Advances in Pharmacological Actions and Mechanisms of Flavonoids from Traditional Chinese Medicine in Treating Chronic Obstructive Pulmonary Disease

Home , Casticin, Isoorientin, Isovitexin

Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 8871105, 10 pages https://doi.org/10.1155/2020/8871105

Review Article Advances in Pharmacological Actions and Mechanisms of Flavonoids from Traditional Chinese Medicine in Treating Chronic Obstructive Pulmonary Disease

Yang Yang ,1 Xin Jin ,2 Xinyi Jiao ,1 Jinjing Li ,1 Liuyi Liang ,1 Yuanyuan Ma ,1 Rui Liu ,1 and Zheng Li 1

1State Key Laboratory of Component-Based Chinese Medicine, College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China 2Military Medicine Section, Logistics University of Chinese People’s Armed Police Force, Tianjin 300309, China

Correspondence should be addressed to Rui Liu; [email protected] and Zheng Li; [email protected]

Received 13 August 2020; Revised 11 December 2020; Accepted 15 December 2020; Published 31 December 2020

Academic Editor: Ihsan Ul Haq

Copyright © 2020 Yang Yang et al. ,is 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. Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality. ,e conventional therapies remain palliative and have various undesired effects. Flavonoids from traditional Chinese medicine (TCM) have been proved to exert protective effects on COPD. ,is review aims to illuminate the poly-pharmacological properties of flavonoids in treating COPD based on laboratory evidences and clinical data and points out possible molecular mechanisms. Animal/laboratory studies and randomised clinical trials about administration of flavonoids from TCM for treating COPD from January 2010 to October 2020 were identified and collected, with the following terms: chronic obstructive pulmonary disease or chronic respiratory disease or inflammatory lung disease, and flavonoid or nature product or traditional Chinese medicine. Pharmacokinetic studies and external application treatment were excluded. A total of 15 flavonoid compounds were listed. Flavonoids could inhibit inflammation, oxidative stress, and cellular senescence, restore corticosteroid sensitivity, improve pulmonary histology, and boost pulmonary function through regulating multiple targets and signaling pathways, which manifest that flavonoids are a group of promising natural products for COPD. Nevertheless, most studies remain in the research phase of animal testing, and further clinical applications should be carried out.

1. Introduction the end result of lifelong, dynamic, and cumulative gene- environment interactions, which modulate the develop- Chronic obstructive pulmonary disease (COPD) is a dev- ment, maintenance, and function of the lungs through astating lung disease characterized by incomplete reversible complex and varied biologic mechanisms [4]. More than 3 air flow limitations that often develop progressively [1]. In million people die from COPD, which causes a major the past few decades, COPD has been rifely accepted as a healthcare burden worldwide [5]. In 2014-2015, estimated self-inflicted illness attributed to tobacco smoking. Although overall prevalence of COPD was 13.6% among Chinese smoking is the major identified risk factor for COPD, one- adults aged 40 years and above, indicating that COPD has third of worldwide patients are nonsmokers [2]. Further- become a dominating public health challenge in China [6]. more, exposure to smoke from burning of biomass fuel and ,erefore, it is imperative to clarify the pathogenesis of high levels of air pollution are also major environmental risk COPD and take corresponding treatment measures. factors for COPD in many places around the globe [3]. COPD is a heterogeneous disease with intricate patho- ,erefore, some researchers have suggested that COPD is genesis. ,ere is endless inflammatory infiltration in the 2 Evidence-Based Complementary and Alternative Medicine airways, alveoli, and microvasculature of COPD patients [5]. the protective effects of flavonoids on COPD through re- Besides, impaired immune regulation plays a role in COPD, lieving symptoms and improving lung functions [22]. ,e since inflammation and environmental damage in lungs pharmacological activities and structures of flavonoids for expose some epitopes for the autoimmune attack [7]. Cell treating COPD are shown in Table 1 and Figure 1, re- senescence generally leads to decreased proliferation with spectively. ,e schematic diagram of poly-pharmacological preserved metabolic activity, resulting in increased in- properties of flavonoids is displayed in Figure 2. flammation, reduced cell regeneration, and carcinogenesis [8]. In addition to the factors mentioned earlier, the fetal 3. Roles of Flavonoids on Chronic Obstructive stage has been involved in the pathogeny of COPD, which Pulmonary Disease might be programmed early in life [7]. Currently, a series of therapeutic strategies have been developed to inhibit or 3.1. Inflammation. COPD is a progressive inflammatory avoid the etiologic factors. disease of the microvasculature, the alveoli, and the airways, Treatment strategies for COPD include smoking ces- in where inflammation-associated cells including macro- sation, physical activity, and pharmacotherapy. ,ereinto, phages, neutrophils, eosinophils, and dendritic cells are the mainstay of drug treatment for COPD involves inhaled recruited to form the innate immune response [42]. In long-acting β2 agonists (LABAs), long-acting muscarinic COPD, inflammatory tissue damage is endless. ,erefore, antagonists (LAMAs), inhaled corticosteroids, oral phos- relieving inflammation has a certain therapeutic effect on phodiesterase-4 inhibitors, and macrolides [5]. Although COPD. bronchodilator therapy (LABA, LAMA, or a combination of Isolating from the root of Scutellariae radix, baicalin is both) has been shown to be generally safe, there have been an isoflavone and has various biological activities. To clarify adverse cardiac events in clinical studies [9]. Inhaled cor- the effects of baicalin on COPD, the rat model and cell ticosteroids are related to a higher risk of pneumonia in models were established by using cigarette smoke (CS) and patients with severe COPD [10]. Phosphodiesterase-4 in- cigarette smoke extract (CSE), respectively. ,e results hibitors have several side effects such as diarrhoea and showed that baicalin reduced production of proin- nausea [5]. ,erefore, novel strategies are needed for better flammatory cytokines and had significant anti-inflammatory therapeutic response and reduced side effects. effects on COPD [23–25]. ,e anti-inflammatory effect is In recent years, an increasing number of studies have likely achieved via suppressing the nuclear factor-kappa B shown that flavonoids from traditional Chinese medicine (NF-κB) pathway [23] and enhancing histone deacetylase 2 (TCM) have certain protective effect on COPD [11–13]. (HDAC2) activity [24]. Although there have been many research studies on flavo- Oroxylin A, a natural flavonoid isolated from the me- noids in treating COPD, the mechanisms of action of fla- dicinal herb Scutellariae radix, has been proved to have anti- vonoids are still not totally clear and few securable reviews inflammatory and antioxidative properties [43]. Oroxylin A illustrate the comprehensive and multiple pharmacological dose-dependently attenuated CS-induced inflammatory effects of flavonoids on COPD. Herein, this review aims to cytokine and chemokine production [26]. illuminate the pharmacologic actions and underlying Liquiritin apioside is a main flavone from Glycyrrhizae mechanisms of TCM-derived flavonoids on COPD, based radix et rhizoma. Liquiritin apioside was reported to at- on experimental evidences as well as clinical data to lay the tenuate tumor necrosis factor-α (TNF-α) and transforming basis for subsequent research studies and developments of growth factor-β (TGF-β) in human type II alveolar epithelial anti-COPD medications. cell line (A549) [27]. Moreover, liquiritin apioside significantly inhibited goblet cells containing mucus in the at- 2. Flavonoids in TCM mosphere in a CS-induced mouse model [27]. Phloretin is a chalcone that exists in Crotonis fructus and As the most common secondary metabolites, flavonoids are Rubi fructus and possesses diverse biologic properties. a large group of polyphenolic compounds and exist widely in Phloretin was reported to suppress the mucus hypersecre- plants as free aglycones or glycosides. ,e biosynthesis of tion and decrease inflammatory in a mice model induced by flavonoids proceeds via the acetate pathway and the shiki- CS [28]. ,e results of in vitro experiment using NCI–H292 mate pathway [14]. Constructing from a 15-carbon skeleton, cells were consistent with in vivo experiments [28]. ,e anti- flavonoids are composed of two benzene rings connected by inflammatory effect is achieved via restraining phosphory- 3-carbon linking chain and mainly classified into flavones, lation of mitogen-activated protein kinase (MAPK) path- flavonols, flavanone, flavanonol, flavan, flavanol, isoflavone, ways [28]. ,e above data indicate that phloretin could be as and chalcone [14]. a potential therapy approach to COPD. However, it has not Flavonoids have various functions both in plants and been approved for clinical use. living organisms. ,e wide variety and high diversity of Hesperidin is a flavone with stable biological activity, flavonoids are pivotal for plants to interact with the envi- which exists in various Chinese herbs such as Citrus ronment to defense both biotic and abiotic threats [15]. reticulata, Schizonepetae herba, and Chrysanthemi flos. In Flavonoids have a variety of biological properties such as vivo, hesperidin was proved to mitigate inflammation in antianaphylaxis [16], antibiosis [17], anti-inflammatory [18], COPD mice by evaluating the levels of related cytokines in vasodilatory [19], antimutagenic [20], and anticarcinogenic bronchoalveolar lavage fluid (BALF) and lung tissues [29]. activities [21]. Recently, increasing research studies showed ,e mechanism of action of hesperidin was associated Evidence-Based Complementary and Alternative Medicine 3

Table 1: ,e effects of flavonoids in TCM on chronic obstructive pulmonary disease. Flavonoids TCM sources Models Effects Inhibition of inflammation; prevention of pulmonary CS-induced rat model function [23]; reducing oxidative stress [24] Reduction of inflammation; protection of pulmonary CS-induced mice model function [25] Baicalin Scutellariae radix In vitro model using CSE-exposed (C H O ) Prevention of inflammation [23] 21 18 11 type II pneumocytes CSE-induced human type II alveolar epithelial carcinoma cell line Moderation of inflammation response [25] (A549 cells) CS-induced mice model Alleviation of inflammation and oxidative stress [26] Oroxylin A Scutellariae radix CSE induced BEAS-2B bronchial Upregulation of Nrf2 expression and total cellular (C H O ) 16 12 5 epithelial cells and RAW264.7 cells glutathione level [26] Inhibition of inflammation, myeloperoxidase activity, CS-induced mice model Liquiritin apioside Glycyrrhizae radix and increased SOD activity [27] (C26H30O13) et rhizoma In vitro model using CSE-exposed Attenuation of cytotoxicity, inflammation, and depleted A549 cells GSH levels [27] Suppression of the mucus hypersecretion and CS-induced mice model Phloretin Crotonis fructus; inflammatory cell release [28] (C H O ) Rubi fructus Moderation of inflammatory cytokines and the 15 14 5 CSE-induced NCI–H292 cell model phosphorylation of MAPK pathways [28] Hesperidin Inhibition of inflammation and oxidative stress Citrus reticulata CSE-induced mice model (C28H34O15) responses [29] Suppression of inflammation and oxidative stress [30] Silybl fructus CS-induced mice model Silymarin Attenuation of autophagy [31] (C H O ) Moderation of inflammatory cytokines in an autophagy- 25 22 10 Silybl fructus CSE-induced BEAS-2B cell model and ERK/p38 MAPK-dependent manner [31] Protecting pulmonary function and decreasing CS-induced mice model Naringenin inflammatory cells and cytokines [32] Menthae herba (C H O ) In vitro model using CSE-exposed 15 12 5 Suppression of inflammation [32] A549 cells Fisetin Inhibition of inflammation and oxidative stress; Gleditsiae spina CS-induced rat model (C15H10O6) prevention of tissue damage [33] Casticin Inhibition of inflammatory cytokines and chemokines Viticis fructus CS-induced C57BL/6 mice model (C19H18O8) [34] Reduction of the infiltration of inflammatory cells and Isoliquiritigenin Glycyrrhizae radix CS-induced mice model cytokines; reversion of lung pathological injuries and (C H O ) et rhizoma 15 12 4 oxidative stress levels [35] Male Hartley guinea pigs and female Biochanin A Suppression of inflammation response [36] Triflolium pratense BABL/c mice model (C16H12O5) PM 2.5-induced rat model Amelioration of inflammation and oxidative stress [37] Isoorientin In vitro model using CSE-exposed Anthopterus wardii Anti-inflammatory activity [37] (C21H20O11) human SAE cells Mangiferin Anemarrhenae In vitro model using PAH-exposed Ameliorating oxidative stress, speeding up wound (C19H18O11) rhizoma BEAS-2B cells healing and restoring proliferation [38] Quercetin Polygoni avicularis ACH-induced mice model Relieving precontracted airway smooth muscle [39] (C15H10O7) herba Patients with COPD Restoring corticosteroid sensitivity [40] Genistein Iridis tectori Suppression of the NF-κB, TNF-α, and MMP-9- Patients with COPD (C15H10O5) rhizoma associated pathways [41]

with NAD-dependent protein deacetylase sirtuin-1 kinase (ERK)/p38 MAPK pathways [30] and suppressing (SIRT1)/PGC-1α/NF-κB signaling axis [29]. ,ese data autophagy activation [31]. Silymarin might be an ideal agent provide the laboratory evidence of hesperidin in treating treating inflammatory pulmonary diseases, but more clinical COPD patients. research studies are needed. Silymarin is a flavonoid compound extracted from the Naringenin is a plant-derived flavonone with a variety of Silybl fructus. Silymarin has been proved to alleviate lung biological activities. Naringenin was found to significantly inflammation by regulating extracellular signal-regulated decrease inflammatory cells and reduce the levels of 4 Evidence-Based Complementary and Alternative Medicine

O OH O HO OH

O OH O HO O O O OH HO OH O O OH HO HO O OH OH O OH O HO O OH OH OH OH Phloretin Hesperidin Liquiritin apioside

HO O OH O OH OH OH O HO O O O O HO HO O O HO O HO OH O HO OH

Baicalin Oroxylin A Silymarin

O OH O OH O OH OH

HO O HO O HO O OH OH OH OH OH Naringerin Fisetin Quercetin

OH OH H HO OH OH O O H OH HO OH O O HO H HO O

HO O OH OH OH

Isoliquiritigenin Biochanin A Isoorientin

OH OH O OH O O OH O O H OH O HO O O OH OH OH HO O OH HO O OH Mangiferin Genistein Casticin Figure 1: Chemical structure of flavonoids for the treatment of chronic obstructive pulmonary disease. proinflammatory cytokines by restraining the NF-κB Fisetin, a plant flavonoid present in Gleditsiae spina, has pathway in the BALF and serum of CS-induced BALB/c been shown to be effective in lowering inflammation and mice [32]. However, its role in COPD patients is not yet oxidative stress associated with different disease conditions. clear. Fisetin (25 or 50 mg) demonstrated a significant decrease in Evidence-Based Complementary and Alternative Medicine 5

Mangiferin Baicalin Oroxylin A Oroxylin A Phloretin Baicalin Hesperidin Oroxylin A Casticin Liquiritin apioside Isoliquiritigenin Phloretin Hesperidin Silymarin Baicalin Naringenin Naringenin Isoliquiritigenin Oroxylin A Biochanin A Isoorientin Baicalin Genistein Oroxylin A Casticin Liquiritin apioside Fisetin Hesperidin Silymarin Quercetin Fisetin Isoliquiritigenin Mangiferin Figure 2: ,e diverse mechanisms of flavonoids targeting chronic obstructive pulmonary disease, representing the inhibiting effect. inflammatory mediators such as TNF-α, granulocyte-mac- From the literature mentioned above, flavonoids from rophage colony-stimulating factor (GM-CSF), and inter- TCM could inhibit inflammatory response both in vitro and leukin (IL)-1β, IL-4, and IL-10 [44]. ,e anti-inflammatory in vivo mainly via suppressing TNF-α/NF-κB and MAPK mechanism of fisetin was related to suppressing the TNF- signaling pathways. α-activated NF-κB cascade via targeting protein kinase C [33]. ,e involved proteins in NF-κB pathway that inhibited by fisetin are shown in Figure 3 [45]. 3.2. Oxidative Stress. Oxidative stress refers to the over- Isolated from Viticis fructus, casticin is a flavone with generation oxides in the biological system when the or- various pharmacological effects. In a CS-induced murine ganism is exposed to a harmful environment and has a model, administration of casticin significantly restrained the significant driving role in the pathogenesis of COPD [50]. influx of inflammatory cells (macrophages, neutrophils, Oxidants consist of reactive oxygen species (ROS) and re- and lymphocytes) and reduced proinflammatory cytokines active nitrogen species (RNS) and result from CS and in- and chemokines in BALF [34]. ,ese data suggest that flammatory cells [51]. Nuclear factor erythroid 2-related casticin could be a promising candidate for suppressing lung factor 2 (Nrf2) is a transcription factor that binds to anti- inflammation in COPD. oxidant response element and originates the transcription of Isoliquiritigenin, a natural chalcone derived from Gly- antioxidant genes in response to oxidative stress [34]. Hence, cyrrhizae radix et rhizoma, has various benefits including therapy directed towards increasing Nrf2-regulated anti- antioxidant, anti-inflammation, and antiapoptotic proper- oxidants could be a therapeutic strategy for relieving the ties [35, 46, 47]. It was reported that isoliquiritigenin could effects of oxidative stress in COPD. attenuate CS-induced inflammatory cytokines levels (TNF- Baicalin (80, 160 mg/kg) could significantly reduce oxidant α, IL-1β) and the number of cells (neutrophils, and mac- malondialdehyde (MDA) production, which reflects the degree rophages) in BALF via suppressing the NF-κB signaling of damage induced by oxidative stress and increases total pathway [48]. antioxidant capacity (T-AOC), superoxide dismutase (SOD), Biochanin A is a phytoestrogenic isoflavone of Triflolium and heme-oxygenase (HO)-1 level in in the CS-induced model pratense. It was clearly showed that biochanin A could inhibit of COPD [24]. Oroxylin A suppressed CS-induced oxidative the number of total inflammatory cells, neutrophils, eosinophils, lung injury by inhibiting 8-isoprostane and augmenting glu- and levels of cytokines, including IL-2, IL-4, IL-5, and TNF-α, in tathione (GSH) level [26]. And the antioxidant mechanism of BALF of the mice [36]. In a PM2.5-exposed rat model, Biochanin oroxylin A was related to the activation of the Nrf2 signaling A decreased apoptosis and the levels of proinflammatory factors pathway. Liquiritin apioside inhibited myeloperoxidase (MPO) including TNF-α, IL-2, IL-6, and IL-8 [37]. activity and increased SOD activity in a dose-dependent Isoorientin, vitexin, and isovitexin are natural flavones manner [27]. Hesperidin was proved to alleviate oxidative isolated from Anthopterus wardii. Human SAE cells were stress through reducing oxidants level and increasing antiox- treated with 5% CSE to evaluate the effects of isoorientin, idants level [29]. vitexin, and isovitexin on COPD. ,e results revealed that Mangiferin ameliorated oxidative stress in vitro through these flavones could significantly inhibit the level of IL-8 and inhibiting ROS level [38]. High-dose silymarin (50 mg/kg/ MMP-1 at 100 μg/ml [49]. ,erefore, isoorientin, vitexin, day) administration prevented CS-induced elevation in and isovitexin could play a therapeutic role in the treatment MDA levels and decrease in SOD activities in vivo [30]. of COPD, but more in vivo and clinical research studies are Fisetin significantly enhanced lung HO-1, GSH peroxidase- needed to clarify their efficacy and safety. 2, reduced GSH, SOD, nitric oxide (NO), and NFR2 levels in 6 Evidence-Based Complementary and Alternative Medicine

NF-kappa B signaling pathway Calcium signaling DAG pathway Genotoxic agent DNA damage Lck +p T-cell receptor PLCγ1 2+ MHC/antigen TCR Zap LAT IP PCK8 signaling pathway PARP1 3 Ca ATM PIASy NEMO Ubs9 +p BLNK B-cell receptor PLCγ2 DAG PCKβ SUMOylation Antigen BCR Syk Btk signaling pathway Shuttling Lyn 2+ IP Ca NEMO NEMO 3 +p +p Apoptosis PIDD MyD88 CARMA ELKS RIP1 IL-1β IL-1R IRAK1/4 Bc110 Autoubiquitination TRAF6 +u cIAP1/2 MALT1 RIP1 c-IAP1/2 c-FLIP XIAP TNFα TNF-R1 TRADD Proteasome Bcl-XL Bcl-2 gadd45β TRAF2/5 Survival –u TRAF1/2 A1/Bf1-1 CYLD NEMO Ubiquitin-mediated EDA-A1 EDAR EDARADD TRAF6 +p (S32, S36) p100 Activation of IKKα +p α noncanonical pathway TRAF3 TAK1 IKKβ IkBα Degradation (Antigen, TNF- ) EDA-A2 XEDAR TRAF6 TAB IL-8 Survival p50 DNA +u TRIM25 β α p65 IL-1 TNF- Positive feedback Virus RIG-I TRAF2/6 Canonical pathway NFkB A20 IkBα Negative feedback Infammation LBP COX2 LPS (G–) α, β CD14 TIRAP IRAR1/4 (TNF- IL-1 , LPS) MyD88 TRAF6 RIG-I-like receptor MD - 2 MIP-1β MIP-2 VCAM-1 Infammation TLR4 Btk signaling pathway (TNF-α) TRAM RIP1 (Y42) TRIF TRAF6 Pervanadate, +p hypoxia/reoxygenation IkBα Degradation (H/R), Toll-like receptor H O , EGF, CNTF, NGF DNA signaling pathway 2 2 p50 uPA Cytokine-cytokine p65 receptor interaction (H/R) Survival NFkB Bcl-XL TRAF6 (S/T(PEST)) (NGF) CD40L CD40 cIAP1/2 +p TRAF3 +u UV, HER2 CK2 IkBα Degradation TRAF2 Autoubiquitination Atypaical pathways DNA Bcl-XL TRAF6 p50 RANKL RANK Survival TRAF2 p65 A1/Bf1-1 NFkB (UV) Osteoclast diferentiation

LTA TRAF2 Partial NIK LTB TRAF5 degradation BLC ELC LT-βR Lymphoid-tissue +p +p (S866, S870) LIGHT TRAF2 p52 SLC homing NIK IKKα p100 TRAF3 DNA Myeloiesis and Re1B SDF-1α +u B-cell lymphopoiesis NFkB B-cell development TRAF2 Noncanonical pathway BAFF BAFF BAFF-R B-cell survival TRAF3 +u cIAP1/2 ICAM Lymphocyte adhesion T-cell contimulation TRAF3 (LT/LIGHT) EDA-A2 XEDAR TRAF6

04064 4/12/19 Kanehisa Laboratories Te red boxes represent genes inhibited by fsetin Figure 3: KEGG pathway: map04064.

CS-exposed rats [33]. Isoliquiritigenin was also reported to and clinical research. Oroxylin A could protect both epithelial attenuate MPO activity and MDA level via upregulating the cells and macrophages from damage by CS via activating the Nrf2 signaling pathway in a dose-dependent manner [48]. Nrf2 signaling pathway [26].

3.3. Cellular Senescence. Defining as complete and irreversible 3.4. Corticosteroid Resistance. In contrast to many other in- loss of the replicative capacity in primary somatic cells, cellular flammatory diseases, corticosteroids are largely ineffective in senescence has participated in the pathogenesis of COPD patients with COPD [40]. Peripheral blood mononuclear cells [7, 49]. Senescent cells secrete multiple inflammatory proteins (PBMCs) from patients with COPD show corticosteroid in- known as the senescence-associated secretory phenotype, sensitivity and oxidative stress reduces corticosteroid sensitivity leading to low-grade chronic inflammation, which further in vitro [54, 55]. Corticosteroid insensitivity in COPD lungs drives senescence [52]. Senescence influences lung structure explains why high doses of inhaled corticosteroids fail to slow and inflammatory cells, fibroblasts, and progenitors, making disease progression or reduce mortality [56]. ,erefore, in- repair and regeneration insufficient [53]. creasing sensitivity of corticosteroids may be an effective It is clearly shown that mangiferin produced intense therapeutic measure for COPD. cytoprotective effect in bronchial epithelial cells (BEAS-2B) Quercetin is a naturally occurring flavone isolated from [38]. Furthermore, mangiferin sped up wound healing process Polygoni avicularis herba. ,e in vitro model, quercetin and restored proliferation rate of bronchial epithelium [38]. (10 μM), was competent to restore CSE-induced cortico- Such protective effects of mangiferin stimulate further in vivo steroid insensitivity and activate adenosine monophosphate- Evidence-Based Complementary and Alternative Medicine 7 activated protein kinase (AMPK) pathways in the human in COPD patients, the percentage of NF-κB-positive cells monocytic cell line U937 and peripheral blood mononuclear and the concentrations of TNF-α and MMP-9 were mark- cells [40]. ,erefore, combining with corticosteroids, edly increased. Compared with control treatment, the levels quercetin had the potential to be a novel medication for of NF-κB-positive cells, TNF-α, and MMP-9 were reduced treating COPD. by genistein treatment. ,is clinical research indicated that genistein may provide a strategy for protecting patients with COPD. 3.5. Pulmonary Histology. Following CS exposure, there are Quercetin could inhibit acetylcholine chloride-induced significant changes in the histology of lungs in experimental continuous contractions in human bronchial airway smooth animals. In CS-exposed groups, the lung slices showed muscle strips, which indicated that quercetin could be de- enhanced peribronchial inflammatory cell infiltration, air- veloped as a bronchodilator [39]. Although quercetin has the way epithelial cell hyperplasia, airway epithelium thickening, potential to be a novel medication treating COPD, the safety alveolar space collapse, interstitial edema, and lumen ob- of quercetin in patients with COPD is still not clear. A struction by mucus and cell debris. Fortunately, these randomised clinical trial was performed to assess safety of changes can be alleviated by flavonoid treatment. quercetin [57]. COPD patients with mild-to-severe lung Baicalin relieved inflammatory cell infiltration and re- disease with FVE ranging between >35% and <80% were duced both the mean linear intercepts and the destructive 1 recruited and administrated with either placebo or quercetin index [23, 25]. Oroxylin A weakened interstitial edema, at 500, 1000, or 2000 mg/day in a dose-escalation manner. soakage of inflammatory cells, and thickened alveolar wall ,e results showed that there are no quercetin-related severe [26]. Phloretin abated peribronchial inflammatory cell in- adverse events in the patients based on evaluating lung filtration, airway epithelial cell hyperplasia, airway epithe- function, blood profile, and COPD assessment test ques- lium thickening, and lumen obstruction [28]. Hesperidin tionnaire. ,erefore, quercetin was safely tolerated up to mitigated the infiltration level of inflammatory cells, alveolar 2000 mg/day. However, the drawbacks of this trial are the space, and alveolar sacs [29]. Casticin alleviated inflam- small sample size and the short treatment time of quercetin. matory cell infiltration [34]. Similarly, isoliquiritigenin eased Hence, the safety of quercetin should be ascertained in a inflammatory cell infiltration and intra-alveolar edema [48]. larger cohort of patients for a longer time.

3.6. Pulmonary Function. Biochanin A (20 mg/kg, orally) 5. Current Trends markedly relieved airway resistance (RL), enhanced pause (Penh), and increased lung dynamic compliance (Cdyn) values COPD is an intractable respiratory disease with complicated induced by methacholine in sensitized and challenged mice pathogenic factors. Increasing studies have shown that [36]. flavonoids have certain therapeutic effects on COPD. Some ,e whole-body plethysmography method was of them exert a variety of pharmacological effects. For ex- employed to evaluate the protective effect of naringenin on ample, oroxylin A not only inhibits inflammation, oxidative the pulmonary function of CS-exposed mice [32]. ,e results stress, and cell senescence but also restores damaged lung showed that naringenin significantly improved the param- tissue. Baicalin could relieve symptoms of COPD by eters of breathing such as peak expiratory flow (PEF), peak restraining the levels of inflammation-associated cytokines inspiratory flow (PIF), and minute ventilation (MV). and oxidative stress, enhancing pulmonary function. ,e Baicalin was reported to increase the peak expiratory above findings manifest that the protective effects of fla- flow rate (PEFR), maximum ventilatory volume (MVV), and vonoids are relevant to a multitarget mode action. Fur- the forced expiratory volume in 0.3 s (FEV0.1)/functional thermore, many flavonoids could alleviate inflammation residual capacity (FRC) in CS-induced rat models [42]. response and oxidative stress via regulating NF-κB and Nrf2 Moreover, baicalin could significantly enhance the venti- signaling pathways, respectively. Based on the structure- latory parameters, including PEF, PIF, and MV in CS-ex- activity relationship theory, the collective anti-inflammatory posed mice [25]. Compared with the model group, CS- and antioxidant properties could be due to structural sim- induced rats treated with different concentrations of baicalin ilarities. Consequently, exploiting the structural similarity displayed an increased FEV0.1/FRC ratio and vital capacity may help to develop flavonoid-based novel lead compounds [24]. Moreover, administration of 40 mg/kg baicalin treating COPD. markedly prevented PaCO2 augmentation and increased However, most research studies on the treatment of PaO2 level [24]. ,ese results indicated that baicalin exerts a COPD with flavonoids are still in the laboratory stage and lung function protection role in cigarette smoke COPD rats. there are few clinical studies on flavonoids. Consequently, the roles and safety of flavonoids on patients with COPD are 4. Roles of Flavonoids in Clinical Testing vague, which greatly limits the application in the treatment of COPD. Based on the current situation, more clinical Genistein is an isoflavone that exists in various Chinese research studies are required to elucidate the efficacy and herbs such as Iridis tectori rhizoma, Sojae Semen Praepar- safety of flavonoids. In addition, we found that cigarette atum, and Sojae Semen Nigrum. Patients with COPD (n � 34; smoke or cigarette smoke extracts are commonly used in age, 71.8 ± 9.0 years) were recruited to assess the effects of laboratories to trigger off oxidative stress and inflammation genistein on COPD [41]. In the supernatant of lymphocytes to establish COPD models; however, the pathogenesis of 8 Evidence-Based Complementary and Alternative Medicine

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