapeutic agent for from Angelica sinensis, inhibits diabetic cardiovascular disease, which protects lipopolysaccharide-induced cytokine release by endothelial dysfunction in diabetic atherosclerosis [72]. targeting glycogen synthase kinase 3 in monocytes Isoliquiritigenin, a flavonoid natural compound from G. [58]. AEDC, isolated from Actaea vaginata, modulates uralensis, Sinofranchetia chinensis, and Dalbergia macrophage-adipocyte crosstalk to alleviate adipose odorifera, can be used to protect against diabetic tissue inflammation [59]. nephropathy progression by ameliorating renal fibrosis, apoptosis, and the deterioration of the renal function in Neurodegenerative diseases diabetic mice [73]. Steatohepatitis is a common disease caused by the storage of extra fat in the liver. However,

Submit a manuscript: https://www.tmrjournals.com/tmr 5 doi: 10.12032/TMR20210616237 REVIEW no medication has been approved and researchers are [87]. Oridonin, a diterpene compound, ameliorates the still trying to find natural drugs to treat fatty liver depressive symptoms of mice by increasing the level disease. In addition, tetrahydroxystilbene glucoside, of PPAR-γ and GluA1 phosphorylation [88]. isolated from Polygonum multiflorum, regulates the crosstalk between macrophages and hepatocytes in Other diseases alcoholic hepatosteatosis [74]. Hypericin, one of the main active ingredients of Hypericum perforatum L., is Many bioactive compounds from herbs also exist to used for treating nonalcoholic fatty liver disease by treat other diseases in addition to the aforementioned regulating lipid metabolism [75]. summarized diseases. For example, catalpol, an active Cyanidin-3-O-glucoside isolated from Glycine max compound from Rehmannia glutinosa, can be affects in the nonalcoholic fatty liver disease [76]. developed as a promising potential therapy for Roseotoxin B, a natural compound from Trichothecium osteoclast-related bone diseases [89]. Corylin, a natural roseum, possesses a beneficial effect on cholestatic flavonoid from Psoralea corylifolia L., has liver fibrosis [77]. Protocatechuic acid attenuates antiosteogenic activities [90]. Aucubin from E. high-fat diet-induced fatty acid metabolism disorder in ulmoides has antiosteoporotic effects which promotes nonalcoholic fatty liver disease [78]. Furthermore, cytokines expression associated with osteoblast pristimerin from Celastrus orbiculatus is a novel differentiation [91]. Moreover, cardamonin from compound for the treatment of NLRP3-related Alpinia katsumadai has been used to treat metabolic disorder [79]. Gypenosides, from autosomal-dominant polycystic kidney disease by Gynostemma yixingense, have therapeutic potential for reducing the formation and enlargement of cyst in the metabolic syndrome [80]. Madin-Darby canine kidney cyst model [92]. Chrysophanol from R. palmatum L. has an inhibitory Infectious diseases effect on renal interstitial fibrosis by suppressing the expressions of fibrotic markers including collagen I Some infectious diseases have been conquered by the and alpha-smooth muscle actin [93]. Furthermore, discovery of antibiotics agents. However, natural ethyl-p-methoxycinnamate, a natural compound from products still are needed to be widely studied as drugs the medicinal herb Kaempferia galangal maintains against infectious diseases. Rosmarinic acid, a self-renewal and pluripotency of stem cells [94]. compound extracted from Rosmarinus officinali, exerts Myricetin, a flavonoid derived from Myrica rubra Sieb. antiviral effects on EV-A71 by affecting the early stage et Zucc, inhibits the activation of lung fibroblasts by of viral infection [81]. Semiperfoliata, extracted from targeting the heat shock protein 90 to regulate Euphorbia amygdaloides, induces HIV transcription transforming growth factor-beta/Smad and non-Smad and reactivates HIV-1 in CD4+ T cells [82]. Baicalein, signaling pathways [95]. Clausenamide, an alkaloid a natural compound from Scutellaria baicalensis, is an isolated from Clausena lansium (Lour.) Skeels, shows effective inhibitor of multidrug-resistant a protective effect on acetaminophen-induced Staphylococcus aureus that directly binds to vWbp and hepatocyte ferroptosis in vitro and in vivo [96]. In blocks its coagulase activity [83]. In the previous 2 addition, salidroside alleviates pain and joint swelling years, the new coronavirus has affected the whole in the early acute osteoarthritis stage [97]. world, and herbal medicine has played an important Chrysophanol, an anthraquinone extracted from R. role in the treatment and prevention of the new palmatum L., significantly ameliorates kidney damage coronavirus. Salvianolic acid C extracted from S. and decreases the production of fibrotic markers [98]. miltiorrhiza Bunge suppresses SARS-CoV-2 infection Quercetin protects bones and prevents through regulating the hydrophobic pocket in the HR1 unloading-caused bone loss in mice [99]. Moreover, region of SARS-CoV-2 and blocking the six-helix quercetin promotes the maturation and early bundle formation between HR1 and HR2 [84]. embryonic development of oocytes in vitro from aged Cardenolides are expected to exert significant mice and humans [100]. Furthermore, atractylenolide I, anticoronaviral activities for porcine TGEV and human a sesquiterpenoid lactone derivative of the Chinese HCoV-OC43 [85]. Perillaldehyde, a natural medicine Atractylodes macrocephala, may be a monoterpenoid agent extracted from Perilla therapeutic biologic agent for renal fibrosis prevention frutescence, affects the oropharyngeal candidiasis by [101]. Osthole, the main active ingredient of the resisting Candida albicans [86]. Chinese medicine Cnidium monnieri, shows pharmacological effect in inhibiting airway Depression and mental disorders hyperreactivity by enhancing autocrine PGE2-mediated airway dilation [102]. In 2020, only a few studies reported that traditional medicine can treat depression and mental disorders. Conclusion Epidiole is reported to regulate the one-carbon cycle components, which are deregulated in a Dravet model The number of pharmacological studies on traditional 6 Submit a manuscript: https://www.tmrjournals.com/tmr Traditional Medicine Research doi: 10.12032/TMR20210616237 medicines and their bioactive compounds has have decreased during the previous year. Particularly, maintained a momentum of rapid growth in the year an unexpected increase of the studied on traditional 2020. Moreover, studies on traditional medicines for herbal treatments for bone loss and organ fibrosis has cancer, metabolic diseases, and inflammation are still been observed (Table1). Therefore, the authors in a leadership position, indicating a further cause for speculate that the trend toward herbal medicine will concern. Meanwhile, the current study noticed that the show a diversification trend in the future. reports on cardiovascular and cerebrovascular diseases

Table 1 Natural herbs researches related to various diseases published in 2020 Diseases Models Functions Signaling pathways

Cancer Colorectal cancer [1, 3, 5, 6] Proliferation [1, 6, 28–30] Ras/MEK/Erk [1]

Lung cancer [11, 15, 25–27] Angiogenesis [7–15, 33] PI3K/AKT/mTOR [1, 28], Akt/FOXO3a [21] Breast cancer [16–22] Apoptosis [21, 25, 30] ROS accumulation [4, 5, 7]

Liver cancer [25–27] Pyroptosis [24, 26] Wnt/β-catenin [6]

Digestive system cancer [28–30] Invasion [25, 28]

Cardiovascular and Hypertension [34, 35] Oxidative stress [36, 40] Yes-associated protein [38] cerebrovascular diseases Cardiovascular disease [36–39] MAPK signaling [40] Sodium channels [36] Hypertrophy [40, 41] AMPK/NADPH oxidase [40]

Inflammation-related Digestive system inflammation [42–47] Anti-inflammatory cytokines [42] REV-ERBα [43] diseases Respiratory system inflammation [50–53] Pro-inflammatory [42, 59] Hrd1 [46]

Adipose tissue inflammation [59] Gut barrier or microbiota [44, 45,47] NF-κB/NLRP3 [52] NLRP3 [51] Peritonitis [57] Depolarization [55] GSK-3 [58]

Immune cells [55, 58] AKT-MEK1/2-ERK1/2 [54]

Neurodegenerative Alzheimer’s disease [60,61,63] Neuroprotection [61, 63–66] diseases Parkinson’s disease [64, 65] Behavior improvement [60–64]

Multiple sclerosis [66] Butyryl cholinesterase [63]

Diabetes and related diseases [68–73] Blood glucose regulation [70, 71] PTP1B inhibitor [71]

Endothelial protection [68, 69, 72]

Liver diseases [74–78] Lipid metabolism [75, 76, 78]

Infectious diseases Viral infection [81–83] Coagulase activity [83] vWbp inhibitor [83]

Coronaviral [85]

Depression and Depressive symptoms [88] PPAR-γ/ GluA1 [88] mental disorders Depression and Depressive symptoms [88] PPAR-γ/ GluA1 [88] mental disorders ROS, reactive oxygen species; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinases; AMPK, adenosine monophosphate-activated protein kinase; GSK-3, glycogen synthase kinase 3; PTP1B, protein tyrosine phosphatase 1B; NLRP3, NACHT, LRP and PYD domains-containing protein 3; PPAR-γ, peroxisome proliferator-activated receptor gamma.

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