Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects

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Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects Jianqin Zhanga, Chuxuan Wua, Li Gaoa, Guanhua Dub, Xuemei Qina,∗ a

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China ∗ Corresponding author: e-mail address: [email protected] b

Contents 1. 2. 3. 4. 5.

Introduction The protective effect of AS-IV on nervous system The protective effect of AS-IV on liver The anti-cancer effect of AS-IV The protective effect of AS-IV on diabetes 5.1 Pharmacological effects of AS-IV on diabetic nephropathy 5.2 Pharmacological effects of AS-IV on vascular complications 5.3 Pharmacological effects of AS-IV on diabetic retinopathy 6. The latest research progress of AS-IV 7. Pharmacokinetics and toxicity of AS-IV 8. Conclusion Acknowledgments Conflict of interest References Further reading

4 5 7 8 9 10 15 15 15 16 17 18 19 19 24

Abstract Decoctions prepared from the roots of Astragali Radix are known as “Huangqi” and are widely used in traditional Chinese medicine for treatment of viral and bacterial infections, inflammation, as well as cancer. Astragaloside IV (AS-IV), one of the major compounds from the aqueous extract of Astragalus membranaceus, is a cycloartane-type triterpene glycoside chemical. To date, many studies in cellular and animal models have demonstrated that AS-IV possesses potent protective effects in cardiovascular, lung, kidney and brain. Based on studies over the past several decades, this review systematically summarizes the pharmacological effects, pharmacokinetics and the toxicity of AS-IV. We analyze in detail the pharmacological effects of AS-IV on neuroprotection, liver

Advances in Pharmacology ISSN 1054-3589 https://doi.org/10.1016/bs.apha.2019.08.002

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2019 Elsevier Inc. All rights reserved.

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protection, anti-cancer and anti-diabetes, attributable to its antioxidant, antiinflammatory, anti-apoptotic properties, and the roles in enhancement of immunity, attenuation of the migration and invasion of cancer cells and improvement of chemosensitivity of chemotherapy drugs. In addition, the latest developments in the combination of AS-IV and other active ingredients of traditional Chinese medicine or chemical drugs are detailed. These pharmacological effects are associated with multiple signaling pathways, including the Raf-MEK-ERK pathway, EGFR-Nrf2 signaling pathway, Akt/PDE3B signaling pathway, AMPK signaling pathway, NF-κB signaling pathway, Nrf2 antioxidant signaling pathways, PI3K/Akt/mTOR signaling pathway, PKC-α-ERK1/2NF-κB pathway, IL-11/STAT3 signaling pathway, Akt/GSK-3β/β-catenin pathway, JNK/ c-Jun/AP-1 signaling pathway, PI3K/Akt/NF-κB pathway, miRNA-34a/LDHA pathway, Nox4/Smad2 pathway, JNK pathway and NF-kB/PPARγ pathway. This review will provide an overall understanding of the pharmacological functions of astragaloside IV on neuroprotection, liver protection, anti-cancer and anti-diabetes. In light of this, AS-IV will be a potent alternative therapeutic agent for treatment of the above mentioned diseases.

Abbreviations AAA Akt AMPKα AR AS-IV ATF4 Bax BCL2 B7-H3 CAG CHOP CRC CREB1 CNS DRG Drp-1 EGFR eIF2α EMT eNOS ERG ERK1/2 Fis-1 GA GLUT4 G6Pase GRP78 HBeAg

abdominal aortic aneurysm serine/threonine-specific protein kinase AMP-activated protein kinase α retina aldose reductase astragaloside IV activating transcription factor-4 B-cell lymphoma 2-associated X protein B-cell lymphoma 2 a member of the B7 family of immunoregulatory proteins cycloastragenol C/EBP homologous protein colorectal cancer CAMP responsive element binding protein 1 central nervous system dorsal root ganglia dynamin-related protein 1 epidermal growth factor receptor eukaryotic translation initiation factor-α the epithelial-mesenchymal transition endothelial nitric oxide synthase electroretinogram extracellular signal-regulated protein kinases 1 and 2 mitochondrial fission protein 1 glycated albumin glucose transporter glucose-6-phosphatase glucose-regulated protein 78 hepatitis B e antigen

ARTICLE IN PRESS Review on the pharmacological effects of astragaloside IV

HBsAg HCC HFD HK-2 ICAM-1 IDO IKK IL-1β ILK IR iNOS JNK MCP-1 MEK1/2 MFF mTOR MNNG NAFLD NAG NFAT2 NF-κB NGAL NO NOTCH3 Nox4 Nrf2 OGD/R ORP150 Ox-LDL PDE3B PERK PI3K PINK1 PKC-α PLGC P2X3 RCECs RGCs RSK2 SERCA2b SOD TGF-β1 TLR4 TM TNF-α TRAF5 TRPA1

hepatitis B surface antigen hepatocellular carcinoma high-fat diet proximal renal tubular epithelial cells intercellular adhesion molecule-1 indoleamine 2,3-dioxygenase inhibitory κB kinase interleukin-1β integrin-linked kinase insulin resistance inducible nitric oxide synthase c-Jun N-terminal kinases monocyte chemoattractant protein-1 mitogen-activated protein kinase mitochondrial fission factor mammalian target of rapamycin N-methyl-N0 -nitro-N-nitrosoguanidine non-alcoholic fatty liver disease N-acetyl-β-D-glucosaminidase nuclear factor of activated T cells nuclear factor kappa-light-chain-enhancer of activated B cells neutrophil gelatinase-associated lipocalin nitric oxide eurogenic locus notch homolog protein 3 NADPH oxidase 4 NF-E2-related factor 2 oxygen and glucose deprivation/re-oxygenation 150 kDa oxygen-regulated protein low density lipoproteins the predominant isoform of phosphodiesterase protein kinase RNA (PKR)-like ER kinase phosphoinositide 3-kinases PTEN-induced putative kinase 1/Parkin protein kinase C alpha type precancerous lesions of gastric carcinoma anti-P2X purinoceptor 3 capillary endothelial cells retinal ganglion cell ribosomal S6 kinase 2 sarcoendoplasmic reticulum Ca2 + ATPase 2b superoxide dismutase transforming growth factor-beta 1 toll-like receptor 4 tunicamycin tumor-necrosis factor-α tumor-necrosis factor (TNF) receptor (TNFR)-associated factor 5 transient receptor potential ankyrin 1

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TRPC6 TRPV1 VSMC

transient receptor potential channel 6 transient receptor potential cation channel subfamily V member 1 vascular smooth muscle cell

1. Introduction Astragalus was formally described in 1753 by Carl Linnaeus in his Species Plantarum. Astragalus membranaceus was initially recorded in one of the most famous ancient Chinese medical book, Shen Nong Ben Cao Jing, in 200 AD with a wide range of therapeutical effects and no toxicity (Sun & Sun, 2010). In the Chinese Pharmacopeia (ISBN 978-7-50678929-5) 2015 edition, Astragali Radix, also known as Huangqi, is defined as the dried roots of A. membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge. Astragali Radix is considered to be a high-grade traditional Chinese medicine, which nourishes Qi and blood, and has multiple protective effects on immune system, cardiovascular system, nervous system, liver and kidney (Auyeung, Han, & Ko, 2016; Liu, Bao, & Liu, 2014). As reported，three main chemical compounds are contained in Astragali Radix (Huangqi), including polysaccharides (heteropolysaccharide and dextran), saponins and flavonoids. With the development of extraction and separation technologies, more than 40 constituents of astragalus saponins have been identified from the dried astragalus roots by using HPLC and GC-MS (Liu et al., 2014). Astragaloside IV (AS-IV, also known as astragalus saponin IV, Fig. 1) is one of the main active ingredients of A. membranaceus and is used as a quality control marker of Huangqi in the Chinese Pharmacopeia (2015 version). AS-IV is 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol and its molecular formula is C14H68O14. AS-IV has various pharmacological activities, including protective effects on cerebral injury and CNS, cardiovascular disease, respiratory system, kidney, endocrine system, organic immune system, liver and cancer due to its wide range of pharmacological actions, such as antioxidant, cardioprotective effects, anti-inflammatory, antiviral, antibacterial, antifibrosis, anti-diabetes and immunoregulation effects (Li, Hou, Xu, Liu, & Tu, 2017; Ren, Zhang, Mu, Sun, & Liu, 2013).

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Review on the pharmacological effects of astragaloside IV

OH O OH H

H HO O

HO

OH

O H OH

OH

O

O OH

OH

Fig. 1 Chemical structure of astragaloside IV.

In this study, we summarize the pharmacological effects of AS-IV on neuroprotection, liver protection, anti-cancer and anti-diabetes and the latest research on other diseases.

2. The protective effect of AS-IV on nervous system At present, millions of people around the world are affected by neurological disorders such as stroke, dementia, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Huge treatment costs have put enormous economic pressure on society for amelioration of these afflictions. Environmental, genetic factors and functional and sensory loss occurs due to neuronal cell damage can contribute to the neurological diseases (Costa et al., 2018). Oxidative stress, defined as the increased generation of reactive oxygen species and its oxidative products of biomacromolecules (Li et al., 2016), is an important component of neurodegenerative diseases (An, Wei, Qian, Li, & Wang, 2018; Zhang et al., 2012). The pharmacological mechanism of AS-IV in Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebral ischemia and autoimmune encephalomyelitis has been thoroughly and systematically summarized by Costa et al. in 2018 (Costa et al., 2018). Based on 16 articles published between 2007 and

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2017, the authors concluded that AS-IV can attenuate behavioral and neurochemical deficits due to its antioxidant, anti-apoptotic and antiinflammatory properties, which point to new strategies in drug development (Costa et al., 2018). In addition, other experiments revealed the function of neuroprotective effect by using different cell models, damage models in murine cortical neurons and mouse models of sciatic nerve injury. The spontaneous discharge of cultured primary hippocampal neurons is regarded as a good model for physiological and pathological neuronal networks in vitro. Zhu et al. (2008) investigated the changes in the spontaneous neuronal excitability induced by AS-IV with the cultured hippocampal network. A dose of 40 mg/L AS-IV (dissolved in DMSO) could inhibit the frequencies of synchronized spontaneous Ca2+ oscillations to 59.39%  3.25% (mean  SEM). The application of 40 mg/L AS-IV could significantly decrease the frequency of the spontaneous postsynaptic currents to 43.78%  7.72% (mean  SEM) and the spontaneous excitatory postsynaptic currents to 49.25%  7.06% (mean  SEM), while there was no difference in the frequency in the DMSO group, respectively. Also, AS-IV repressed voltage-gated K+ and Na+ currents of cultured rat hippocampal neurons. These data suggest that AS-IV may depress the spontaneous neuronal excitability, which provides a new insight for AS-IV as a neuroprotector， although these findings lack information relevant for interpretation of the data, including dose/concentration dependency data as well as a comparison to other active moieties (Zhu et al., 2008). Nowadays, the proteomic is considered to be a powerful tool in the development of novel biomarker candidates for early detection of disease and identification of new targets for therapeutics, based on the protein expression changes under the organism’s different physiological states and the stages of disease progress (Hanash, 2003). A comprehensive shotgun proteomic profiling procedure, based on an online 2D-nano-LC-MS/MS system, was used to investigate proteomic variations after treatment with 100 μM AS-IV in PC12 cells, which exposed to 5 mM glutamate at 24 h. The findings of this work demonstrated that proteins related to signal transduction, immune system, signaling molecules and interaction, and energy metabolism play key roles in the neuroprotective effect of AS-IV. The Raf-MEK-ERK pathway was involved in the neuroprotective effect of AS-IV against glutamate-induced neurotoxicity in PC12 cells (Yue et al., 2015). AS-IV may exert a therapeutic effect on ischemia stroke. Studies have shown that pretreatment of AS-IV (10–50 μM, for 6 h) significantly

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inhibited oxygen and glucose deprivation/re-oxygenation (OGD/R) induced neuron viability loss. Importantly, the activation of EGFR-Nrf2 signaling pathway is responsible for the neuroprotection of AS-IV on cortical neurons against OGD/R damages (Gu et al., 2015). In addition to its neuroprotective effects, AS-IV also exhibits pharmacological effects in refractory neuropathic pain. Shi et al. (2015) systematically investigated the antinociceptive activity of AS-IV in an animal model of chronic constriction injury (CCI) in neuropathic pain. AS-IV could alleviate neuropathic pain by two ways: (a) down-regulation of the expressions of important molecules associated with neuropathic pain in the DRG, such as P2X3, TRPA1, and TRPV1, and (b) restoration of the histological structure of the damaged sciatic nerve by accumulating GFRα1 in the debris of myelin between the Schwann cells and the damaged axon (Shi et al., 2015). In the peripheral nervous system, AS-IV also can protect and promote peripheral nerve regeneration (Cheng et al., 2006). Growth-associated protein 43, as a specific molecular marker during nerve injury plays a vital role in nerve growth, development and regeneration (Shen & Meiri, 2013). AS-IV (10 or 5 mg/kg per day) may contribute to sciatic nerve regeneration and functional recovery in mouse model of sciatic nerve injury with the underlying mechanism of the up-regulation of growth-associated protein-43 expression (Zhang & Chen, 2013).

3. The protective effect of AS-IV on liver As the largest solid organ，the liver carries out many vital roles in the human body, such as detoxification, the production of chemicals and drug metabolism, which are the main causes of oxidative stress, drug-induced liver injury, and insulin resistance (IR) injury. Recent studies have shown that AS-IV offers protection of the liver through various pharmacological effects, such as antioxidation (Han, Li, Lin, Ma, & Huang, 2014), antiinfection (Wang et al., 2009) and anti-inflammation (Wei, Liu, Chen, Sheng, & Liu, 2019). In general, high-fat diet feeding can result in adipose dysfunction with inducing endogenous glucose production in mice. Du et al. noted that pretreatment with AS-IV contributed to the limitation of hepatic lipid deposition and the depression of excessive hepatic glucose through reduction of cAMP accumulation via regulation of Akt/PDE3B (Du et al., 2017). IR is a crucial factor for non-alcoholic fatty liver disease, with the characterization of lipid accumulation in hepatocytes. AS-IV exerts the potential to be

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developed as a drug for treatment of hepatic steatosis due to its strong activities in inhibiting IR and lipid accumulation in HepG2 cells via regulating AMPK-dependent phosphorylation of SREBP-1c at Ser372 (Wang, Li, Hao, & Li, 2018).

4. The anti-cancer effect of AS-IV Many recent studies have shown that AS-IV exerted beneficial anticancer effects against various tumor types based on immune-enhancement activity (Li, Ye, & Chen, 2018), inhibition of tumor growth (Zhang et al., 2014) and inhibition of tumor migration and invasion (Zhu & Wen, 2018). Lung cancer is the most frequently occurring cancer and the leading cause of death (18.4%) among all cancer deaths worldwide (Bray et al., 2018). It was reported that AS-IV had certain protective and adjuvant therapeutic effects on lung-related diseases and lung cancer (Zhang et al., 2014; Zhang, Chen, Xu, & Tian, 2018; Zhou, Zhuo, & Cai, 2018). In an orthotopic lung cancer model induced by IDO-overexpression in C57BL/6 mice, AS-IV remarkably suppressed the growth of tumor in vivo. AS-IV can improve the immune response by inhibiting the expression of Tregs and inducing the activity of CTLs (Zhang et al., 2014). AS-IV attenuates the migration and invasion of A549 cells by regulating PKC-αERK1/2-NF-κB pathway (Cheng et al., 2014). In addition, AS-IV enhances chemosensitivity to cisplatin in human non-small cell lung cancer cells via inhibition of B7-H3, which can be used as a potential therapeutic approach for lung cancer patients (He et al., 2016). Hepatocellular carcinoma (HCC) is the seventh most prevalent malignancy in both sexes (Bray et al., 2018). At present, some progress has been made with AS-IV in the treatment of liver cancer. AS-IV successfully inhibited migration ability, cell viability and invasiveness of HCC cells through blocking IL-11/STAT3 signaling pathway via significantly down-regulating the expression of lncRNA-ATB in a dose- and timedependent manner (Li, Ye, & Chen, 2018), and suppressing epithelialmesenchymal transition by targeting the Akt/GSK-3β/β-catenin pathway (Qin et al., 2017). Multidrug resistance has become a major obstacle in cancer chemotherapy, which is considered to be mediated by P glycoprotein (P-gp) encoded by the multidrug resistance (mdr1) gene (Chen et al., 2016). Wang et al. found that AS-IV (0.1 mM) reversed the drug resistance of Bel-7402/FU human hepatic cancer cells by depressing the expression of

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mdr1 and blocking the JNK/c-Jun/AP-1 signaling pathway, although authors did not examine the effects of down-regulation of mdr1 gene expression on oral bioavailability and clearance of other drugs (Wang et al., 2017). Gastric cancer (including cardia and noncardia gastric cancer) is an important cancer worldwide and considered to be the fifth most frequently diagnosed cancer and the third leading cause of cancer death (Bray et al., 2018). It has been reported that AS-IV possesses anti-metastasis activity of gastric cancer cells through inhibition of the PI3K/Akt/NF-κB pathway (Zhu & Wen, 2018). Because the diagnosis of gastric carcinoma tends to be at an advanced stage, in-depth research of precancerous lesions of gastric carcinoma (PLGC) is becoming important in preventing the formation and development of gastric carcinoma (Yoon & Kim, 2015). Recent research demonstrates that AS-IV protects the gastric mucosal injury, prevents and cures gastric mucosal atrophy in MNNG-induced precancerous lesions of gastric carcinoma in rats (Cai et al., 2018), and it could reverse PLGC via regulation on glycolysis through the miRNA-34a/LDHA pathway (Zhang et al., 2018). According to the statistics, colorectal cancer (CRC), is another frequent cancer and the second leading cause of cancer death (9.2%) with a poor prognosis in both males and females (Bray et al., 2018). Similar to previous reports in lung cancer, AS-IV also enhances cisplatin chemosensitivity in human colorectal cancer through inhibition of NOTCH3 (Xie, Li, Li, & Luo, 2016), and AS-IV inhibits cell proliferation of CRC cells by downregulating the expression of B7-H3 (Wang, Mou, Cui, Wang, & Zhang, 2018). Ye, Su, Chen, Zheng, & Liu (2017) found that AS-IV could suppress EMT and reduce chemotherapy-resistant by inducing miR-134 expression which significantly down-regulated the CREB1 signaling in colorectal cancer cell Line SW-480 (Ye et al., 2017).

5. The protective effect of AS-IV on diabetes Diabetes is a metabolic disorder characterized by elevated blood glucose. Insulin can uptake glucose by the cells, when the body does not make sufficient insulin or does not use insulin well, glucose will stay in the blood (Zhu, Zheng, Chen, Gu, & Huang, 2016). Without treatment, the high level of glucose can damage the eyes, kidneys, heart, gastric mucosa, and can also lead to coma and death (Chen et al., 2008; Ding et al., 2014; Ju et al., 2019; Liu et al., 2017; Mai, Li, Yin, & Li, 2015; Wang, Siu, &

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Zhang, 2017). Accumulating evidence suggests that AS-IV exhibits a hypoglycemic effect in diabetic mice (Lu, Li, Guo, Chen, & Li, 2015; Lv et al., 2010) and can alleviate the above mentioned complications of diabetes through a variety of underlying molecular mechanisms (Table 1).

5.1 Pharmacological effects of AS-IV on diabetic nephropathy Diabetic nephropathy (DN) is the chronic loss of kidney function occurring in conjunction with diabetes mellitus (Song et al., 2018; Sun et al., 2016). Proteinuria (Gui, et al., 2013; Wang et al., 2015), hypertension, podocyte apoptosis (Yao et al., 2016) and increased reactive oxygen species (He et al., 2018) are pathological features of DN. Recently, several in vitro and in vivo studies indicated that AS-IV could attenuate DN through the following mechanisms:

5.1.1 AS-IV protects against kidney injury by inhibiting oxidative stress and NF-κB-mediated inflammatory pathway The findings of a recent study demonstrated that AS-IV can prevent rat kidney injury induced by iatrogenic hyperinsulinemia through inhibiting oxidative stress, IL-1β and TNF-α overproduction, repressing ERK1/2 activation, and improving TRPC6 expression (He et al., 2018). Likewise, Qi et al. found that AS-IV can ameliorate EMT induced by glycated albumin in NRK-52E cell line by regulation of the impaired redox balance (Qi, Niu, Qin, Qiao, & Gu, 2014). AS-IV attenuates DN by ameliorating oxidative stress (Chen et al., 2018; Gui et al., 2012), inhibiting NF-κB mediated inflammatory genes expression in streptozotocin (STZ)-induced diabetic rats (Gui et al., 2013) and in human mesangial cells (Sun et al., 2014).

5.1.2 AS-IV protects against kidney injury through ameliorating albuminuria Albuminuria is an important hallmark feature in the development of DN. The mechanisms in the renoprotective function of AS-IV in the pathogenesis of DN through reducing albuminuria via decreasing ER-stress (Wang et al., 2015), inhibiting NF-κB mediated inflammatory genes expression (Gui et al., 2013), and restoring the balance of Bax and Bcl-2 expression and inhibiting caspase-3 activation (Gui et al., 2012).

Table 1 Astragaloside IV prevention mechanism of diabetes complications. Diabetes Modeling complications Model class method Pharmacological effect

Diabetic nephropathy

The immortalized mouse podocyte cell

HG

Mouse podocytes HG

Molecular mechanism

Improves HG-induced α3β1 integrin ", ILK # podocyte adhesion dysfunction

Prevents HG-induced podocyte apoptosis

Bax #, Bcl-2 ", caspase-3 #

References

Chen et al. (2008)

Gui et al. (2012)

STZ

Sprague-Dawley rats

STZ

Gui et al. (2013) Inhibits NF-κB mediated TNF-α #, MCP-1 #, ICAMinflammatory genes expression 1 #, α1-chain type IV collagen #

Sprague-Dawley rats

STZ

Inhibits of endoplasmic reticulum stress-induced podocyte apoptosis

PERK #, ATF4 #, CHOP #, TRB3 #, Bcl-2 ", Bax #, eIF2α #, GRP78 #

Chen et al. (2014)

Human HG glomerular mesangial cell line

Prevents damage to human mesangial cells

ROS #, NF-κB#, Nox4 ", Akt #, Nox4 #, IκBα #

Sun et al. (2014)

The rat proximal glycated tubular epithelial albumin cell line NRK52E

Induces NRK-52E cell line SOD #, NADPH oxidase #, Qi, Niu, Qin, Qiao, EMT through oxidative stress E-cadherin ", α-smooth muscle and Gu (2014) actin #

Sprague-Dawley rats

STZ

Attenuates proteinuria

Human podocytes

TM

Mouse podocytes HG

GRP78 #, ORP150 #, caspase- Wang et al. (2015) 3 #, eIF2α #, PERK #, JNK #

Continued

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Sprague-Dawley rats

Table 1 Astragaloside IV prevention mechanism of diabetes complications.—cont’d Diabetes Modeling complications Model class method Pharmacological effect Molecular mechanism

References

STZ

Decreases blood glucose levels Integrin β1 ", ILK #, α-actinin- Lu, Li, Guo, Chen, 4# and Li (2015)

Sprague-Dawley rats

STZ

Inhibits oxidative stress

TRPC6 ", IL-1β #, TNF-α, Erk1/2 #

He et al. (2018)

Mouse podocytes HG

Prevents HG-induced podocyte apoptosis

Bax #, NFAT2 #, TRPC6 #, intracellular Ca2+#

Yao et al. (2016)

db/db mice

STZ

Reduces albuminuria

Akt/mTOR #, NF-κB #, Erk1/2 #

Sun et al. (2016)

db/db mice

STZ

Modulates the mitochondrial

Drp-1 #, Fis-1 #, MFF #, PINK1/Parkin-mediated mitophagy #

Liu et al. (2017)

C57BL/6J mice

STZ, HG Inhibits podocyte apoptosis and ER-stress

SERCA2b ", AMPKα ", Angiotensinogen #,mTOR #

Guo et al. (2017)

Proximal renal palmitic tubular epithelial acid cells

Alleviates PA-induced apoptosis of HK-2 cells

Bax #, cleaved-caspase3 #, Nrf2 ", Bcl-2 "

Chen et al. (2018)

C57BL/6J mice

Reduces albuminuria and serum creatinine levels, ameliorates mesangial matrix expansion and greater foot process width

ERK1/E2 #, MEK1/2 #, RSK2 #, NAG #, NGAL #, TGF-β1#

Song et al. (2018)

STZ

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Sprague-Dawley rats

Sprague-Dawley rats

STZ

Attenuates albuminuria and decreases podocyte apoptosis

TRAF5 #, lncRNA -TUG1 "

mouse podocytes HG (MPC5)

Diabetic gastropathy

Sprague-Dawley rats

STZ

Suppresses podocyte apoptosis MIR-378 ", TRAF5 #

Sprague-Dawley rats

HFD, STZ

Inhibits ER-stress-induced renal tubular epithelial cells apoptosis

GRP78 #, p-PERK #, ATF4 #, Ju et al. (2019) CHOP #, caspase-3 #, Bax/Bcl2#

db/db mice

STZ

Improves the amplitude in pattern ERG and reduces the apoptosis of RGCs

AR #, ERK1/2 #, NF-κB#

Sprague-Dawley rats RCECs

HG

Antioxidative function

Nox4 #, SOD ", GSH ", GSH- Qiao, Fan, and peroxidase ", CAT " Tang (2017)

Sprague-Dawley rats

STZ

Antioxidative function

iNOS #, COX-2 #, mucin1 "

Wang, Siu, and Zhang (2017)

HG

Inhibits proliferation and promotes apoptosis in HG-induced rat vascular smooth muscle cells

α-smooth muscle actin ", ΔΨm #

Yuan et al. (2008)

Diabetes Vascular smooth vascular muscle cell complications

Lei, Zhang, Li, and Ren (2018) and Lei, Zhang, Ren, and Luo (2018)

Ding et al. (2014)

Continued

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Diabetic retinopathy

Lei, Zhang, Li, and Ren (2018) and Lei, Zhang, Ren, and Luo (2018)

Table 1 Astragaloside IV prevention mechanism of diabetes complications.—cont’d Diabetes Modeling complications Model class method Pharmacological effect Molecular mechanism

Diabetes Human umbilical STZ vascular vein endothelial complications cells

References

Inhibits H2O2-induced human Transforming growth factor-β Mai, Li, Yin, and Li umbilical vein endothelial cell 1 #, Nox4 #, Smad2 #, Bax #, (2015) apoptosis Caspase-3 #, Bcl-2 " Promotes cell proliferation, reduces cell apoptosis

TNF-α #, IL-1β#, JNK #, You et al. (2019) Bax #, cytochrome c #, cleavedcaspase-9 #, cleaved-caspase3 #, Bcl-2 "

Type 2 diabetic

C57BL/6J mice

Decreases the blood glucose, TG and insulin levels

Glycogen phosphorylase #, G6Pase #

Diabetes

The mouse Palmitate Facilitates glucose transport myoblast cell line C2C12

STZ, HFD

Lv et al. (2010)

Insulin-stimulated translocation Zhu, Zheng, Chen, of GLUT4 ", TLR4 #, IKK #, Gu, and Huang IκBα #, NF-κB #, MCP-1 #, (2016) IL-6 #, TNF-α #

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Human umbilical HG vein endothelial cell

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5.1.3 AS-IV protects against kidney injury through attenuating podocytes apoptosis Podocytes apoptosis has been considered a key factor contributing to the development of diabetic nephropathy and albuminuria. It is welldocumented that AS-IV suppresses podocytes apoptosis through different underlying molecular mechanisms, such as modulating TRAF5 expression through enhancing the expression of miR-378 (Lei, Zhang, Ren, & Luo, 2018) and regulating TUG1 (Lei, Zhang, Li, & Ren, 2018), down-regulating TRPC6 (He et al., 2018; Yao et al., 2016), inhibiting endoplasmic reticulum stress and oxidative stress (Chen et al., 2014; Gui et al., 2012; Guo et al., 2017) and improving HG-induced podocyte adhesion dysfunction by α3β1 integrin up-regulation and ILK inhibition (Chen et al., 2008).

5.2 Pharmacological effects of AS-IV on vascular complications Vascular complications are a main cause of morbidity and mortality in diabetic patients. AS-IV prevents human umbilical vein endothelial cell apoptosis by inhibiting Nox4 expression through the Nox4/Smad2 pathway (H2O2-induced cell apoptosis) (Mai et al., 2015) and suppressing the JNK pathway (HG-induced cell apoptosis) (You et al., 2019). Yuan et al., also found that AS-IV protects VSMC against HG-induced cell proliferation by promoting apoptosis and regulating phenotypic modulation of VSMC (Yuan et al., 2008).

5.3 Pharmacological effects of AS-IV on diabetic retinopathy Diabetic retinopathy, one of the most common microvascular complications of diabetes, is considered to be the major cause of blindness in adults (Ding et al., 2014). Administration of AS-IV significantly down-regulates AR activity, depresses the activation of ERK1/2 phosphorylation and NF-kB, and reduces the apoptosis of RGCs in db/db mice with DR (Ding et al., 2014). Qiao et al. found that AS-IV exerts protective effects in HG-injured RCECs by its anti-oxidative function (Qiao, Fan, & Tang, 2017).

6. The latest research progress of AS-IV As an important active compound from Chinese herbal medicine, AS-IV has been used for therapeutic purposes in cardiovascular disease in China (Wang et al., 2018). Previous studies have demonstrated that AS-IV possesses cardioprotective action through antioxidant, anti-inflammatory and anti-apoptosis

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effects (Li et al., 2017; Zheng et al., 2018). Abdominal aortic aneurysm (AAA), characterized by macrophage infiltration-mediated inflammation and oxidative stress, is a potentially life-threatening cardiovascular disease. Recent research noted that the protective action of AS-IV against 3,4-Benzopyrene-induced abdominal aortic aneurysm is due to the abrogation of oxidative stress and the improvement of phosphorylation of PI3K/AKT. These results indicated that AS-IV provides potential interference in the formation of AAA (Wang, Zhou, et al., 2018). Based on literature research, it appears that most pharmacological studies of AS-IV concentrated on the individual compounds. Compound medicine is one of the main features of traditional Chinese medicine (Sun & Sun, 2010). Recent studies have shown that AS-IV, as one of the key active components of A. membranaceus, has promising efficacy in combination with other compounds in many cells or animal disease models (Chu et al., 2017; Wang et al., 2013). For cerebral ischemia injury, studies demonstrated that AS-IV combined with Ginsenoside Rg1, Ginsenoside Rb1, and Notoginsenoside R1 (the active ingredients of Panax notoginseng) could enhance the protective effects on cerebral ischemia injury by antiinflammation and anti-apoptosis (Huang et al., 2015). Meanwhile, Chu et al. noted that combined administration of paeoniflorin and AS-IV could relieve ischemic brain edema through depression of connexin43 expression via activation of JNK and ERK pathways (Chu et al., 2017). Similarly, compared with the control group, combined administration of AS-IV and atorvastatin significantly inhibited the development of atherosclerotic lesions via the NF-kB/PPARg pathway (Sun, Rui, Pan, Zhang, & Wang, 2018). Endothelium dysfunction is considered to be a crucial factor in the development of vascular disease in diabetes mellitus. Recent experimentation indicated that AS-IV combined with ferulic acid protects against vascular endothelial dysfunction in diabetic rats, related to NF-κB pathway involving down-regulation of Ox-LDL, up-regulation of NO and eNOS, and activation of NF-κB P65, MCP-1 and TNF-α (Yin, Qi, Song, Zhang, & Teng, 2014). Moreover, combined administration of AS-IV and ferulic acid has significant effects on synergistic promotion of blood vessel regeneration from electrospun fibrous scaffolds (Wang et al., 2013).

7. Pharmacokinetics and toxicity of AS-IV The bioavailability of AS-IV after p.o. administration is only 7.4% in beagle dogs and 3.66% in rats (Zhang, Zhu, Chen, & Du, 2007), such low

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absolute bioavailability will restrict its application in oral administration. Meanwhile, Huang et al. found that the low absorption in Caco-2 cells mainly due to its poor intestinal permeability, high molecular weight, low lipophilicity and its paracellular transport (Huang et al., 2006). Following i.v. injection of AS-IV (1.5 mg/kg), AS-IV can be detected in the selected tissues, including skin, adipose tissue, heart, muscle, duodenum, brain, kidney, lung, spleen, liver, stomach and ovary in rats (Zhang et al., 2006). After i.v. administration, the highest concentration of AS-IV is observed in liver, lung and kidney (Chang et al., 2012; Zhang et al., 2006). AS-IV have linear pharmacokinetic characteristics in both rats and dogs. The rate of AS-IV combining with plasma protein is about 83–90% (Zhang et al., 2006, 2007). AS-IV can be slowly eliminated by hepatic clearance (0.004 l/kg/min) (Zhang et al., 2006). In order to ensure the clinical safety of AS-IV, its preclinical toxicity was conducted. Zhu et al. found that AS-IV has maternal toxic after intravenous administration (1.0 mg/kg) in rats and fetal toxicity at a dose higher than 0.5 mg/kg, while it is devoid of teratogenic effects in rats and rabbits (Zhu et al., 2009). The research of further reproductive toxicity test in Sprague-Dawley rats showed that AS-IV causes the delay for fur development, eye opening, and cliff parry reflex of pups after maternal under 1.0 mg/kg AS-IV exposure for 4 weeks, while no influence over the memory and learning of F1 pups (Wan et al., 2010). Based on these findings, AS-IV should be used with caution to women during peripartum.

8. Conclusion Over the last few decades, an increasing number of literatures have provided abundant evidence that AS-IV, as one of the important chemical extracted from A. membranaceus, exerts various pharmacological effects on neuroprotection, liver protection, anti-cancer and anti-diabetes, which are mainly due to its antioxidant, anti-inflammatory, anti-apoptotic properties, and the roles of enhancement of immunity, attenuation of the migration and invasion of cancer cell and improvement of chemosensitivity to chemotherapy drugs. Numerous studies have shown that the multi-level, multi-target pharmacological effects of AS-IV are in line with the complex pathogenesis of diseases, and may be a potential candidate clinical drug for the treatment of diseases and disease-related complications. There are still many problems in the development and utilization of AS-IV as a new clinical drug:

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(1) Direct target and specific molecular mechanism of AS-IV in the treatment of diseases is still uncertain. As part of the research process of AS-IV for treatment of diseases, bioinformatics methods should be introduced to predict the target of drugs or to verify the interaction between drugs and targets in vitro and in vivo to determine the targets of AS-IV for treatment of specific disease. (2) Combining AS-IV with other agents may be an effective to treat diseases. In the theory of Chinese medicine, Astragali Radix, known as the “ten medicine and eight Astragali Radix,” is a commonly used as a “bu Qi” Chinese herbal medicine, emphasizing the importance of AS-IV combinations. The combination of astragaloside IV with other active ingredients of traditional Chinese medicine or chemical drugs may be an effective way to achieve complementary advantages, reduce toxicity and increase efficiency. (3) AS-IV, as an important bioactive chemicals derived from A. membranaceus has poor clinical application due to its low watersoluble and oral bioavailability. It is a feasible and effective method to develop new water-soluble derivatives of AS-IV. LS-102, a novel water-soluble derivative of AS-IV, showed a pharmacokinetic profile different from AS-IV with higher bioavailability. No acute toxicity effect was detected in mice treated with LS-102 even at the high dose of 5000 mg/kg body weight (Qing et al., 2019). Thus, it is reasonable to speculate that LS-102 might provide better clinical efficacy and be a potential candidate for the new drug (Sun et al., 2019). (4) At present, few studies have been done on the toxicity and the potential adverse effects of AS-IV in vivo and in vitro. For more safe clinical application, research on toxicity and side effects of AS-IV should be given attention. Cycloastragenol (CAG), the main metabolite of AS-IV, can inhibit the UGT1A8 and UGT2B7 activity in vivo (Ran et al., 2016). This result indicates that an in vivo herb–drug interaction between AST/CAG and drugs mainly undergoing UGT1A8- or UGT2B7-catalyzed metabolism might occur.

Acknowledgments The Applied Basic Research of Shanxi Province (No. 201601D202058), 2016 Provincial Support National Research Foundation of Shanxi Province (No. 226546001), Key laboratory of Effective Substances Research and Utilization in TCM of Shanxi province (201605D111004).

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Conflict of interest The authors report no conflicts of interest.

References An, H. T., Wei, D. F., Qian, Y. J., Li, N., & Wang, X. M. (2018). SQYZ granules, a traditional Chinese herbal, attenuate cognitive deficits in AD transgenic mice by modulating on multiple pathogenesis processes. American Journal of Translational Research, 10(11), 3857–3875. Auyeung, K. K., Han, Q. B., & Ko, J. K. (2016). Astragalus membranaceus: A review of its protection against inflammation and gastrointestinal cancers. The American Journal of Chinese Medicine, 44(1), 1–22. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68, 394–424. Cai, T. T., Zhang, C. Z., Zhao, Z. M., Li, S. Y., Cai, H. B., & Chen, X. D. (2018). The gastric mucosal protective effects of astragaloside IV in mnng-induced GPL rats. Biomedicine & Pharmacotherapy, 104, 291–299. Chang, Y. X., Sun, Y. G., Li, J., Zhang, Q. H., Guo, X. R., Zhang, B. L., et al. (2012). The experimental study of Astragalus membranaceus on meridian tropsim: The distribution study of astragaloside IV in rat tissues. Journal of Chromatography B, 911, 71–75. Chen, Y. F., Gui, D. K., Chen, J. G., He, D. Y., Luo, Y. L., & Wang, N. S. (2014). Downregulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats. Cellular Physiology and Biochemistry, 33(6), 1975–1987. Chen, J. G., Gui, D. K., Chen, Y. F., Mou, L. J., Liu, Y., & Huang, J. H. (2008). Astragaloside IV improves high glucose-induced podocyte adhesion dysfunction via α3β1 integrin upregulation and integrin-linked kinase inhibition. Biochemical Pharmacology, 76(6), 796–804. Chen, C. Y., Liu, N. Y., Lin, H. C., Lee, C. Y., Hung, C. C., & Chang, C. S. (2016). Synthesis and bioevaluation of novel benzodipyranone derivatives as P-glycoprotein inhibitors for multidrug resistance reversal agents. European Journal of Medicinal Chemistry, 118, 219–229. Chen, Q. Q., Su, Y., Ju, Y. H., Ma, K. K., Li, W. Z., & Li, W. P. (2018). Astragalosides IV protected the renal tubular epithelial cells from free fatty acids-induced injury by reducing oxidative stress and apoptosis. Biomedicine & Pharmacotherapy, 108, 679–686. Cheng, X. D., Gu, J. F., Zhang, M. H., Yuan, J. R., Zhao, B. J., Jiang, J., et al. (2014). Astragaloside IV inhibits migration and invasion in human lung cancer A549 cells via regulating PKC-α-ERK1/2-NF-κB pathway. International Immunopharmacology, 23, 304–313. Cheng, C. Y., Yao, C. H., Liu, B. S., Liu, C. J., Chen, G. W., & Chen, Y. S. (2006). The role of astragaloside in regeneration of the peripheral nerve system. Journal of Biomedical Materials Research Part A, 76(3), 463–469. Chu, H. I., Huang, C. Y., Gao, Z. D., Dong, J., Tang, Y. P., & Dong, Q. (2017). Reduction of ischemic brain edema by combined use of paeoniflorin and astragaloside IV via downregulating connexin 43. Phytotherapy Research, 31(9), 1410–1418. Costa, I. M., Lima, F. O. V., Fernandes, L. C. B., Norrara, B., Neta, F. I., Alves, R. D., et al. (2018). Astragaloside IV supplementation promotes a neuroprotective effect in experimental models of neurological disorders: A systematic review. Current Neuropharmacology, 16, 1–18.

ARTICLE IN PRESS 20

Jianqin Zhang et al.

Ding, Y. Z., Yuan, S. T., Liu, X. Y., Mao, P. A., Zhao, C., Huang, Q., et al. (2014). Protective effects of astragaloside IV on db/db mice with diabetic retinopathy. PLoS One, 9(11) e112207. Du, Q., Zhang, S. H., Li, A. Y., Mohammad, I. S., Liu, B. L., & Li, Y. W. (2017). Astragaloside IV inhibits adipose lipolysis and reduces hepatic glucose production via Akt dependent PDE3B expression in HFD-fed mice. Frontiers in Physiology, 9, 15. Gu, D. M., Lu, P. H., Zhang, K., Wang, X., Sun, M., Chen, G. Q., et al. (2015). EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages. Biochemical and Biophysical Research Communications, 457, 391–397. Gui, D. K., Guo, Y. P., Wang, F., Liu, W., Chen, J. G., Chen, Y. F., et al. (2012). Astragaloside IV, a novel antioxidant, prevents glucose-induced podocyte apoptosis in vitro and in vivo. PLoS One, 7(6) e39824. Gui, D. K., Huang, J. H., Guo, Y. P., Chen, J. G., Chen, Y. F., & Xiao, W. Z. (2013). Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression. Cytokine, 61(2013), 970–977. Guo, H. J., Wang, Y., Zhang, X. M., Zang, Y. J., Zhang, Y., Wang, L., et al. (2017). Astragaloside IV protects against podocyte injury via SERCA2-dependent ER stress reduction and AMPKα-regulated autophagy induction in streptozotocin-induced diabetic nephropathy. Scientific Reports, 7(1), 6852. Han, L., Li, J., Lin, X., Ma, Y. F., & Huang, Y. F. (2014). Protective effect of astragaloside IV on oxidative damages of chang liver cell induced by ethanol and H2O2. China Journal of Chinese Materia Medica, 39(22), 4430–4435, [in Chinese]. Hanash, S. (2003). Disease proteomics. Nature, 422, 226–232. He, K. Q., Li, W. Z., Chai, X. Q., Yin, Y. Y., Jiang, Y., & Li, W. P. (2018). Astragaloside IV prevents kidney injury caused by iatrogenic hyperinsulinemia in a streptozotocininduced diabetic rat model. International Journal of Molecular Medicine, 41(2), 1078–1088. He, C. S., Liu, Y. C., Xu, Z. P., Dai, P. C., Chen, X. W., & Jin, D. H. (2016). Astragaloside IV enhances cisplatin chemosensitivity in non-small cell lung cancer cells through inhibition of B7-H3. Cellular Physiology and Biochemistry, 40, 1221–1229. Huang, X. P., Ding, H., Lu, J. D., Tang, Y. H., Deng, B. X., & Deng, C. Q. (2015). Effects of the combination of the main active components of Astragalus and Panax notoginseng on inflammation and apoptosis of nerve cell after cerebral ischemia-reperfusion. The American Journal of Chinese Medicine, 43(7), 1–20. Huang, C. R., Wang, G. J., Wu, X. L., Li, H., Xie, H. T., LV, H., et al. (2006). Absorption enhancement study of astragaloside IV based on its transport mechanism in caco-2 cells. European Journal of Drug Metabolism and Pharmacokinetics, 31(1), 5–10. Ju, Y. H., Su, Y., Chen, Q. Q., Ma, K. K., Ji, T. J., Wang, Z. Y., et al. (2019). Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. Biomedicine & Pharmacotherapy, 109, 84–92. Lei, X., Zhang, L. M., Li, Z. L., & Ren, J. G. (2018). Astragaloside IV/lncRNA-TUG1/ TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats. Drug Design, Development and Therapy, 12, 2785–2793. Lei, X., Zhang, B. d., Ren, J. G., & Luo, F. L. (2018). Astragaloside suppresses apoptosis of the podocytes in rats with diabetic nephropathy via miR-378/TRAF5 signaling pathway. Life Sciences, 206, 77–83. Li, T., Chen, S., Feng, T., Dong, J., Li, Y., & Li, H. (2016). Rutin protects against agingrelated metabolic dysfunction. Food & Function, 7(2), 1147–1154. Li, X. Z., Ding, Y. Z., Wu, H. F., Bian, Z. P., Xu, J. D., Gu, C. R., et al. (2017). Astragaloside IV prevents cardiac remodeling in the apolipoprotein E-deficient mice

ARTICLE IN PRESS Review on the pharmacological effects of astragaloside IV

21

by regulating cardiac homeostasis and oxidative stress. Cellular Physiology and Biochemistry, 44, 2422–2438. Li, L., Hou, X. J., Xu, R. F., Liu, C., & Tu, M. (2017). Research review on the pharmacological effects of astragaloside IV. Fundamental and Clinical Pharmacology, 31, 17–36. Li, Y. L., Ye, Y., & Chen, H. Y. (2018). Astragaloside IV inhibits cell migration and viability of hepatocellular carcinoma cells via suppressing long noncoding RNA ATB. Biomedicine & Pharmacotherapy, 99(2018), 134–141. Liu, D. L., Bao, H. Y., & Liu, Y. (2014). Progress on chemical constituents and pharmacological effects of Astragali Radix in recent five years. Food and Drug, 16, 68–70, [in Chinese]. Liu, X. H., Wang, W. J., Song, G. F., Wei, X., Zeng, Y. J., Han, P. X., et al. (2017). Astragaloside IV ameliorates diabetic nephropathy by modulating the mitochondrial quality control network. PLoS One, 12(8) e0182558. Lu, W. S., Li, S., Guo, W. W., Chen, L. L., & Li, Y. S. (2015). Effects of Astragaloside IV on diabetic nephropathy in rats. Genetics and Molecular Research, 14(2), 5427–5434. Lv, L., Wu, S. Y., Wang, G. F., Zhang, J. J., Pang, J. X., Liu, Z. Q., et al. (2010). Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Phytotherapy Research, 24(2), 219–224. Mai, Y. h., Li, W. Z., Yin, Y. Y., & Li, W. P. (2015). AST IV inhibits H2O2-induced human umbilical vein endothelial cell apoptosis by suppressing Nox4 expression through the TGF-β1/Smad2 pathway. International Journal of Molecular Medicine, 35, 1667–1674. Qi, W. W., Niu, J. Y., Qin, Q. J., Qiao, Z. D., & Gu, Y. (2014). Astragaloside IV attenuates glycated albumin-induced epithelial-to-mesenchymal transition by inhibiting oxidative stress in renal proximal tubular cells. Cell Stress & Chaperones, 19(1), 105–114. Qiao, Y., Fan, C. L., & Tang, M. K. (2017). Astragaloside IV protects rat retinal capillary endothelial cells against high glucose-induced oxidative injury. Drug Design, Development and Therapy, 11, 3567–3577. Qin, C. G., Ma, D. N., Ren, Z. G., Zhu, X. D., Wang, C. H., Wang, Y. C., et al. (2017). Astragaloside IV inhibits metastasis in hepatoma cells through the suppression of epithelial-mesenchymal transition via the Akt/GSK-3β/β-catenin pathway. Oncology Reports, 37, 1725–1735. Qing, L. S., Chen, T. B., Sun, W. X., Chen, L., Luo, P., Zhang, Z. F., et al. (2019). Pharmacokinetics comparison, intestinal absorption and acute toxicity assessment of a novel water-soluble astragaloside IV derivative (astragalosidic acid, LS-102). European Journal of Drug Metabolism and Pharmacokinetics, 44(2), 251–259. Ran, R. X., Zhang, C. Z., Li, R. S., Chen, B. W., Zhang, W. H., Zhao, Z. Y., et al. (2016). Evaluation and comparison of the inhibition effect of astragaloside IV and aglycone cycloastragenol on various UDP-glucuronosyl transferase (UGT) isoforms. Molecules, 21, 1616. Ren, S., Zhang, H., Mu, Y. P., Sun, M. Y., & Liu, P. (2013). Pharmacological effects of Astragaloside IV: A literature review. Journal of Traditional Chinese Medicine, 33(3), 413–416. Shen, Y., & Meiri, K. (2013). GAP-43 dependency defines distinct effects of netrin-1 on cortical and spinal neurite outgrowth and directional guidance. International Journal of Developmental Neuroscience, 31(1), 11–20. Shi, G. B., Fan, R., Zhang, W., Yang, C., Wang, Q., Song, J., et al. (2015). Antinociceptive activity of astragaloside IV in the animal model of chronic constriction injury. Behavioural Pharmacology, 26(5), 436–446. Song, G. F., Han, P. X., Sun, H. L., Shao, M. M., Yu, X. W., Wang, W. J., et al. (2018). Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice. Journal of International Medical Research, 46(7), 2883–2897.

ARTICLE IN PRESS 22

Jianqin Zhang et al.

State Pharmacopoeia Commission. (2015). Pharmacopoeia of the People’s Republic of China (1st ed.) (p. 301). . Beijing: Chemical Industry Press. in Chinese. Sun, L., Li, W. P., Li, W. Z., Xiong, L., Li, G. P., & Ma, R. (2014). Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/ Akt/N-κB pathway under high glucose conditions. International Journal of Molecular Medicine, 34(1), 167–176. Sun, B., Rui, R. P., Pan, H. Y., Zhang, L. C., & Wang, X. L. (2018). Effect of combined use of astragaloside IV (AsIV) and atorvastatin (AV) on expression of PPAR-g and inflammation-associated cytokines in atherosclerosis rats. Medical Science Monitor, 24, 6229–6236. Sun, X. Y., & Sun, F. Y. (2010). Shen Nong Ben Cao Jing. Taiyuan: Shanxi Science and Technology Press, pp. 112–113. in Chinese. Sun, H. L., Wang, W. J., Han, P. X., Shao, M. M., Song, G. F., Du, H., et al. (2016). Astragaloside IV ameliorates renal injury in db/db mice. Scientific Reports, 6, 32545. Sun, W. X., Zhang, Z. F., Xie, J., He, Y., Cheng, Y., Ding, L. S., et al. (2019). Determination of a astragaloside IV derivative LS-102 in plasma by ultra-performance liquid chromatography-tandem mass spectrometry in dog plasma and its application in a pharmacokinetic study. Phytomedicine, 53, 243–251. Wan, X. Y., Zhu, J. B., Zhu, Y. P., Ma, X. L., Zheng, Y. W., Zhang, T. B., et al. (2010). Effect of astragaloside IV on the general and peripartum reproductive toxicity in Sprague-Dawley rats. International Journal of Toxicology, 29, 505–516. Wang, C. Y., Li, Y., Hao, M. J., & Li, W. M. (2018). Astragaloside IV inhibits triglyceride accumulation in insulin-resistant HepG2 cells via AMPK-induced SREBP-1c phosphorylation. Frontiers in Physiology, 9, 345. Wang, S. G., Li, J. Y., Huang, H., Gao, W., Zhuang, C. l., Li, B., et al. (2009). Anti-hepatitis B virus activities of astragaloside IV isolated from radix astragali. Biological and Pharmaceutical Bulletin, 32(1), 132–135. Wang, P. P., Luan, J. J., Xu, W. K., Wang, L., Xu, D. J., Yang, C. Y., et al. (2017). Astragaloside IV downregulates the expression of MDR1 in Bel-7402/FU human hepatic cancer cells by inhibiting the JNK/c-Jun/AP-1 signaling pathway. Molecular Medicine Reports, 16, 2761–2766. Wang, S. X., Mou, J. G., Cui, L. S., Wang, X. G., & Zhang, Z. Q. (2018). Astragaloside IV inhibits cell proliferation of colorectal cancer cell lines through down-regulation of B7-H3. Biomedicine & Pharmacotherapy, 102, 1037–1044. Wang, N. D., Siu, F., & Zhang, Y. B. (2017). Effect of astragaloside IV on diabetic gastric mucosa in vivo and in vitro. American Journal of Translational Research, 9(11), 4902–4913. Wang, Z. S., Xiong, F., Xie, X. H., Chen, D., Pan, J. H., & Cheng, L. (2015). Astragaloside IV attenuates proteinuria in streptozotocin-induced diabetic nephropathy via the inhibition of endoplasmic reticulum stress. BMC Nephrology, 16, 44. Wang, H., Zhang, Y., Xia, T., Wei, W., Chen, F., Guo, X. Q., et al. (2013). Synergistic promotion of blood vessel regeneration by astragaloside IV and ferulic acid from electrospun fibrous mats. Molecular Pharmaceutics, 10, 2394–2403. Wang, J. N., Zhou, Y. Y., Wu, S. Z., Huang, K. Y., Thapa, S., Tao, L. Y., et al. (2018). Astragaloside IV attenuated 3,4-benzopyrene-induced abdominal aortic aneurysm by ameliorating macrophage-mediated inflammation. Frontiers in Pharmacology, 9, 496. Wei, R. D., Liu, H., Chen, R., Sheng, Y. J., & Liu, T. (2019). Astragaloside IV combating liver cirrhosis through the PI3K/Akt/mTOR signaling pathway. Experimental and Therapeutic Medicine, 17, 393–397. Xie, T., Li, Y., Li, S. L., & Luo, H. F. (2016). Astragaloside IV enhances cisplatin chemosensitivity in human colorectal cancer via regulating NOTCH3. Oncology Research, 24, 447–453.

ARTICLE IN PRESS Review on the pharmacological effects of astragaloside IV

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Yao, X. M., Liu, Y. J., Wang, Y. M., Wang, H., Zhu, B. B., Liang, Y. P., et al. (2016). Astragaloside IV prevents high glucose-induced podocyte apoptosis via downregulation of TRPC6. Molecular Medicine Reports, 13(6), 5149–5156. Ye, Q., Su, L., Chen, D. G., Zheng, W. Y., & Liu, Y. (2017). Astragaloside IV induced miR134 expression reduces EMT and increases chemotherapeutic sensitivity by suppressing CREB1 signaling in colorectal cancer cell line SW-480. Cellular Physiology and Biochemistry, 43, 1617–1626. Yin, Y. H., Qi, F. H., Song, Z. H., Zhang, B., & Teng, J. L. (2014). Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats. Bioscience Trends, 8(4), 217–226. Yoon, H., & Kim, N. (2015). Diagnosis and management of high risk group for gastric cancer. Gut and Liver, 9(1), 5–17. You, L. Z., Fang, Z. H., Shen, G. M., Wang, Q., He, Y., Ye, S., et al. (2019). Astragaloside IV prevents high glucos-induced cell apoptosis and inflammatory reactions through inhibition of the JNK pathway in human umbilical vein endothelial cells. Molecular Medicine Reports, 19(3), 1603–1612. Yuan, W., Zhang, Y., Ge, Y. K., Yan, M., Kuang, R., & Zheng, X. X. (2008). Astragaloside IV inhibits proliferation and promotes apoptosis in rat vascular smooth muscle cells under high glucose concentration in vitro. Planta Medica, 74(10), 1259–1264. Yue, R. C., Li, X., Chen, B. Y., Zhao, J., He, W. W., Yuan, H., et al. (2015). Astragaloside IV attenuates glutamate-induced neurotoxicity in PC12 cells through Raf-MEK-ERK pathway. PLoS One, 10(5), e0126603. Zhang, C. Z., Cai, T. T., Zeng, X. H., Cai, D. K., Chen, Y. X., Huang, X. J., et al. (2018). Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway. Phytotherapy Research, 32, 1364–1372. Zhang, X. H., & Chen, J. J. (2013). The mechanism of astragaloside IV promoting sciatic nerve regeneration. Neural Regeneration Research, 8(24), 2256–2265. Zhang, X. Z., Chen, J., Xu, P., & Tian, X. (2018). Protective effects of astragaloside IV against hypoxic pulmonary hypertension. Medicinal Chemistry Communications, 9, 1715. Zhang, Z. G., Wu, L., Wang, J. L., Yang, J. D., Zhang, J., Zhang, J., et al. (2012). Astragaloside IV prevents MPP +-induced SH-SY5Y cell death via the inhibition of Bax-mediated pathways and ROS production. Molecular and Cellular Biochemistry, 364, 209–216. Zhang, W. D., Zhang, C., Liu, R. H., Li, H. L., Zhang, J. T., Mao, C., et al. (2006). Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sciences, 79, 808–815. Zhang, A. l., Zheng, Y. H., Que, Z. J., Zhang, L. L., Lin, S. C., Le, V., et al. (2014). Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO. Journal of Cancer Research and Clinical Oncology, 140(11), 1883–1890. Zhang, Q., Zhu, L. L., Chen, G. G., & Du, Y. U. (2007). Pharmacokinetics of stragaloside iv in beagle dogs. European Journal of Drug Metabolism and Pharmacokinetics, 32(2), 75–79. Zheng, Q., Zhu, J. Z., Bao, X. Y., Zhu, P. C., Tong, Q., Huang, Y. Y., et al. (2018). A preclinical systematic review and meta-analysis of astragaloside IV for myocardial ischemia/reperfusion injury. Frontiers in Physiology, 9, 795. Zhou, M. Q., Zhuo, L. Y., & Cai, C. (2018). Astragaloside IV inhibits cigarette smokeinduced pulmonary inflammation in mice. Inflammation, 41(5), 1671–1680. Zhu, S. Q., Qi, L., Rui, Y. F., Li, R. X., He, X. P., & Xie, Z. P. (2008). Astragaloside IV inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons. Acta Pharmacologica Sinica, 29(1), 57–64.

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Zhu, J. B., Wan, X. Y., Zhu, Y. P., Ma, X. L., Zheng, Y. W., & Zhang, T. B. (2009). Effect of astragaloside IV on the embryo-fetal development of Sprague-Dawley rats and New Zealand White rabbits. Journal of Applied Toxicology, 29, 381–385. Zhu, J. H., & Wen, K. (2018). Astragaloside IV inhibits TGF-β1-induced epithelial mesenchymal transition through inhibition of the PI3K/Akt/NF-κB pathway in gastric cancer cells. Phytotherapy Research, 2018, 1–8. Zhu, R. F., Zheng, J. J., Chen, L. H., Gu, B., & Huang, S. G. (2016). Astragaloside IV facilitates glucose transport in C2C12 myotubes through the IRS1/AKT pathway and suppresses the palmitate-induced activation of the IKK/IκBα pathway. Internatonal Journal of Molecular Medicine, 37(6), 1697–1705.

Further reading Cheng, M. X., Chen, Z. Z., Cai, Y. L., Liu, C. A., & Tu, B. (2011). Astragaloside IV protects against ischemia reperfusion in a murine model of orthotopic liver transplantation. Transplantation Proceedings, 43, 1456–1461. Li, L., Huang, W. X., Wang, S. K., Sun, K. C., Zhang, W. X., Ding, Y. M., et al. (2018). Astragaloside IV attenuates acetaminophen-induced liver injuries in mice by activating the Nrf2 signaling pathway. Molecules, 23, 2032.