Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2018, Article ID 8259280, 17 pages https://doi.org/10.1155/2018/8259280

Review Article Hydroxysafflor Yellow A: A Promising Therapeutic Agent for a Broad Spectrum of Diseases

Hui Ao ,1,2 Wuwen Feng ,1 and Cheng Peng 1

1 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China 2Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

Correspondence should be addressed to Cheng Peng; [email protected]

Received 9 May 2018; Accepted 12 August 2018; Published 25 September 2018

Academic Editor: Ching-Liang Hsieh

Copyright © 2018 Hui Ao et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hydroxysafor yellow A (HSYA)is one of the major bioactive and water-soluble compounds isolated from Carthami Flos, the fower of safower (Carthamus tinctorius L.). As a natural pigment with favorable medical use, HSYA has gained extensive attention due to broad and efective pharmacological activities since frst isolation in 1993. In clinic, the safor yellow injection which mainly contains about 80% HSYA was approved by the China State Food and Drug Administration and used to treat cardiac diseases such as angina pectoris. In basic pharmacology, HSYA has been proved to exhibit a broad spectrum of biological efects that include, but not limited to, cardiovascular efect, neuroprotection, liver and lung protection, antitumor activity, metabolism regulation, and endothelium cell protection. Although a great number of studies have been carried out to prove the pharmacological efects and corresponding mechanisms of HYSA, a systemic review of HYSA has not yet been seen. Here, we provide a comprehensive summarization of the pharmacological efects of HYSA. Together with special attention to mechanisms of actions, this review can serve as the basis for further researches and developments of this medicinal compound.

1. Instruction (a) Carthamus tinctorius L. (Safower). (b) Carthami Flos (the dried fower of Carthamus tinctorius L.). (c) Hydrox- Carthamus tinctorius L. (Figure 1(a)), also named safower, ysafor yellow A (the main efective compound of Carthami belongstothegenusCarthamusfamilyCompositae.As Flos). Hydroxysafor yellow A (HYSA, Figure 1(c)) is a water- a multipurpose cash crop in agriculture, industry, and soluble compound mainly responsible for the medicinal medicine, it is cultivated for its seeds, meals, and fowers. In activities of Carthami Flos. It was frstly separated from terms of medical use, safower is widely applied in East Asia Carthamus tinctorius L. by Meselhy et al.in1993[2]and especially in China [1]. is regarded as one of the standard components for quality Carthami Flos (Figure 1(b)), also named Honghua in control of Carthami Flos according to the Chinese Pharma- China, is the dried foret of safower and known as a blood copoeia, because of its rich abundance and strong activities stasis promoting herb. Golden Chamber Synopsis (Jin Gui [3]. In 2005, the Safor yellow injection which contained 45 Yao Nue)¨ by Zhang Zhongjing in the Han Danasty deemed mg HSYA per 50 mg was approved as a novel cardiovascular the decoction of Carthami Flos as an efective remedy for drug by China State Food and Drug Administration and gynaecological problems. Carthami Flos was frstly intro- began to be widely used for treatment of cardiac diseases such duced as a medicinal herb in Annotation of Materia Medica as angina pectoris. Te systematic evaluations demonstrated (Xin Xiu Ben Cao) of the Tang Dynasty for the treatment of that this injection was signifcantly efective for both angina lockjaw, hemonode, and postpartum illness. Since then, the pectoris and cerebral infarction [4, 5]. Apart from the efect extracts of Carthami Flos have been extensively applied to on cardiovascular disorders, HYSA showed neuroprotection, treat several diseases such as cardiovascular and cerebrovas- anticancer properties, and metabolism regulation as well as cular disorders caused by blood stasis. liver, lung, and endothelium cell protection. In this review, 2 Evidence-Based Complementary and Alternative Medicine

(a) (b) OH

OH OOHO OH

OH

OH HO O OH HO O

OH HO

OH (c)

Figure 1: Hydroxysafor yellow A (HYSA) and its sources.

we managed to give a comprehensive review and analysis blood viscosity ex vivo [6, 7]. It could also prolong prothrom- of the pharmacological properties of HYSA, supporting the bin time (PT) of rat plasma and recalcifcation time (RT) of potential application of HYSA in clinic. rabbit plasma in vitro [8].

2.1.2. Efect on Myocardial Ischemia. As an antiangina drug, 2. Pharmacology the cardiac protection of HYSA has been observed in vivo and 2.1. Cardiovascular Efects. In clinic, products containing in vitro. HSYA could reverse the haemodynamic alteration, HYSA are mostly used for treatment of cardiovascular enhance the survival rate, alleviate the myocardial damage, diseases. Te therapeutic efect of HYSA on cardiovascular andpromotetheangiogenesisintheischemicmyocardium diseases is related to its anticoagulant efect, antimyocardial by enhancing expression of nucleolin and thus upregulat- ischemia activity, vasorelaxative efect, etc. ing expressions of vascular endothelial growth factor A (VEGF-A) and matrix metallopeptidase 9 (MMP-9) in the myocardial ischemia (MI) rats induced by occlusion of lef 2.1.1. Anticoagulant Efect. Te anticoagulant action of HYSA anterior descending coronary artery (LAD) [9]. In addi- was investigated mainly in vitro.HYSAcouldelicitsuppres- tion, HYSA could also lower the levels of cardiac troponin � sive efects on thrombosis formation in the normal rats and I (cTnI) and 8-hydroxy-2 -deoxyguanosine (8-OHdG) in rabbit platelet aggregation induced by adenosine diphosphate theMImiceinducedbyLAD[10].In vitro,HYSAcould (ADP) and platelet activating factor (PAF) as well as rabbit relieve the nuclear morphological changes and levels of Evidence-Based Complementary and Alternative Medicine 3

malondialdehyde(MDA)andreactiveoxygenspecies(ROS), of lef ventricular pressure (-dp/d�max)intheisolatedrat 2+ lower the activities of creatine kinase-MB (CK-MB) and heart [18]. Mechanistically, large conductance Ca -activated + lactate dehydrogenase (LDH), and increase mitochondrial K channel (BKCa) and ATP-sensitive potassium channel membrane potential (MMP) and expressions of peroxisome (KATP ) was responsible for the efects of HYSA on blood proliferator-activated receptor gamma coactivator-1� (PGC- pressure and cardiac function [18]. Te test in vitro showed 1�) and nuclear factor erythroid 2-related factor 2 (Nrf2) in that HSYA could enhance the reduced diastolic response H9C2 cells sufered from oxygen-glucose deprivation (OGD) induced by acetylcholine (Ach) and sodium nitroprusside [11]. (SNP) and attenuate the vascular contractile efect of PE in Inhibition of mitochondrial permeability transition pore the aorta ring isolated from the model [19]. In rat thoracic (MPTP) opening can protect heart from ischemia/reper- aorta rings, HSYA inhibited PE-induced endothelium- fusion (I/R) injury. Te protective efect of HSYA on the independent vasoactive response via inhibiting inositol 1,4,5- myocardial ischemia/reperfusion (MI/R) rats and the ven- triphosphate (IP3) receptor in VSMCs and thus reducing 2+ 2+ tricular myocytes isolated from those animals could be extracellular Ca infux and intracellular Ca release attenuated by a MPTP opener called atractyloside and a [20]. restrainer of nitric oxide synthase (NOS) named L-NAME Vascular adventitia proliferation and hyperplasia are of [12]. Meanwhile, in the isolated cardiac myocytes stimulated great importance for hypertension occurrence. HSYA has a by anoxia/reoxygenation or ionomycin, HYSA increased rod suppressive efect on rat adventitial fbroblasts proliferation shapecellsintheclosedMPTPconditionanddecreased and collagen synthesis stimulated by angiotensin II (Ang II) round cells with open MPTP [13]. Another two targets of in vitro. It also inhibited the elevated expressions of matrix HYSA against MI or MI/R damage are hemeoxygenase-1 metallopeptidase-1 (MMP-1), TGF-�1, �-smooth muscle (HO-1) and hemeoxygenase-2 (HO-2). HSYA was able to actin (�-SMA), and NF-�B p65 in this model [21]. HYSA promote neovascularization and cardiac function recovery inhibited proliferation and dediferentiation of aorta vascular in vivo and in vitro by acting through the HO-1/VEGF- smooth muscle cells (VSMCs) exposed to platelet-derived A/stromal cell derived factor-1 (SDF-1�)cascade[14].In growth factor- (PDGF-) BB into a proliferative phenotype, hypoxia/reperfusion- (H/R-) induced H9C2 cells, HYSA which might be associated with its inhibition of nitrous oxide exhibited antiapoptotic and antioxidative efects by mediating (NO) and cyclic guanosine monophosphate (cGMP) produc- the protein kinase B (Akt)/Nrf2/HO-1 signaling pathway [10, tion, Akt signaling activation, and cycle related proteins as 15]. Jia et al. [16] also reported that HSYA could signifcantly well as its elevation of HO-1 in VSMCs [22]. At the same increase HO-2 expression, adenosine triphosphate (ATP) time, HYSA could suppress proliferation and migration of level, and Mn-superoxide dismutase (SOD) activity and VSMCs induced by LPS and downregulate levels of TNF-� restrain cytochrome c (cyto c) release and MDA level in H9C2 and interleukin-6 (IL-6) as well as interleukin-8 (IL-8) via the cells sufered from H/R, and this cardioprotective property TLR-4/ ras-related C3 botulinum toxin substrate 1 (Rac1)/Akt of HSYA was mainly mediated via the phosphoinositide pathway [23]. 3-kinase (PI3K)/Akt/HO-2 pathway independent of extra- HSYA could also act on pulmonary artery. It dose- cellular regulated protein kinases (ERK)/glycogen synthase dependently blocked the progression of pulmonary artery kinase-3� (GSK-3�)pathway. remodeling, decreased the cell count in the small pulmonary Te toll-like receptor 4 (TLR4) signaling pathway may bronchioles, attenuated right ventricular hypertrophy, and alsotakepartintheprotectiveefectofHSYA.Administration reduced mean right ventricular systolic pressure (mRVSP) in of HSYA inhibited the elevated expression of TLR4 as well the pulmonary arterial hypertension (PAH) rats induced by as the increased indexes including infarct size, CK-MB, and hypoxic [24]. In addition, HSYA exerted a vasorelaxing efect LDH activity caused by MI/R. Further evidence was that on phenylephrine- (PE-) stimulated vascular constrictive HYSA failed to lessen MI/R damage in the TLR4-knockout action in rat pulmonary artery (PA) rings in a concentration- mice. Additionally, in neonatal rat ventricular myocytes dependent manner via Kv activation of pulmonary artery (NRVMs) subjected to H/R and lipopolysaccharide (LPS), smooth muscle cells (PASMCs) [25]. Further study demon- HSYA increased cell viability and downregulated excessive strated that HYSA could reduce pulmonary arterial hyper- tumor necrosis factor � (TNF-�)andinterleukin-1� (IL-1�) tension via increasing SOD activity and decreasing levels of and overexpressions of TLR4 and nuclear factor-kappa B MDA and 8-hydroxydeoxyguanosine (8-OHdG) and mRNA (NF-�B) [17]. of IL-1�,IL-6,andTNF-� [26].

2.1.3. Antihypertension Efect. Hydroxysafor yellow A 2.1.4.EfectonCardiacHypertrophy. In the overload-induced ofered the potential for reducing blood pressure. Te mean cardiac hypertrophy rats, HSYA exhibited signifcantly ame- arterial pressure (mAP) and HR (heart rates) in both of the liorative efect on lef ventricular mass index (LVMI) induced normotensive rats and the spontaneously hypertensive rats by the ligation of abdominal aorta, as a consequence of the (SHR) could be markedly reduced by HSYA [18]. Further alleviation of pathological lesion, including smaller cardiac study disclosed that HSYA could downregulate the levels muscle fbers and lightly stained cardiomyocytes nuclei of lef ventricular systolic pressure (LVSP), lef ventricular [27]. Additionally, HSYA treatment inhibited cell apopto- end-diastolic pressure (LVEDP), and the maximum rate of sis by upregulating Bcl-2/Bax ratio and decreasing matrix increase of lef ventricular pressure (+dp/d�max)aswellas metallopeptidase-2 (MMP-2) and MMP-9 levels in serum HR but had little efect on the maximum rate of decrease [27]. 4 Evidence-Based Complementary and Alternative Medicine

2.2. Neuroprotective Efects. HYSA ofered the therapeutic expression earlier, resulting in later appearance of neuronal potential for being natural sources on brain diseases includ- apoptosis. Te later study showed that the TLR4 pathway ing cerebral ischemia, dementia, Parkinson’s disease (PD), played a role in the protective efect of HYSA [42]. More- and traumatic brain injury (TBI). Previous studies in vivo over, in cerebral ischemia, release of excessive glutamate and in vitro provided further support and evidence for the always leads to N-methyl-D-aspartate receptors (NMDARs) neurological use of HYSA. overactivation and excitotoxic neuron injury. Without any efect on the expressions of NR2B-containing NMDARs, 2.2.1. Efect on Cerebral Ischemia. HYSA is considered as a HSYA protected rat cortical neurons subjected to N-methyl- protective agent against cerebral ischemia, which is now a d-aspartate (NMDA) from cell apoptosis via decreasing Bax hot research topic of modern medicine. Boring the similar expression, increasing Bcl-2 expression and downregulat- potency to nimodipine, HSYA was found to exert signifcant ing expressions of NR2B-containing NMDARs instead of neuroprotective efects on the permanent middle cerebral NR2A-containing NMDARs [43]. Wang et al. further eluci- artery occlusion (MCAO) induced focal cerebral ischemic dated that HSYA concentration-dependently inhibited exci- rats as expressed by the reduced neurological defcit scores, tatory postsynaptic currents (EPSCs) mediated by NMDARs infarct area, edema extend, and cell apoptosis [28–30]. Te and increased P2/P1 ratio (PPR) of both NMDAR EPSCs anticerebral ischemic efect of HYSA might result from its and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid suppression of platelet aggregation, thrombin generation, receptor (AMPAR) EPSCs resulting in suppressing release cerebrovascular contraction, cerebrovascular permeability, of presynaptic transmitter in the mouse hippocampus CA1 and thrombin-mediated infammation as well as promo- region, with a mechanism that HSYA inhibited the membrane tion of prostacyclin (PGI2)/thromboxane (TXA2) ratio and depolarization current magnitude induced by NMDARs and hemorheology. HYSA could also decrease Ang II, resulting ischemic long-term-potentiation (LTP) stimulated by OGD in NF-�B p65 nuclear translation, p65 binding activity, ele- [44]. Moreover, the NMDA-mediated and NMDAR-induced 2+ vation of ICAM-1 mRNA and protein levels, and neutrophils intracellular Ca infux, the NMDAR-induced cell apoptosis infltration [6, 31, 32]. andnecroticcelldeath,andtheNMDA-inducedmitochon- Te neuroprotective actions of HSYA in vivo resulted drial injury were inhibited by HYSA in hippocampal neurons from several reasons. Chen et al. reported that HSYA critically [44]. decreased the apoptosis cell number and increased the Bcl- Notably,mitochondriaarealsolikelytobeinvolvedinthe 2/Baxproportioninthepenumbralcortexofratssubjected underlying mechanism. In the cortex mitochondria of rats, to the transient MCAO for 2 h and followed by 24 h HYSA ameliorated the damage induced by cerebral ischemia � 2+ reperfusion by the PI3K/Akt/GSK-3 pathway [33]. Also, by inhibiting overloaded Ca and scavenge capability of free HSYA treatment could cause an increase in the level of brain- radicals, increasing the membrane fuidity and the activities derived neurotrophic factor (BDNF) in the MCAO mice of respiratory enzymes and decreasing the edema degree and due to inhibiting the TLR4 signaling pathway [34]. A study the membrane phospholipid decomposability [45]. However, by Qi et al. [35] revealed that this efect could be blocked this protective efect would be attenuated by inhibition of the by an Akt inhibitor. Te further study indicated that the opening of MPTP [46]. And the in vitro study found out promotion of HSYA on Akt-autophagy pathway occurred in 2+ that Ca -andH2O2-stimulated swelling of mitochondria neuronal-specifc cells of penumbra tissue. Additionally, it isolated from rat brains was inhibited by HYSA. Meanwhile, was found that HYSA inhibited NF-�Bpathwayandrestored 2+ HYSA reduced Ca overload-induced ROS generation, themetabolismpathwaysintheMCAOrats[36]. improved mitochondrial energy metabolism, and increased Blood-brain barrier (BBB), the main shield between ATP level and the respiratory control ratio [47]. cerebral capillaries and brain parenchyma for delivering ther- apeutic compounds into the brain, shows close relationship with brain ischemic damage. HYSA could penetrate across 2.2.2. Efect on Dementia. Recent fndings have discovered BBB, downregulate expressions of 12/15-lipoxygenase (12/15- the antidementia property of HYSA and provided a founda- LOX) and its metabolite, and trigger decrease of BBB perme- tion for its clinical use in both of vascular dementia (VD) ability and improvement of tight junction in the MCAO mice and Alzheimer's disease (AD). HSYA could improve spatial via attenuating of occludin, claudin-5, and ZO-1 expressions learning and memory in the rat model of VD via upregulating as well as regulating the tight junction pathway [37–39]. the expressions of VEGF-A, N-methyl-D-aspartic acid recep- In vitro, HYSA inhibited neurons injury stimulated by tor 1 (NR1), BDNF, and NMDAR in the hippocampal, which glutamate, sodium cyanide (NaCN), and OGD by preventing enhanced LTP and increased synaptic plasticity consequently cell death and LDH release in cultured rat fetal cortical [48, 49]. HSYA could signifcantly reverse cognitive impair- cells[28,29].Additionally,HSYAalleviatedtyrosinenitration ment induced by homocysteine (Hcy) in rats, and this was induced by authentic peroxynitrite in bovine serum albumin related to attenuation of A�40 and A�42 levels in hippocampus and primary cortical neurons [40]. Te further study showed partially via suppressing PS1 protein level, rescuing apoptosis, HSYA protected PC12 cells from OGD-induced apoptosis and increasing LTP in the AD model [50]. Zhang et al. � followed by reperfusion through suppressing intracellular implied that the protective efect of HYSA on the A 1-42- oxidative stress and mitochondrial-mediated pathway [41]. induced AD mice could be explained by inhibition of infam- In the LPS-activated coexistence system for microglia and mation via enhancing the phosphorylation of JAK2/STAT3 neurons, HYSA activated microglia by suppressing TLR4 pathway [51, 52]. HYSA also displayed a protective efect from Evidence-Based Complementary and Alternative Medicine 5

� neurotoxicity induced by A 25-35 in rat pheochromocytoma and preventing release of proinfammatory molecules with (PC12) cells by increasing cell viability, stabilizing mitochon- inhibition of NF-�B[57]. drial function, and inhibiting oxidative stress characterized by reduced levels of lactate LDH, intracellular ROS and MDA, 2.3. Hepatoprotective Efects. Te hepatoprotective activities and neuronal apoptosis [53]. of HYSA have attracted the attention from the researchers. Recent evidences support HYSA as an antifbrotic agent in 2.2.3. Efect on Parkinson’s Disease. HYSA is also a poten- hepatic disorders. tial candidate drug for PD, a long-term degenerative dis- order. Tis agent had a neuroprotective role in the 6- 2.3.1. Efect on Hepatic Fibrosis. Te hepatoprotective efects hydroxydopamine- (6-OHDA-) induced PD rats. It could of HYSA are especially related to its antifbrotic and antiox- also increase the levels of dopamine and its metabolites, idative actions. In respect of antihepatic fbrosis assay in glial cell line-derived neurotrophic factor (GDNF) and brain- vivo, HSYA treatment could not only reduce the serum levels derived neurotrophic factor (BDNF) in striatum of PD of alanine aminotransferase (ALT), aspartate transaminase rats [58]. Meanwhile, HSYA could efectively relieve motor (AST), hyaluronan (HA), laminin (LN), and type III procolla- dysfunction of the PD mice model induced by rotenone gen (PC III) as well as the hepatic levels of ROS and MDA but and protect dopamine neurons by elevating TH-containing alsoelevatetheactivityandmRNAofSOD,glutathioneper- dopaminergic neurons and dopamine content in the stria- oxidase (GPx), and expression of TGF-�1inlivertissueofthe tum in the PD mice. It was suggested that BDNF/tyrosine long-term alcohol-injured rats [62]. Te histological studies kinase receptor type B (TrkB)/dopamine receptor 3 (DRD3) suggested the alcohol induced liver damage such as hepatic signaling pathway was responsible for the pharmacological fbrogenesis which could be greatly alleviated by HYSA [62]. efect of HSYA [59]. Additionally, afer coadministration of Also, HYSA could decrease levels of total cholesterol (TC), HSYA with L-DOPA, the 6-OHDA-induced PD rat model triglyceride (TG), and mRNA expressions of transforming exerted the attenuated dyskinesia, the prolonged motor growth factor � receptor I (TGF�-R I), transforming growth response duration, and the downregulated expression of factor � receptor (TGF�-R II), mitogen-activated protein dopamine D receptor in the striatum, compared with the (MAP), ERK, MAP/ERK kinase kinase 3 (MEKK3), and PD rats administrated by L-DOPA only [60]. Besides, it was MAP kinase kinase-5 (MEK5) as well as phosphorylation of demonstrated that HSYA improved cell viability, reduced ERK5 in the tetrachloride- (CCl4-) induced hepatic fbrosis cell apoptosis, and increased levels of SOD and glutathione rats [63, 64]. Te precise mechanism of the hepatoprotec- (GSH), the ratio of Bcl-2/Bax, and mRNA levels of neuron- tive property was that HSYA strengthened expressions of specifc enolase (NSE) and microtubule-associated protein- peroxisome proliferator-activated receptor-� (PPAR�)and 2 (MAP-2), providing a mechanism of HYSA protecting the MMP-2, downregulated expressions of TGF-�1 and TIMP- diferentiation of mesenchymal stem cells (MSCs) against �- 1, and reduced �-SMA level by stimulating PPAR� activity mercaptoethanol (BME) causes oxidation [61]. [65]. Meanwhile, the ameliorative efects of HYSA on the CCl4/ high fat diet- (HFD-) stimulated liver fbrosis rats were signifcantly alleviated by the PPAR� inhibitor, which was a 2.2.4. Efect on Traumatic Brain Injury. Te activities of SOD result of blocking p38 MAPK phosphorylation [66]. Hepatic andcatalase(CAT),thelevelofGSH,andtheGSH/oxidized stellate cells (HSCs) appear to be vital in the development of glutathione (GSSG) ratio were enhanced while the levels liver fbrosis [67]. Te testing in vitro suggested proliferation of MDA and GSSG were reduced in the brain of the TBI of HSCs stimulated by H2O2 was inhibited by HSYA because rats afer HSYA treatment [54]. Another report confrmed of HSYA’s blockage of the cell cycle from G0/G1 to G1/S [65]. that HYSA increased activities of mitochondrial ATPase and Moreover, in HSCs, HYSA also inhibited cell proliferation tissue plasminogen activator (t-PA) and decreased plasma and induced cell apoptosis in a dose- and time-dependent plasminogen activator inhibitor-1 (PAI-1) activity and MMP- fashion accompanying with decreasing expressions of type I 9 expression in the hippocampus of the TBI rats [55]. alpha collagen (Col I �), �-SMA and type III alpha collagen (Col III �), Bcl-2, and myocyte enhancer factor 2C (MEF2C) 2.2.5. Efect on Other Nervous System Diseases. HSYA treat- and increasing expressions of cyto c, Caspase-9, and Caspase- ment markedly alleviated lymphostatic encephalopathy- (LE- 3, which resulted from the activation of the extracellular ) induced brain injury in rats by dramatically decreasing regulated protein kinases (ERK5) pathway as well as the the neurological scores, attenuating histological changes extracellular regulated protein kinases 1/2 (ERK1/2) pathway especially cell apoptosis in the rostral ventrolateral medulla [68, 69]. (RVLM) and reducing heart rate variability. Additionally, downregulation of endothelial nitric oxide synthase (eNOS) 2.3.2. Efect on Hepatic Ischemia. HSYA reduced serum expression in both of mRNA and protein levels of the RVLM ASTandALTlevelsandexpressionsofTNF-� and IL- in LE rats were prevented by HYSA [56]. In the spinal 1�, ameliorated infammation and necrosis, and blocked cord compression injury rats, HSYA treatment signifcantly macrophage recruitments in the I/R mice. Similarly, in vitro, attenuated spinal cord edema and improved motor function pretreatment of HYSA resulted in the weakened migratory outcomes in rats, and the potential mechanism of this reaction and the reduced infammatory cytokines in the H/R- action was through ameliorating extent of oxidative stress challenged RAW264.7. Te further study showed that HSYA 6 Evidence-Based Complementary and Alternative Medicine had suppressive efect on expressions of MMP-9 and ROS, injection of LPS to the mice resulted in upregulation of NF-�B activation, and p38 phosphorylation in the injured protein expressions of TLR4, myeloid diferentiation factor 88 RAW264.7 cells [70]. (MyD88) and Toll/IL-1 receptor- (TIR-) domain-containing adapter-inducing interferon-� (TRIF) and phosphorylation of MAPKs, translocation of NF-�B/p65, and downregulation 2.4. Pulmonary Protective Efect. Te various researches � � exhibited remarkable pulmonary protective properties of of I B- , all of which could be deteriorated by HSYA [77]. HYSA in vivo and in vitro,especiallyabouttheinhibitory Zhang et al. observedthenegativeinfuenceofHSYAon efectonchronicobstructivepulmonarydisease(COPD), the binding of LPS to the cell membrane receptor in the acute lung injury (ALI), and lung fbrosis. LPS-caused ARDS mice model [78]. And injection of HYSA alleviated the mRNA and protein levels of Col I, type III collagen (Col III), �-SMA, myeloid diferentiation-2 (MD-2), 2.4.1. Efect on Airway Infammation. HSYA treatment could and cluster of diferentiation 14 (CD14) as well as infamma- attenuate the airway hyperresponsiveness (AHR) cell chemo- toryfactorsinplasmaorlungandthecollagendeposition taxis, proinfammatory cytokines, type 2 helper T cell 2 (T2) in lung via suppressing the TLR4/NF-�Bpathway.Tein cytokines, total and ovalbumin- (OVA-) specifc IgE and vivo test demonstrated the inhibitory efect of HYSA on the adhesion molecules in bronchoalveolar lavage fuid (BALF), specifc binding of LPS to receptors on A549 or Eahy926 cell and infammatory responses levels in the lung tissue of the membranes, suggesting the TLR4 receptor a target of HSYA OVA-induced asthmatic mice. Study suggested that HSYA on the cell membrane [78]. treatment inhibited the transcriptional activity of NF-�B by inhibiting NF-�B p65 nuclear translocation and nuclear factor of I�B-�phosphorylation and degradation [71]. Wang 2.4.3. Efect on Lung Fibrosis. Injection of HYSA attenu- et al. reported that HSYAmarkedly suppressed the thickening ated the pathologic changes of pulmonary infammation, and collagen deposition of the small airway and weakened increased the body weight, PaO2 and decreased PaCO2, TGF-�1 mRNA and protein expression as well as type I mRNA expressions of TNF-�,IL-1�,TGF-�1, and IL-6, MDA collagen (Col I) and �-SMA expressions in the lung of the activity, and the count of NF-�B p65 positive cells in the COPD model in the rats stimulated by cigarette smoke BLM-injured acute infammation rats. Tis protective efect and LPS. In addition, HSYA elicited inhibitory efect on of HYSA might be due to inhibition of NF-�Bactivationand phosphorylation of p38 mitogen-activated protein kinase p38MAPKphosphorylationinlungtissue[79,80].Moreover, (MAPK) in the rat lung tissue [72]. 21 days of HSYA to the BLM-induced chronic pulmonary fbrosis rats resulted in fbrosis amelioration by decreasing collagen deposition, and mRNA expression of TGF-�1, �- 2.4.2. Efect on Acute Lung Injury. HSYA could alleviate SMA and Col I connective tissue growth factor (CTGF) as pulmonary edema, reduce acidosis, increase partial pressure well as �-SMA level [80, 81]. of oxygen (PaO2), and inhibit infammatory cell infltra- Assayed with human alveolar epithelial A549 cells, HYSA tion, lung mRNA expressions of TNF-� and ICAM-1, and was found to inhibit Smad3 phosphorylation and Col I levels of plasma IL-6 and IL-1� [73]. HSYA signifcantly mRNA expression stimulated by TGF-�1[81].AndHSYA increased the activities of antioxidant enzymes, inhibited exhibited inhibitory efects on LPS-induced infammatory the infammatory response via the cAMP/PKA pathway response in A549 cells by suppressing myeloid diferentiation activation, and attenuated OA-induced lung injury [74]. factor 88 (MyD88), TLR-4, TNF-�, ICAM-1, IL-1�,andIL- Additionally, HSYA decreased lung permeability, platelet 6 at the mRNA and protein expression levels and leuko- count,andADP-mediatedplateletaggregationaswellas cytesadhesiontoA549cells.Temechanismwasdueto cytokine levels in serum and BALF in the aged rats with its negative regulation of NF-�Bp65nucleartranslocation gasoline engine-induced lung injury. Moreover, it suppressed and p38 MAPK phosphorylation [82]. Meanwhile, TGF-�1- overexpressions of ICAM-1, vascular cell adhesion molecule- induced alteration in proliferation, migration, extracellular 1 (VCAM-1), and proinfammatory cytokines in platelets matrix (ECM) accumulation, and degradation of human fetal andlungtissue.AnddecreaseincAMPlevelinlungand lung fbroblasts MRC-5 were inhibited by HYSA. Further platelets and PKA activity and PPAR� expression in platelets study disclosed that HSYA blocked the binding of TGF-�1 induced by gasoline engine exhaust were also reversed by to the cytoplasmic receptors of TGF-�1-stimulated MRC- HYSA [75]. Meanwhile, in the sepsis-associated ALI mice, 5includingTGF�-R II and suppressed the lung patholog- the infammatory infltration and proinfammatory cytokine ical alteration and �-SMA, Col I�1,andFNexpressions expressions in lung, pneumochysis, and respiratory insuf- as well as phosphorylation of mothers against decapenta- fciency induced by LPS were greatly relieved by HYSA plegic homolog 2 (Smad2), mothers against decapentaplegic treatment. Its suppression of p38MAPK phosphorylation as homolog 3 (Smad3) and ERK, nuclear translocation of Smad2 well as NF-�B activation was responsible for this protective and Smad3, and the binding of Smad3 to Col I promoter efect [76]. Also, HSYA ameliorated the pathological state [83, 84]. and lung vascular permeability of the LPS-induced ALI in mice. Tis efect was accompanied with the negative efect on pulmonary myeloperoxidase (MPO) activity and levels 2.5. Antitumor Efects. Several reports have provided strong of serum TNF-�,IL-1�,IL-6,andinterferon-� (IFN-�). evidences that HYSA is valuable for oncotherapy. HYSA Te further investigation demonstrated that intraperitoneal was considered as a natural compound which could inhibit Evidence-Based Complementary and Alternative Medicine 7 multistage carcinogenesis processes such as progression, formation and N-acetyl-glycyl-lysine methyl Ester (G.K.) adhesion, invasion, and migration. In HYSA-treated MCF- peptide-mediated ribose glycation. Also, HSYA could defend 7cells,Liet al. [85] observed increased cell apoptosis and against MGO-induced damage in cultured human brain ROS level, upregulated expressions of Bax and p53, blocked microvascular endothelial cells (HBMEC) by increasing cell cell cycle, downregulated Bcl-2 and cyclin D1, released cyto viability and decreasing cell mortality. It suppressed cell c, activated Caspase-3, and disrupted MPP with the mech- apoptosis and Caspase-3 expression in HBMEC and inhibited anism of its negative regulation on the NF-�B/p65 nuclear AGEs accumulation in HBMEC afer treated with MGO [97]. translocation. Also, HSYA, acting as a PPAR� agonist, showed inhibitory efect on proliferation and cell cycle transition and 2.7. Endothelium Cell Protection. In vivo,HSYAefectively stimulatory efect on cell apoptosis in BGC-823 cells [86]. recovered perfusion of ischemic hindlimb tissue and gave As for abnormally proliferated HUVECs cultured in HepG2 a rise of the arteriole and capillary densities in the femoral cell cultural supernatant, HSYA suppressed the expressions artery-interrupted ischemic gastrocnemius muscles of the of vascular endothelial growth factor (VEGF) and its kinase mice [98]. Ox-LDL-caused endothelial injury could be insert domain receptor (KDR) through the Ras-Raf-MEK- relieved by HSYA dose-dependently. Proteomic investiga- ERK1/2 signaling pathway and dephosphorylated the corre- tion revealed that this efect was related to the antiapop- sponding kinase molecules [87]. Moreover, HYSA exerted totic activity of voltage dependent anion-selective channel inhibitoryefectoncancercellgrowthoftumor-bearingmice. 2 (VDAC2) [99]. Moreover, HSYA promoted the viability Tisefectwasassociatedwithitsdownregulationofangio- of LPS-injured HUVEC. It also inhibited the subsequent genesis. Xi et al. [88] proved that it reduced the microvessel infammation induced by LPS in HUVEC including NF-�B count and microvessel density of the transplanted tumors p65 subunit DNA binding, I�B� phosphorylation, ICAM-1, in the BGC-823 cell bearing mice while Yang et al.[89] and E-selectin mRNA levels elevation and phosphorylation reportedthisdrughadtheadvantageofdecreasingVEGF- of p38 MAPK or c-Jun N-terminal kinase (JNK) MAPK, cell A, basic fbroblast growth factor (bFGF), vascular endothelial surface ICAM-1 protein expression, and leukocyte adhesion growth factor receptor 1 (VEGFR1), and mRNA expression to HUVEC [100]. Meanwhile, HYSA elicited a protective levels of cyclin D1, c-myc, and c-fos in the BGC-823 tumor- efect on HUVECs from hypoxia by attenuating cell apoptosis bearing mice through suppressing the ERK/MAPK and and cell cycle arrest, which was the result of the upregulation the NF-�B pathway. Additionally, along with the ability of of the Bcl-2/Bax ratio and the hypoxia inducible factor-1�- inhibiting the process of SMMC-7721 covering proliferation, (HIF-1�-) VEGF pathway as well as NO contend and eNOS adhesion, invasion, and migration, HYSA could suppress expression and downregulation of p53 protein expression pulmonary metastasis of liver cancer. In the pulmonary [101]. However, with little efect on the normal HUVEC, metastatic mouse model of H22 cells, the formation of a HSYA caused an increase of the capillary-like tube formation complex with E-cadherin/�-catenin induced by HYSA could and migration of HUVEC, which could be reversed by an activate the expression of PPAR� andinhibittheactivity anti-Tie-2 neutralizing antibody. Expression of angiopoietin of MMP-2, fnally leading to decrease in degradation of 1 and phosphorylation of Tie2, Akt, and ERK 1/2 were greatly ECM and suppression of epithelial-mesenchymal transition elevated by HSYA [102]. (EMT) [90]. In addition, HSYA could reversibly and non- competitively inhibit of human recombinant aldehyde dehy- drogenase 1 (ALDH1) (Ki = 0.267 ± 0.024 mM) indicating 2.8. Other Efects. As an anti-infammatory molecule, HYSA it as a potential agent for treating ALDH1-associated cancers could inhibit LPS-induced NLRP3 infammasome activa- [91]. tion via binding to Xanthine Oxidase in mouse RAW264.7 macrophages [103]. HSYA-mediated sonodynamic therapy 2.6. Metabolic Regulation Efect. Te quantity of pread- could induce ROS-dependent autophagic response via the ipocytes, adipocytes diferentiation, and lipid accumulation PI3K/Akt/mTOR signaling pathway in THP-1 macrophages play a key role in lipid metabolism [92]. HSYA signifcantly [104]. Besides, HSYA inhibited rabbit polymorphonuclear time- and dose-dependently prohibited the proliferation of (PMN) activation induced by LPS by reducing LPS-induced 3T3-L1 cells. Tis efect was accompanied by a decline in the elevated adhesion potency, free calcium concentration, TNF- amount of intracellular lipid and triglyceride (TG) and a rise � and IL-6 mRNA expression, and NF-�Bp65nuclear in mRNA expression of hormone-sensitive lipase (HSL) and translocation [105]. Also, HYSA exhibited anti-infammatory promoter activities [93]. HSYA competitively inhibited �- efect as evidenced by inhibiting the IL-1�-induced release glucosidase in a reversible way with IC50 =1.1± 0.22 mM and of IL-6, IL-8, and MMP-1 in SW982 human synovial cell, Ki=1.04 ± 0.23mM, respectively. HSYA-induced structural and this was associated with suppression of ERK, NF-�B, change of �-glucosidase was mainly regional unfolding [94]. and activator protein-1 (AP-1) signaling [106]. And HSYA Advanced glycation end products (AGEs) and methylglyoxal could reduce strike-triggered local oedema and neutrophil (MGO) accumulation usually appear in individuals with infltration in skeletal muscle via inhibiting p38 MAPK diabetes and cause the occurrence of vascular complica- phosphorylation and suppressing NF-�B pathway activation tion [95]. Ni et al. [96] demonstrated that MGO-induced [107].Itwasalsoanefectivetherapeuticagentinameliorating bovine serum albumin (BSA) glycation could be inhibited sepsis-induced apoptosis of cluster of diferentiation 4+ by HYSA. Besides, HSYA showed signifcantly inhibitory (CD4+) T lymphocytes through its anti-infammatory and efect on glucose- (GLU-) induced development of AGEs antiapoptotic efects [108]. 8 Evidence-Based Complementary and Alternative Medicine [7] [8] [9] [6] [6] [6] [11] [11] [13] [13] [17] [17] [12] [12] [14] [14] [10] [16] Ref. [10, 15] and � t, enhancing the p/ d and expressions of TLR4 and � − d tand and Nrf2. p/ d � and reducing apoptotic signals, TGF- and IL-1 � � and Nrf2. � Inhibiting platelet aggregation induced by ADP and PAF and decreasing blood viscosity. Reducing CK-MB, ROS, cTnI and 8-OHdG expression, and increasing SOD activity. Details Reversing the haemodynamic changes including + d LVSP, Inhibiting WRP aggregation and PMNs aggregation induced by PAF survival rate, increasing expressions of nucleolin and VEGF-A. ReducingCK-MB,LDH,MDA,ROSandcellapoptoticnumberandincreasingMMP,SOD activity, and expressions of PGC-1 Reducing CK-MB, LDH, MDA, ROSincreasing and MMP, SOD cell activity apoptotic and number, expressions of inhibiting PGC-1 cell apoptosis and Reducing mitochondria swelling, increasing phosphorylated eNOSdeath protein and and depolarization preventing of cell the mitochondrial membrane. Inhibiting aggregation. Inhibiting thrombosis formation. Increasing EF, FS, EPC number, VEGF-A andCol SDF-1 I. Reducing LDH, apoptosis index, Bcl-2/Bax ratio,and cleaved activity Caspase-3 of and HO-1, increasing Akt expression phosphorylationIncreasing cell and viability, Nrf2 ATP, Mn-SOD translocation. and HO-2index and and reducing Caspase-3. cyto c, MDA, LDH,Increasing apoptosis cell viability and reducing levels of TNF- Reducing cell viability and closed MPTP rods, and increasing opened MPTPIncreasing round opened cells. MPTP round cells and decreasing closed MPTPIncreasing CXCR4 rods. expression. Reducing the infarct size and the release of LDH. � B. NF- Reducing TLR4 expression, infarct size, CK-MB and LDH activity. Prolonging PT and RT. Table 1: Summary about the cardiovascular protection of HYSA. � -induced ventricular myocytes 2+ Rabbit plasma Model Platelets exposed to ADP LAD-induced MI mice Rats Blood sample from rabbits Blood sample from rabbits LAD-induced MI rats H9C2 cells subjected to OGD ISO-induced MI rats MI/R rats Ca MI mice caused by the artery coronary ligation of lef H9C2 exposed to H/R H9C2 exposed to H/R NRVMs subjected to H/R and LPS Cardiac myocytes stimulated by anoxia and reoxygenation Cardiac myocytes introduced by ionomycin EPCs stimulated by SDF-1 MI/R rats accompanied hyperlipidemia trigged by high-fat diet Efects Anti-coagulant efect Myocardial ischemia Evidence-Based Complementary and Alternative Medicine 9 [21] [18] [19] [19] Ref. [23] [25] [22] [27] [24] [24] [26] [20] � 1, in the mRNA � and HR in the max � ,IL-6andIL-8. t infux and intracellular p/ d d 2+ � ,IL-6andTNF- , and down-regulating + LVEDP, LVSP, in vivo Table 1: Continued. release. 2+ level and SOD activity and decreasing levels of MDA and 8-OHdG. Reducing mPAP, RVSP, RV/LVPS, the mean percent wallthe thickness vascular of muscularization pulmonary and arterioles increasing expressions and of IL-1 Blocking the progression of pulmonary arterypulmonary remodeling, bronchioles, attenuating decreasing right the ventricular cell hypertrophy countprotein and in decreasing expressions the mRVSP of and small PCNA and Ki67. Showing vasorelaxing efect independent of PA endothelium. Inhibiting proliferation and migration and down-regulating levels of TNF- Inhibiting proliferation and cell cycle. Inhibiting proliferation and collagen synthesis and� -SMA decreasing and expressions� Bp65. NF- of MMP-1, TGF- Reducing cell viability, cyclin D1, cyclininhibiting E, phenotype CDK2, switching CDK4, and cGMP increasing level HO-1 and expression. NO content and Reducing mAP and HR Reducing LVMI, inhibiting cell apoptosis byexpressions up-regulating of Bcl-2/Bax MMP-2 ratio and and MMP-9. decreasing Reducing systolic BP, HR, ET, ox-LDL andthoracic NO aortic and relieving endothelium. the histologicalEnhancing change the in diastolic the response inducedcontractile by efect Ach of and PE. SNP and attenuatingInhibiting the IP3 vascular receptor in VSMCs and thus reducing extracellular Ca isolated rat heart. Ca PE-induced rat PA PAH rats stimulated by MCT PASMCs under hypoxia PAH rats induced by hypoxic VSMCs induced by LPS Ang II-stimulated rat adventitial fbroblasts VSMCs exposed to PDGF-BB ModelSHR and the normotensive rats Details Overload-induced cardiac hypertrophy rats induced by the ligation ofaorta abdominal Immunized rats Aorta ring isolated from the immunized rats Rat thoracic aorta rings induced by PE Efects Artery constriction Cardiac hypertrophy 10 Evidence-Based Complementary and Alternative Medicine [6] [6] [41] Ref. [33] [35] [39] [43] [28] [45] [29] [36] [34] [42] [40] [40] [44] [44] [31, 32] [37, 38] [28–30] and NO. � ,IL-1and � /Bax proportion, 2 � ,IL-1 infux, NMDAR-induced 2+ ic cells and expressions of Bax, Caspase-3 and � B, improving glucose metabolism and and NF- - � phosphorylation in the penumbral cortex. � � ,TNF and scavenge capability of free radicals, increasing the membrane 2+ � B p65, ERK1/2, JNK and p38 and secretion of TNF- � B p65 nuclear translation, p65 binding activity, elevating ICAM-1 mRNA and and NO and increasing BDNF expression. � phosphorylation in the penumbral cortex. � � ,IL- Inhibiting NMDA-mediated and NMDAR- induced intracellular Ca Inhibiting EPCs, postsynaptic NMDAR activity andNMDAR-mediated pre-synaptic OGD-evoked glutamate membrane transmitter depolarization release, current andischemic NMDAR-dependent LTP induced by OGD. elevating levels of Akt and GSK-3 fuidity and activities of respiratory enzymesphospholipid and decomposability decreasing in edema the degree cortex and mitochondria. membrane Inhibiting overloaded Ca cell apoptosis and necrotic cell deaths, and NMDA-induced mitochondrial injury. Decreasing apoptotic cell number, increasing Bcl-2/Baxand proportion, GSK-3 and elevating levels of Akt Reducing neurological defcit scores, infarct area,Bax, edema Caspase-3, extend, ICAM-1, cell IL-1 apoptosis andincreasing expressions of expressions of GFAP, NGF and Bcl-2. Having a stronger efect on cerebrovascular vasodilatationReducing than neurological on defcit cardiovascular scores, vasodilatation.generation, suppressing NF- thrombin generation, suppressingprotein thrombin levels and neutrophils infltration and decreasing Ang II. Decreasing infarct volume, and increasing BDNFphosphorylation and of decreasing NF- TLR4 expression, Reducing infarct volume, improving neurological scores andReducing activating infarct Akt-autophagy. volume, neurological defcit scores,IL-6, inhibiting and expressions p65 of translocation TNF- and bindingthe activity, metabolism up-regulating pathways. expression of IL-10 andDecreasing restoring BBB permeability, improving tight junction,claudin-5 attenuating expressions and of ZO-1 occludin, and regulating the tight junction pathway. Details Preventing cell death and release of LDH and NO. Promoting cell viability, reducing MDA,cyto apoptot c and increasing Bcl-2 expressionSuppressing TLR4 and expression, SOD down-regulating activity. MyD88,� B, NF- JNK,of ERK1/2 TNF- and p38 and release Reducing cell apoptosis, expressions of Baxincreasing and Bcl-2 NR2B-containing expression. NMDA Decreasing receptors and apoptotic cell number, increasing BCl Alleviating tyrosine nitration. Decreasing infarct volume, BBB permeability, brainexpressions edema, of production 12/15-LOX of and carbonyl 15-HETE and andReducing elevating infarct nitrotyrosine. volume, BBB permeability, brainend edema, product expression and of 3-NT iNOS and and improving level neurological of scores. NO Decreasing infarct sizes, neurological defcit scores and cerebrovascular permeability. Table 2: Summary about the neuroprotection of HYSA. Mouse hippocampal neurons Mouse hippocampal slices MCAO rats MCAO rats MCAO rats MCAO rats Coronary artery and basilar arteryof dogs rings MCAO rats MCAO rats MCAO rats MCAO rats MCAO rats Model Rat fetal cortical cells stimulated by OGD. Preventing cell death and LDH release. Rat fetal cortical cells stimulated by glutamate and NaCN OGD-induced PC12 cells LPS-activited co-existance system for microglia and neurons RatcorticalneuronssubjectedtoNMDA Bovine serum albumin and primary cortical neurons induced by authentic peroxynitrite MCAO rats MCAO rats Efects Cerebral ischemia Evidence-Based Complementary and Alternative Medicine 11 [51] Ref. [53] [52] [52] [57] [56] [47] [50] [46] [54, 55] [48, 49] and iNOS, increasing � � , and infarct volume. � ,COX-2andiNOSandprotein � , IL-6, iNOS, COX-2, activities of � ,TNF- and PS1 protein levels, rescuing cell apoptosis and 42 � ,A 40 � and iNOS and up-regulating IL-4, IL-10 and phosphorylation Table 2: Continued. expressions of IL-4 and IL-10 andhippocampi. suppressing activation of microglia and astrocytes in the Decreasing neurological defcit score, MDA, MPO,� BNF- NO, and TNF- Caspase-3, water content inSOD spinal activity. cord and permeability in BSCB and increasing Details Reducing escape latency, prolonged time spentin in the the water platform maze, quadrant and and swimming increasingup-regulating distance LTP expressions and of fnally VEGF-A, NR1, ameliorating BDNF learningShortening and and escape NMDAR memory, in latency, reducing the the hippocampal. numberthe to target cross quadrant, the hidden attenuating platform A and time spent in Reducing contusion volume, MDA and GSSGexpression in in the the brain, hippocampus, plasma and PAI-1 increasing activitymitochondrial activities and ATPase of MMP-9 and SOD, the CAT, GSH, GSH/GSSG t-PA ratio. and Decreasing the neurological scores, cell apoptosisboth in of RVLM, mRNA up-regulating and eNOS protein expression levels in of RVLM and reducing HRV. Increasing cell viability, stabilizing mitochondrial function andMDA reducing and LDH, neuronal intracellular ROS, apoptosis. Increasing latency time on rotarod andand alteration reducing behavior neurological in defcit Y-maze, scores, levels levels of of GSH MDA and and catalase, TNF- increasing LTP. Alleviating swelling, reducing ROS generation, improvingincreasing mitochondrial ATP energy level metabolism and and the respiratory control ratio. Decreasing memory defcits and expressions of Iba-1, GFAP, IL-1, TNF- Increasing cell viability, reducing mRNA levels of IL-1 Promotingcellviabilityandinhibitingcellapoptosis. expressions of COX-2,� TNF- protein expressions of JAK2 and STAT3. -induced 2 1-42 � O 2 and H 2+ -induced PC12 cells -induced AD mice -induced BV-2 cells 1-42 1-42 25-35 A � Spinal cord compression injury rats Model VD rats by 2-VO AD rats induced by Hcy TBI rats LE-induced brain injury in rats MCAO rats A � A � BV-2 cells Mitochondria isolated from rat brains sufered from Ca Neurons and SH-SY5Y cells inhibited by conditioned meadium of A Efects Dementia TBI Other nervous system diseases 12 Evidence-Based Complementary and Alternative Medicine

Cerebral ischemia Hypercoagulative Endothelium cell state Dementia protection Neuroprotective Cardiovascular Hypertension efects PD efects TBI Cardiac hypertrophy HYSA Airway infammation Hepatic fbrosis Pulmonary Hepatoprotective Acute lung injury efects protective efect Lung fbrosis Hepatic ischemia Anti-tumor Metabolic efects regulation efect

Figure 2: Pharmacological efects of HYSA.

Endothelium cell protection VDAC2; HIF-1- VEGF; NO; eNOS; angiopoietin 1/ Tie-2

Cardiovascular efects Anti-tumor efects Nucleolin; MTMP; eNOS;    NF- B/p65; PPAR ; HO-1/VEGF-A/SDF-1 ; Ras-Raf-MEK- Akt/Nrf2/HO-1; TLR4; ERK1/2; ERK/MAPK; PI3K/Akt/HO-2; NO/cAMP; NF-B; E- Akt;TLR-4/Rac1/Akt; cadherin/-catenin BKCa; KATP and KV channels

HYSA

Neuroprotective efects Pulmonary protective efects PI3K/Akt/GSK-3; TLR4/PI3K/Akt/JNK1; NF-B; p38 MAPK;  NF- B p65; cAMP/PKA; TLR4; TR II JAK2/STAT3; JAK2/STAT3/ NF-B; BDNF/TrkB/DRD3

Hepatoprotective efects

ERK5; ERK1/2; PPAR; PPAR-/p38 MAPK

Figure 3: Action mechanism and corresponding mediators of HYSA.

HSYA had protective efect against fbrosis in renal 3. Conclusion cells, through inhibiting TGF-�1/Smad3-mediated epithelial- mesenchymal transition signaling pathway [109]. Topical use Noncommunicable diseases (NCDs), namely, heart disease, ofHSYAcouldrelievetheUV-inducedskindamageinmice stroke, cancer, diabetes, and chronic lung disease, are causing by promoting recovery from stretching, inhibiting epidermal worldwide public health problem and alarmingly leading hyperproliferationandkeepingthestructuralintegrityof causes of almost 70% deaths. Natural chemicals are favorable the skin via antioxidative activity [110]. Moreover, HSYA resources that may be utilized to develop such agents. HYSA, could strongly inhibit tyrosinase by binding and changing the a component isolated from safower with little toxicity [112], tertiary structure of tyrosinase [111]. showed various pharmacological efects in vitro and in vivo Evidence-Based Complementary and Alternative Medicine 13

(summarized in Figure 2), including cardiovascular protec- [7] B. X. Zang, M. Jin, N. Si et al., “Antagonistic efect of hydrox- tion (summarized in Table 1), neuroprotection (summarized ysafor yellow A on the platelet activating factor receptor,” Acta in Table 2), metabolism regulation, antitumor efect, and Pharmaceutica Sinica,vol.37,no.9,pp.696–699,2002. liver, lung, and EC protective activities. Tese activities [8] B. X. Zang, J. Min, and L. Jinrong, “Study on the anti-coagulant indicate the use of HYSA for prevention and/or the treatment efect of Hydroxysafor yellow A,” Chinese Traditional and of NCDs and other intractable diseases such as AD, PD, Herbal Drugs,vol.38,no.5,pp.741–743,2007. TBI, ALI, and fbrotic diseases. Although HYSA possesses [9]J.Zou,N.Wang,M.Liuetal.,“Nucleolinmediatedpro- extensive pharmacological efects, it is currently used as a angiogenic role of Hydroxysafor Yellow A in ischaemic cardiac drug mainly in treating cardiovascular and cerebrovascular dysfunction: Post-transcriptional regulation of VEGF-A and diseases. It needs to be clinically explored in other aspects MMP-9,” Journal of Cellular and Molecular Medicine,vol.22,no. 5, pp. 2692–2705, 2018. especially for respiratory, hepatic and metabolic diseases, and [10]T.Hu,G.Wei,M.Xietal.,“Synergisticcardioprotective malignancy. Recent studies focusing on various bioactivities efects of Danshensu and hydroxysafor yellow A against of HYSA have yielded promising results, demonstrating both myocardial ischemia-reperfusion injury are mediated through the pharmacological efects and the molecular mechanisms the Akt/Nrf2/HO-1 pathway,” International Journal of Molecular of HYSA (summarized in Figure 3). Further investigation of Medicine,vol.38,no.1,pp.83–94,2016. the molecular mechanisms of HYSA is anticipated to expand [11] M. Chen, M. Wang, Q. Yang et al., “Antioxidant efects of the clinical applications of HYSA. hydroxysafor yellow A and acetyl-11-keto-�-boswellic acid in combination on isoproterenol-induced myocardial injury in rats,” International Journal of Molecular Medicine,vol.37,no.6, Conflicts of Interest pp. 1501–1510, 2016. Te authors declared that there are no conficts of interest. [12] Y.-N. Liu, Z.-M. Zhou, and P.Chen, “Evidence that hydroxysaf- for yellow A protects the heart against ischaemia-reperfusion injury by inhibiting mitochondrial permeability transition pore Authors’ Contributions opening,” Clinical and Experimental Pharmacology and Physiol- ogy,vol.35,no.2,pp.211–216,2008. Hui Ao and Wuwen Feng contributed equally to this paper. [13] G. A. Huber, S. M. Priest, and T. P. Geisbuhler, “Cardio- protective efect of hydroxysafor yellow A via the cardiac permeability transition pore,” Planta Medica,vol.84,no.08,pp. Acknowledgments 507–518, 2018. Tis work was supported by funds from Sichuan Youth [14] G. Wei, Y.Yin, J. Duan et al., “Hydroxysafor yellow A promotes neovascularization and cardiac function recovery through HO- Scientifc and Technological Innovation Research Team 1/VEGF-A/SDF-1� cascade,” Biomedicine & Pharmacotherapy, (2017TD0001) and the State Key Laboratory Breeding Base vol.88,pp.409–420,2017. of Systematic Research, Development and Utilization of [15]S.X.Liu,Y.Zhang,Y.F.Wangetal.,“Upregulationofheme Chinese Medicine Resources. oxygenase-1 expression by hydroxysafor yellow A conferring protection from anoxia/reoxygenation-induced apoptosis in References H9c2 cardiomyocytes,” International Journal of Cardiology,vol. 160,no.2,pp.95–101,2012. [1] Z. Ekin, “Resurgence of safower (Carthamus tinctorius L.) [16] J. Min and C. Wei, “Hydroxysafor yellow A cardioprotection in utilization: A global view,” JournalofAgronomy,vol.4,no.2, ischemia–reperfusion (I/R) injury mainly via Akt/hexokinase pp.1812–5379,2005. II independent of ERK/GSK-3� pathway,” Biomedicine & Phar- [2] M. R. Meselhy, S. Kadota, Y. Momose et al., “Two new macotherapy,vol.87,pp.419–426,2017. quinochalcone yellow pigments from carthamus tinctorius [17] D. Han, J. Wei, R. Zhang et al., “Hydroxysafor yellow A 2+ and Ca antagonistic activity of tinctormine,” Chemical & alleviates myocardial ischemia/reperfusion in hyperlipidemic Pharmaceutical Bulletin,vol.41,no.10,pp.1796–1802,1993. animals through the suppression of TLR4 signaling,” Scientifc Reports,vol.6,no.1,ArticleID35319,2016. [3] Pharmacopoeia Commission of People’s Republic of China, [18] P.-H. Nie, L. Zhang, W.-H. Zhang, W.-F. Rong, and J.-M. Zhi, PharmacopoeiaofPeople’sRepublicofChina, 2015 edition, “TeefectsofhydroxysaforyellowAonbloodpressureand Chinese Medicine Science and Technology Publishing House, cardiac function,” Journal of Ethnopharmacology,vol.139,no.3, Beijing, China, 2015. pp. 746–750, 2012. [4] J. H. Li, G. L. Xu, S. M. Lin et al., “Systematic evaluation [19] Z. Jin, W. Zhang, W. Chai, Y. Zheng, and J. Zhi, “Antibodies of efectiveness and safety on Safower Injection in angina against AT1 receptors are associated with vascular endothelial pectoris,” Journal of Emergency in Traditional Chinese Medicine, andsmoothmusclefunctionimpairment:protectiveefectsof vol. 21, no. 6, pp. 932–939, 2012. hydroxysafor yellow A,” PLoS ONE,vol.8,ArticleIDe67020, [5]H.J.Cui,H.Y.He,andZ.H.Xing,“Meta-analysisofSafower 2013. Yellow Injection for the treatment of the overall efectiveness [20] L. Zhang, P. H. Nie, G. H. Zhang et al., “Endothelium- power and safety of acute cerebral infarction,” China Traditional independent vasodilation efect of hydroxysafor yellow A Patent Medicine,vol.33,no.8,pp.1299–1302,2011. in thoracic aorta of Wistar rats,” Journal of Medicinal Plants [6] Y. Sun, D.-P. Xu, Z. Qin et al., “Protective cerebrovascular Research, vol. 5, no. 11, pp. 2187–2191, 2011. efects of hydroxysafor yellow A (HSYA) on ischemic stroke,” [21] W. Yuan, D. Yang, X. Sun et al., “Efects of hydroxysafor European Journal of Pharmacology,vol.818,pp.604–609,2018. yellow A on proliferation and collagen synthesis of rat vascular 14 Evidence-Based Complementary and Alternative Medicine

adventitial fbroblasts induced by angiotensin II,” International against ischemic stroke in rats,” Translational Stroke Research, Journal of Clinical and Experimental Pathology,vol.7,no.9,pp. vol. 5, no. 4, pp. 501–509, 2014. 5772–5781, 2014. [36] Yuanyan Liu, Zeqin Lian, Haibo Zhu et al., “A systematic, [22]Y.Song,L.Long,N.Zhang,andY.Liu,“Inhibitoryefects integrated study on the neuroprotective efects of hydroxysafor of hydroxysafor yellow A on PDGF-BB-induced proliferation yellow A revealed by (1)H NMR-based metabonomics and the and migration of vascular smooth muscle cells via mediating NF-�Bpathway,”Evidence-Based Complementary and Alterna- Akt signaling,” Molecular Medicine Reports,vol.10,no.3,pp. tive Medicine, vol. 2013, Article ID 147362, 14 pages, 2013. 1555–1560, 2014. [37] Y. Lv and L. Fu, “Te potential mechanism for Hydroxysaf- [23] G. Yang, X. Zhou, T. Chen et al., “Hydroxysafor yellow A for yellow A attenuating blood-brain barrier dysfunction via inhibits lipopolysaccharide-induced proliferation and migra- tight junction signaling pathways excavated by an integrated tion of vascular smooth muscle cells via Toll-like receptor-4 serial afnity chromatography and shotgun proteomics analysis pathway,” International Journal of Clinical and Experimental approach,” Neurochemistry International,vol.112,pp.38–48, Medicine, vol. 8, no. 4, pp. 5295–5302, 2015. 2018. [24] L. Li, P. Dong, C. Hou et al., “Hydroxysafor yellow A (HSYA) [38] P.-P. He, F.-H. Fu, T. Wang, C.-K. Li, W.-Y. Xin, and X.- attenuates hypoxic pulmonary arterial remodelling and reverses M. Zhang, “Efect of cerebral ischemia/reperfusion injury on right ventricular hypertrophy in rats,” JournalofEthnopharma- hydroxysafor yellow a penetrating across the blood-brain cology,vol.186,no.20,pp.224–233,2016. barrier,” Scientia Pharmaceutica,vol.76,no.4,pp.713–723, [25]Y.Bai,P.Lu,C.Hanetal.,“HydroxysaforyellowA(HSYA) 2008. from fowers of carthamus tinctorius L. and its vasodilatation [39] L. Sun, L. Yang, and Y.-W. Xu, “Neuroprotection of hydrox- efects on pulmonary artery,” Molecules,vol.17,no.12,pp.14918– ysafor yellow A in the transient focal ischemia: inhibition 14927, 2012. of protein oxidation/nitration, 12/15-lipoxygenase and blood– [26] X.Han,Y.Zhang,Z.Zhou,X.Zhang,andY.Long,“Hydroxysaf- –brain barrier disruption,” Brain Research,vol.1473,no.9,pp. for yellow A improves established monocrotaline-induced pul- 227–235, 2012. monary arterial hypertension in rats,” Journal of International [40] L. Sun, L. Yang, Y. Fu et al., “Capacity of HSYA to inhibit Medical Research, vol. 44, no. 3, pp. 569–584, 2016. nitrotyrosine formation induced by focal ischemic brain injury,” [27]J.Wang,Q.Zhang,X.Mei,andX.Zhang,“Hydroxysafor Nitric Oxide: Biology and Chemistry,vol.35,pp.144–151,2013. yellow A attenuates lef ventricular remodeling afer pressure [41] L.Fan,X.Dang,Z.Shi,C.Zhang,andK.Wang,“Hydroxysafor overload-induced cardiac hypertrophy in rats,” Pharmaceutical Yellow A Protects PC12 Cells Against the Apoptosis Induced Biology,vol.52,no.1,pp.31–35,2014. by Oxygen and Glucose Deprivation,” Cellular and Molecular [28] H. Zhu, Z. Wang, C. Ma et al., “Neuroprotective efects of Neurobiology, vol. 31, no. 8, pp. 1187–1194, 2011. hydroxysafor yellow A: in vivo and in vitro studies,” Planta Medica,vol.69,no.5,pp.429–433,2003. [42] Y. Lv, Y. Qian, A. Ou-yang, and L. Fu, “Hydroxysafor Yellow A attenuates neuron damage by suppressing the [29] S.-Y. Ye and W.-Y. Gao, “Hydroxysafor yellow a protects lipopolysaccharide-induced TLR4 pathway in activated neuron against hypoxia injury and suppresses infammatory microglial cells,” Cellular and Molecular Neurobiology,vol.36, responses following focal ischemia reperfusion in rats,” Archives no. 8, pp. 1241–1256, 2016. of Pharmacal Research,vol.31,no.8,pp.1010–1015,2008. [43] Q. Yang, Z.-F. Yang, S.-B. Liu et al., “Neuroprotective efects [30]L.Deng,H.Wan,H.Zhou,L.Yu,andY.He,“Protective of hydroxysafor yellow A against excitotoxic neuronal death efect of hydroxysafor yellow A alone or in combination with partially through down-regulation of NR2B-containing NMDA acetylglutamine on cerebral ischemia reperfusion injury in rat: receptors,” Neurochemical Research,vol.35,no.9,pp.1353–1360, A PET study using 18F-fuorodeoxyglucose,” European Journal 2010. of Pharmacology,vol.825,pp.119–132,2018. [31] X. Sun, X. Wei, S. Qu, Y. Zhao, and X. Zhang, “Hydroxysafor [44] X. Wang, Z. Ma, Z. Fu et al., “Hydroxysafor yellow A yellow A suppresses thrombin generation and infammatory protects neurons from excitotoxic death through inhibition responses following focal cerebral ischemia-reperfusion in rats,” of NMDARs,” Asn Neurochemistry,vol.8,no.2,ArticleID Bioorganic & Medicinal Chemistry Letters,vol.20,no.14,pp. 1759091416642345, 2016. 4120–4124, 2010. [45]J.W.Tian,F.H.Fu,W.L.Jiangetal.,“Protectiveefect [32] H. B. Zhu, L. Zhang, Z. H. Wang et al., “Terapeutic efects of of hydroxysafor yellow A against rat cortex mitochondrial hydroxysafor yellow A on focal cerebral ischemic injury in rats injuries induced by cerebral ischemia,” Acta Pharmaceutica and its primary mechanisms,” Journal of Asian Natural Products Sinica,vol.39,no.10,pp.774–777,2004. Research,vol.7,no.4,pp.607–613,2005. [46] S. Ramagiri and R. Taliyan, “Neuroprotective efect of hydroxy [33]L.Chen,Y.Xiang,L.Kongetal.,“Hydroxysaforyellowa safor yellow A against cerebral ischemia-reperfusion injury protects against cerebral ischemia-reperfusion injury by anti- in rats: Putative role of mPTP,” JournalofBasicandClinical apoptotic efect through PI3K/Akt/GSK3� pathway in rat,” Physiology and Pharmacology,vol.27,no.1,pp.1–8,2016. Neurochemical Research, vol. 38, no. 11, pp. 2268–2275, 2013. [47] J.Tian,G.Li,Z.Liu,andF.Fu,“HydroxysaforyellowAinhibits [34] Y. Lv, Y. Qian, L. Fu, X. Chen, H. Zhong, and X. Wei, rat brain mitochondrial permeability transition pores by a free “Hydroxysafor yellow A exerts neuroprotective efects in radical scavenging action,” Pharmacology,vol.82,no.2,pp.121– cerebral ischemia reperfusion-injured mice by suppressing the 126, 2008. innate immune TLR4-inducing pathway,” European Journal of [48] N. Zhang, M. Xing, Y. Wang et al., “Hydroxysafor yellow Pharmacology,vol.769,pp.324–332,2015. A improves learning and memory in a rat model of vascular [35]Z.Qi,F.Yan,W.Shietal.,“AKT-Relatedautophagycontributes dementia by increasing VEGF and NR1 in the hippocampus,” to the neuroprotective efcacy of hydroxysafor yellow A Neuroscience Bulletin, vol. 30, no. 3, pp. 417–424, 2014. Evidence-Based Complementary and Alternative Medicine 15

[49]M.Xing,Q.Sun,Y.Wang,Y.Cheng,andN.Zhang,“Hydrox- model of hepatic fbrosis induced by carbon tetrachloride,” ysafor yellow A increases BDNF and NMDARs in the hip- Molecular Medicine Reports,vol.15,no.1,pp.47–56,2017. pocampus in a vascular dementia rat model,” Brain Research, [65]C.Y.Wang,Q.Liu,Q.X.Huangetal.,“ActivationofPPAR� vol. 1642, pp. 419–425, 2016. is required for hydroxysafor yellow A of Carthamus tinctorius [50] Y.-Q. Lu, Y. Luo, Z.-F. He et al., “Hydroxysafor yellow to attenuate hepatic fbrosis induced by oxidative stress,” Phy- a ameliorates homocysteine-induced alzheimer-like patho- tomedicine,vol.20,no.7,pp.592–599,2013. logic dysfunction and memory/synaptic disorder,” Rejuvenation [66] Q. Liu, C. Y. Wang, Z. Liu et al., “Hydroxysafor yellow Research,vol.16,no.6,pp.446–452,2013. A suppresses liver fbrosis induced by carbon tetrachloride [51]Z.Zhang,Z.Wu,X.Zhu,X.Hui,J.Pan,andY.Xu,“Hydroxy- with high-fat diet by regulating PPAR-�/p38 MAPK signaling,” safor yellow A inhibits neuroinfammation mediated by A�1−42 Pharmaceutical Biology,vol.52,no.9,pp.1085–1093,2014. in BV-2 cells,” Neuroscience Letters,vol.562,pp.39–44,2014. [67] J. Trebicka, M. Hennenberg, M. Odenthal et al., “Atorvastatin [52]Z.-H.Zhang,L.-J.Yu,X.-C.Huietal.,“Hydroxy-saforyellow attenuates hepatic fbrosis in rats afer bile duct ligation via AattenuatesA�1−42-induced infammation by modulating the decreased turnover of hepatic stellate cells,” Journal of Hepatol- JAK2/STAT3/NF-�Bpathway,”Brain Research,vol.1563,pp.72– ogy, vol. 53, no. 4, pp. 702–712, 2010. 80, 2014. [68]H.Dong,Y.Liu,Y.Zouetal.,“AlterationoftheERK5pathway [53] S.-Z. Kong, Y.-F. Xian, S.-P. Ip et al., “Protective efects of by hydroxysafor yellow A blocks expression of MEF2C in hydroxysafor yellow a on �-amyloid-induced neurotoxicity in activated hepatic stellate cells in vitro: Potential treatment for PC12 cells,” Neurochemical Research,vol.38,no.5,pp.951–960, hepatic fbrogenesis,” Pharmaceutical Biology,vol.52,no.4,pp. 2013. 435–443, 2014. [54] Y. Wang, C. Zhang, W. Peng et al., “Hydroxysafor yellow A [69] C.-C. Li, C.-Z. Yang, X.-M. Li et al., “Hydroxysafor yellow exerts antioxidant efects in a rat model of traumatic brain A induces apoptosis in activated hepatic stellate cells through injury,” Molecular Medicine Reports,vol.14,no.4,pp.3690– ERK1/2 pathway in vitro,” European Journal of Pharmaceutical 3696, 2016. Sciences,vol.46,no.5,pp.397–404,2012. [55]X.-D.Bie,J.Han,andH.-B.Dai,“Efectsofhydroxysafor [70]S.Jiang,Z.Shi,C.Li,C.Ma,X.Bai,andC.Wang,“Hydrox- yellow A on the experimental traumatic brain injury in rats,” ysafor yellow A attenuates ischemia/reperfusion-induced liver Journal of Asian Natural Products Research,vol.12,no.3,pp. injury by suppressing macrophage activation,” International 239–247, 2010. Journal of Clinical and Experimental Pathology,vol.7,no.5,pp. [56] Y. Pan, D.-Y. Zheng, S.-M. Liu et al., “Hydroxysafor yellow A 2595–2608, 2014. attenuates lymphostatic encephalopathy-induced brain injury [71] H. M> Piao,Q.F.Xue,J.Z.Jiangetal.,“Hydroxysaforyellow in rats,” Phytotherapy Research,vol.26,no.10,pp.1500–1506, A attenuates allergic airway infammation by suppressing the 2012. activity of nuclear factor-kappa B in ovalbumin-induced asth- [57] J. P. Pei, L. H. Fan, K. Nan et al., “HSYA alleviates secondary matic mice,” International Journal of Clinical and Experimental neuronal death through attenuating oxidative stress, infam- Pathology, vol. 9, no. 11, pp. 21595–21604, 2016. matory response, and neural apoptosis in SD rat spinal cord [72]Y.Wang,C.Xue,F.Dongetal.,“HydroxysaforyellowA compression injury,” JournalofNeuroinfammation,vol.14,no. attenuates small airway remodeling in a rat model of chronic 1, Article ID 97, 2017. obstructive pulmonary disease,” Biological & Pharmaceutical [58] B. Han, J. Hu, J. Shen, Y.Gao, Y.Lu, and T. Wang, “Neuroprotec- Bulletin,vol.37,no.10,pp.1591–1598,2014. tive efect of hydroxysafor yellow A on 6-hydroxydopamine- [73] X. F. Wang, M. Jin, J. Tong et al., “Protective efect of hydrox- induced Parkinson’s disease in rats,” European Journal of Phar- ysafor yellow A against acute lung injury induced by oleic acid macology,vol.714,no.1-3,pp.83–88,2013. and lipopolysaccharide in rats,” Acta Pharmaceutica Sinica,vol. [59] T. Wang, L. Wang, C. Li et al., “Hydroxysafor Yellow A 45,no.7,pp.940–944,2010. Improves Motor Dysfunction in the Rotenone-Induced Mice [74]C.Wang,Q.Huang,C.Wangetal.,“HydroxysaforyellowA Model of Parkinson’s Disease,” Neurochemical Research,vol.42, suppress oleic acid-induced acute lung injury via protein kinase no. 5, pp. 1325–1332, 2017. A,” Toxicology and Applied Pharmacology,vol.272,no.3,pp. [60] T. Wang, S.-J. Duan, S.-Y. Wang et al., “Coadministration of 895–904, 2013. hydroxysafor yellow A with levodopa attenuates the dyskine- [75] C. Wang, C. Wang, C. Ma et al., “Hydroxysafor yellow A sia,” Physiology & Behavior,vol.147,pp.193–197,2015. of Carthamus tinctorius attenuates lung injury of aged rats [61]X.Q.Song,L.N.Su,H.P.Weietal.,“Protectiveefects exposed to gasoline engine exhaust by down-regulating platelet of hydroxysafor yellow A against oxidative damage of �- activation,” Phytomedicine,vol.21,no.3,pp.199–206,2014. mercaptoethanol during neural diferentiation of mesenchymal [76] C.-Y.Sun,C.-Q.Pei,B.-X.Zang,L.Wang,andM.Jin,“Teabil- stem cells,” Chinese Herbal Medicines,vol.9,no.3,pp.282–288, ity of hydroxysafor yellow A to attenuate lipopolysaccharide- 2017. induced pulmonary infammatory injury in mice,” Phytotherapy [62]Y.He,Q.Liu,Y.Lietal.,“Protectiveefectsofhydroxysafor Research,vol.24,no.12,pp.1788–1795,2010. yellow A (HSYA) on alcohol-induced liver injury in rats,” [77] Y.-L. Liu, Y.-J. Liu, Y. Liu et al., “Hydroxysafor yellow A Journal of Physiology and Biochemistry,vol.71,no.1,pp.69–78, ameliorates lipopolysaccharide-induced acute lung injury in 2015. mice via modulating toll-like receptor 4 signaling pathways,” [63] Y.-B. Zhang, H.-Y. Dong, X.-M. Zhao et al., “Hydroxysafor International Immunopharmacology,vol.23,no.2,pp.649–657, yellow A attenuates carbon tetrachloride-induced hepatic fbro- 2014. sisinratsbyinhibitingErk5signaling,”American Journal of [78]Y.Zhang,L.Song,R.Pan,J.Gao,B.-X.Zang,andM.Jin, Chinese Medicine,vol.40,no.3,pp.481–494,2012. “Hydroxysafor yellow A alleviates lipopolysaccharide-induced [64]Y.Li,Y.Shi,Y.Sunetal.,“Restorativeefectsofhydroxysafor acute respiratory distress syndrome in mice,” Biological & yellow A on hepatic function in an experimental regression Pharmaceutical Bulletin,vol.40,no.2,pp.135–144,2017. 16 Evidence-Based Complementary and Alternative Medicine

[79] Y. Wu, L. Wang, M. Jin, and B.-X. Zang, “Hydroxysafor yellow kinetics of hydroxysafor yellow A on �-glucosidase,” Journal A alleviates early infammatory response of bleomycin-induced of Biomolecular Structure and Dynamics,vol.36,no.4,pp.830– mice lung injury,” Biological & Pharmaceutical Bulletin,vol.35, 840, 2018. no. 4, pp. 515–522, 2012. [95] N. Ahmed, “Advanced glycation endproducts—role in pathol- [80] M.Jin,L.Wang,Y.Wu,B.-X.Zang,andL.Tan,“Protectiveefect ogy of diabetic complications,” Diabetes Research and Clinical of hydroxysafor yellow A on bleomycin- induced pulmonary Practice,vol.67,no.1,pp.3–21,2005. infammation and fbrosis in rats,” Chinese Journal of Integrative [96]Z.Ni,Z.Zhuge,W.Li,H.Xu,Z.Zhang,andH.Dai,“Inhibitory Medicine,vol.24,no.1,pp.32–39,2018. efectsofhydroxysaforyellowAontheformationofadvanced [81] M. Jin, Y. Wu, L. Wang, B. Zang, and L. Tan, “Hydroxysafor glycation end products in vitro,” Biological & Pharmaceutical Yellow A Attenuates Bleomycin-induced Pulmonary Fibrosis in Bulletin,vol.35,no.11,pp.2050–2053,2012. Mice,” Phytotherapy Research,vol.30,no.4,pp.577–587,2016. [97]W.Li,J.Liu,P.Heetal.,“HydroxysaforyellowAprotects [82] L. J. Song, Y. Zhu, M. Jin et al., “Hydroxysafor yellow a inhibits methylglyoxal-induced injury in the cultured human brain lipopolysaccharide-induced infammatory signal transduction microvascular endothelial cells,” Neuroscience Letters,vol.549, in A549 cells,” Fitoterapia,vol.84,no.1,pp.107–114,2013. pp.146–150,2013. [83] R. Pan, Y. Zhang, B. Zang, L. Tan, and M. Jin, “Hydroxysafor yellowAinhibitsTGF-�1-induced activation of human fetal [98] T. Chen, N. Chen, N. Pang et al., “Hydroxysafor yellow A lung fbroblasts in vitro,” Journal of Pharmacy and Pharmacol- promotes angiogenesis via the angiopoietin 1/ Tie-2 signaling ogy, vol. 68, no. 10, pp. 1320–1330, 2016. pathway,” Journal of Vascular Research,vol.53,no.5-6,pp.245– 254, 2016. [84] R. Y. Pan, Y. Zhang, M. Zheng, B. Zang, and M. Jin, “Hydrox- ysafor yellow A suppresses MRC-5 cell activation induced by [99] F. Ye, J. Wang, W.Meng et al., “Proteomic investigation of efects TGF-�1byblockingTGF-�1 binding to T�RII,” Frontiers in of hydroxysafor yellow A in oxidized low-density lipoprotein- Pharmacology, vol. 8, Article ID 264, 2017. induced endothelial injury,” Scientifc Reports,vol.7,no.1, [85] Y. Li, Y. Wu, Y. Guan, Z. Wang, and L. Zhang, “Hydroxysaf- Article ID 17981, 2017. for yellow A induces apoptosis in MCF-7 cells by blocking [100] M. Jin, C.-Y. Sun, and B.-X. Zang, “Hydroxysafor yellow A NF�B/p65 pathway and disrupting mitochondrial transmem- attenuate lipopolysaccharide-induced endothelium infamma- brane potential,” RSC Advances,vol.4,no.88,pp.47576–47586, tory injury,” Chinese Journal of Integrative Medicine,vol.22,no. 2014. 1, pp. 36–41, 2016. [86] L. Liu, N. Si, Y. Ma et al., “Hydroxysafor-yellow a induces [101]D.B.Ji,M.C.Zhu,B.Zhuetal.,“HydroxysaforyellowA human gastric carcinoma BGC-823 cell apoptosis by activating enhances survival of vascular endothelial cells under hypoxia peroxisome proliferator-activated receptor gamma (PPAR�),” via upregulation of the HIF-1�-VEGFpathwayandregulation Medical Science Monitor,vol.24,pp.803–811,2018. of Bcl-2/Bax,” Journal of Cardiovascular Pharmacology,vol.52, [87] J. Wang, J. Wang, X. Wang et al., “Molecular mechanism of inhi- no. 2, pp. 191–202, 2008. bition of the abnormal proliferation of human umbilical vein [102]D.B.Ji,L.Y.Zhang,C.L.Li,J.Ye,andH.B.Zhu,“Efectof endothelial cells by hydroxysafor-yellow A,” Pharmaceutical Hydroxysafor yellow A on human umbilical vein endothelial Biology,vol.54,no.7-9,pp.1800–1807,2016. cells under hypoxia,” Vascular Pharmacology,vol.50,no.3-4, [88] S.-Y. Xi, Q. Zhang, C.-Y. Liu, H. Xie, L.-F. Yue, and X.-M. pp.137–145,2009. Gao, “Efects of hydroxy safower Yellow-A on tumor capillary [103]X.L.Xu,Y.H.Guo,J.X.Zhaoetal.,“Hydroxysafor angiogenesis in transplanted human gastric adenocarcinoma yellow A inhibits LPS-induced NLRP3 infammasome acti- BGC-823 tumors in nude mice,” Journal of Traditional Chinese vation via binding to xanthine oxidase in mouse RAW264.7 Medicine,vol.32,no.2,pp.243–248,2012. macrophages,” Mediators of Infammation,vol.2016,ArticleID [89] F.Yang,J.Li,J.Zhu,D.Wang,S.Chen,andX.Bai,“Hydroxysaf- 8172706, 2016. for yellow A inhibits angiogenesis of hepatocellular carcinoma [104] Yueqing Jiang, Jiayuan Kou, Xiaobo Han et al., “ROS-dependent via blocking ERK/MAPK and NF-�BsignalingpathwayinH22 activation of autophagy through the PI3K/Akt/mTOR pathway tumor-bearing mice,” European Journal of Pharmacology,vol. is induced by hydroxysafor yellow A-sonodynamic ther- 754, pp. 105–114, 2015. � apy in THP-1 macrophages,” Oxidative Medicine and Cellular [90] L.Ma,L.Liu,Y.C.Maetal.,“TeroleofE-Cadherin/ -Catenin Longevity,vol.2017,ArticleID8519169,16pages,2017. in Hydroxysafor Yellow A inhibiting adhesion, invasion, migration and lung metastasis of hepatoma cells,” Biological & [105] W. Wu, M. Jin, J. Tong et al., “Inhibitory efect of hydroxysafor Pharmaceutical Bulletin, vol. 40, no. 10, pp. 1706–1715, 2017. yellow A against PMN activation induced by LPS,” Acta Phar- maceutica Sinica, vol. 46, no. 2, pp. 153–157, 2011. [91] X. Zhang, D. Shen, Z.-R. Lu¨ et al., “Efects of hydroxysafor yel- low A on ALDH1: Inhibition kinetics and molecular dynamics [106] B.Cheng,Y.Gao,J.Lianetal.,“HydroxysaforyellowAinhibits simulation,” Process Biochemistry,vol.49,no.10,pp.1664–1672, IL-1�-induced release of IL-6, IL-8, and MMP-1 via suppression 2014. of ERK, NF-�B and AP-1 signaling in SW982 human synovial [92] R. S. Ahima and J. S. Flier, “Adipose tissue as an endocrine cells,” Food&Function,vol.7,no.11,pp.4516–4522,2016. organ,” Trends in Endocrinology & Metabolism,vol.11,no.8,pp. [107] F. Dong, C. Xue, Y. Wang et al., “Hydroxysafor yellow A 327–332, 2000. attenuates the expression of infammatory cytokines in acute [93] H.-J. Zhu, L.-J. Wang, X.-Q. Wang et al., “Hormone-sensitive sof tissue injury,” Scientifc Reports,vol.7,no.1,ArticleID lipase is involved in the action of hydroxysafor yellow A 40584, 2017. (HYSA) inhibiting adipogenesis of 3T3-L1cells,” Fitoterapia,vol. [108]J.Wang,P.Wang,S.Q.Guietal.,“HydroxysaforyellowA 93, pp. 182–188, 2014. attenuates the apoptosis of peripheral blood CD4+T lympho- [94]Y.Xu,J.Lee,Y.-D.Park,J.-M.Yang,J.Zheng,andQ.Zhang, cytes in a murine model of sepsis,” Frontiers in Pharmacology, “Molecular dynamics simulation integrating the inhibition vol. 8, Article ID 613, 2017. Evidence-Based Complementary and Alternative Medicine 17

[109]N.Hu,J.Duan,H.Lietal.,“HydroxysaforYellowAAmelio- rates Renal Fibrosis by Suppressing TGF-�1-Induced Epithelial- to-Mesenchymal Transition,” PLoS ONE,vol.11,no.4,Article ID e0153409, 2016. [110] S.-Z. Kong, X.-G. Shi, X.-X. Feng et al., “Inhibitory efect of hydroxysafor yellow A on mouse skin photoaging induced by ultraviolet irradiation,” Rejuvenation Research,vol.16,no.5,pp. 404–413, 2013. [111] S.-J. Yin, K.-Y. Liu, J. Lee et al., “Efect of hydroxysafor yellow A on tyrosinase: integration of inhibition kinetics with computational simulation,” Process Biochemistry,vol.50,no.12, pp. 2112–2120, 2015. [112] Z. Liu, C. Li, M. Li, D. Li, and K. Liu, “Te subchronic toxicity of hydroxysafor yellow A of 90 days repeatedly intraperitoneal injections in rats,” Toxicology,vol.203,no.1–3,pp.139–143, 2004. M EDIATORSof INFLAMMATION

The Scientifc Gastroenterology Journal of Research and Practice Diabetes Research Disease Markers World Journal Hindawi Hindawi Publishing Corporation Hindawi www.hindawi.com Volume 2018 Hindawi Hindawi http://www.hindawi.comwww.hindawi.com Volume 20182013 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018

Journal of International Journal of Immunology Research Endocrinology Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018

Submit your manuscripts at www.hindawi.com

BioMed PPAR Research Research International Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018

Journal of Obesity

Evidence-Based Journal of Stem Cells Complementary and Journal of Ophthalmology International Alternative Medicine Oncology Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2013

Parkinson’s Disease

Computational and Mathematical Methods Behavioural AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018