key: cord-0751053-eo67ema4
authors: Ma, Bo-ning; Li, Xiao-jiaoyang
title: Resveratrol extracted from Chinese herbal medicines: A novel therapeutic strategy for lung diseases
date: 2020-09-18
journal: Chin Herb Med
DOI: 10.1016/j.chmed.2020.07.003
sha: d1e801f49a2493e1e6c5b5fb76d4a69773ab3095
doc_id: 751053
cord_uid: eo67ema4

Lung diseases and their related complications represent a critical source of morbidity and mortality globally and have become a research focus in recent years. There are plenty of hazards that threaten the health of lung by exposure to external environmental stimuli, such as dust, cigarette smoke, PM2.5, air pollution and pathogen infection. These risks lead to the impairment of lung function and subsequent lung diseases including pneumonia, chronic obstructive pulmonary disease (COPD), asthma and idiopathic pulmonary fibrosis (IPF). Compared with antibiotics and corticosteroids therapies, traditional Chinese medicine prescriptions are more effective with fewer side effects. A considerable variety of bioactive ingredients have been extracted and identified from Chinese herbal medicines and are used for the treatment of different lung diseases, including resveratrol. Increasing studies have reported promising therapeutic effects of resveratrol against lung diseases by inhibiting oxidative stress, inflammation, aging, fibrosis and cancer both in vitro and in vivo. In this review, the recent progress in the studies of lung-protective effects and underlying mechanisms of resveratrol and also highlight the potency of resveratrol and traditional Chinese prescriptions containing resveratrol as promising therapeutic options were summarized for the treatment of lung and respiratory diseases.

Lung diseases, including pneumonia, chronic obstructive pulmonary disease (COPD), asthma and idiopathic pulmonary fibrosis (IPF), have become a research focus in recent years, which are associated with substantial morbidity and mortality worldwide.

Surveys of the general population indicated that there were approximately tens of millions of people have a history of respiratory and lung diseases only in the UK.

Based on the data from Lancet Respiratory Medicine, there were more than 3.2 million people died due to COPD worldwide in 2015 (Sorathia, 2019) . As the most frequent chronic disease of childhood, asthma led to over 300 million individuals affected and more than 30 thousand people died around the world in 2012 (Brightling, Gupta, Gonem, & Siddiqui, 2012) . Generally, antibiotics, corticosteroids and lung transplants are the most common and accepted treatment options for patients with different lung diseases. Nevertheless, both systemic and local side effects of these therapies have been intensively reported. Worse yet, lack of healthy donated lungs and various complications, such as chronic lung allograft dysfunction, surgical complications and infection, continually influence transplant recipient survival and long-term consequence. Furthermore, it is difficult to avoid destructive autoimmune responses and consequent chronic impairment of lung function after lung transplantation. These above facts stimulate an increasing interest in new strategies that improve symptoms and complications in different lung diseases.

Generally, traditional Chinese medicine prescriptions consist of two or more kinds of herbs as components, which occupy an extremely important place in clinical Chinese medicine treatment. Additionally, there are several non-drug treatments, including but not limited to Chinese medicine fumigation, acupoint sticking therapy, massage therapy and acupuncture. Importantly, the National Institutes of Health (NIH) indicated that acupuncture could be included in a synthetic management program in many diseases involving asthma. Moreover, TCM therapies have shown the advantages in treating lung disease by effectively decreasing complications and fatality, preventing complications, alleviating symptoms and improving the quality of life.

In recent months, a novel coronavirus named 2019-Novel Coronavirus (2019-nCoV) has broken out and spread rapidly all over the world. Meanwhile, plenty of studies have confirmed that TCM plays an increasingly important role in the treatment of coronavirus by alleviating clinical symptoms such as cough, fever and malaise.

As recorded in Huangdi Neijing and Treatise on Febrile Disease, TCM is historically applied across Asian countries, not only used for maintaining daily health, but also for treating lung diseases. According to clinical reports, TCM has been widely used in the treatment of several lung diseases, including pneumonia, asthma, lung distention and collapsed lung ( Table 1) . TCM is used for the treatment in the acute exacerbation stage of COPD by decreasing inflammation, transforming phlegm, activating blood circulation and releasing lung pressure. Meanwhile, previous studies also report that traditional Chinese medicine prescriptions are used for the treatment of IPF through replenishing qi and activating blood formula (Zhang, Deng, Huang, & Tan, 2014) . As shown in cuspidatum, Huzhang in Chinese) is the most frequently herbal medicine used in these prescriptions. Historically, P. cuspidatum was first recorded in Ming Yi Bie Lu and has been utilized in many herbal formulas for over 2000 years. It can be either used alone or in combination with other herbs to relieve cough, reduce sputum, dispel wind-evil and dampness. Besides, after treatment with traditional Chinese prescriptions containing P. cuspidatum, clinical symptoms such as cough and asthma were eliminated and X-ray examination indicated the disappeared shadow of the lung.

Previous studies also demonstrated that traditional Chinese medicine prescriptions containing P. cuspidatum or its water decoction ameliorated pneumonia and asthma and decreased pulmonary hypertension followed by the remission of COPD symptoms (Table 1) . It has also been reported that P. cuspidatum significantly decreased levels of hydroxyproline in lung tissues and alleviated IPF in rats .

Additionally, it is also important to highlight that Lilium brownii var. viridulum Baker (L. brownii, Baihe in Chinese) is another herb medicine contained in almost all of these traditional Chinese prescriptions (Table 1) .

( 3 (Wu & Huang, 2017) . Furthermore, resveratrol has been characterized with anti-microbial, neuroprotective, anti-aging, cardioprotective and anti-cancer activities both in vivo and in vitro (Lee et al., 2018; Li, Li, & Lin, 2018) . Most recently, resveratrol was shown to protect rat lung in the early stages after lung transplantation (Xu, Lv, Wang, Ye, & Hu, 2019) . Although previous studies suggest that resveratrol or traditional Chinese prescriptions containing resveratrol has been practiced clinically to treat a variety of lung diseases, a comprehensive review with perspectives on the limitations of current pharmacology researches of resveratrol on lung diseases is still missing.

In this review, we mainly focus on the protective effects and underlying mechanisms of resveratrol on four kinds of common lung or respiratory diseases, including pneumonia, COPD, asthma and IPF. Meanwhile, this review comprehensively summarizes recent progresses, highlights findings neglected by earlier studies and provides novel insights regarding the potential use of resveratrol and traditional Chinese prescriptions containing resveratrol as promising therapeutic options for the treatment of lung disease. cuspidatum can be used alone or in combination with other herb medicines to treat lung diseases (Table 1) . Among numerous natural ingredients isolated and identified in P. cuspidatum, resveratrol and polydatin are the highest content of stilbenes (Zhang et al., 2019) .

Since December 2019, 2019-nCoV associated pneumonia has broken out and is caused by a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The unknown β-CoV strain of SARS-CoV-2 showed 79.0% nucleotide identity with the sequence of SARS-CoV. It has been previously confirmed that SARS-CoV was the cause of SARS in 2003. Furthermore, structural analysis in recent studies suggested that these two coronaviruses were able to bind to the same angiotensin-converting enzyme 2 (ACE2) receptor in humans (Lu et al., 2020) . In vivo experiments revealed that SARS-CoV ssRNA caused acute lung injury and high mortality in mice. Earlier reports indicated that resveratrol inhibited SARS-CoV-induced cytotoxic effects in vitro through directly inhibiting the replication of SARS virus (Li et al., 2006) . Although there is no experimental or clinical data to support that resveratrol can inhibit SARS-CoV-2 virus replication, news from Shanghai Institute of Medicine reveals that SARS-CoV-2 may be suppressed by several bioactive ingredients isolated from P.

cuspidatum, which was an important source of resveratrol. These data suggest a potential therapeutic role of resveratrol in SARS-CoV-2-induced severe acute respiratory syndrome, although further experimental evidence is required.

On the one hand, Serratia marcescens is a nosocomial pathogen and has been recognized as an important agent of hospital-acquired pneumonia in the past two decades. Researchers found that pretreatment with resveratrol for 3 d enhanced NK cell activity, markedly elevated alveolar macrophage infiltration and reduced pneumonia via decreasing bacterial burden in the infected lung (Long et al., 2016) .

Activated I-kappa-B-alpha (IκB) kinases (IKKα/β) phosphorylated and degraded IκB to induce the nuclear translocation of nuclear factor-kappa B (NF-κB) p65. As an evolutionarily conserved signaling molecule, phosphorylated NF-κB p65 further enhanced the efficiency of DNA binding and provided an additional interaction site for transcriptional co-activator CBP/p300 to exert many biological activities (Liu et al., 2015) . Emerging evidence suggests that resveratrol alleviated Serratia marcescens-induced acute pneumonia through suppression of IκB phosphorylation and NF-κB activation in rats (Lu, Lai, Hsieh, & Chen, 2008) . On the other hand, resveratrol is an alternative agent for the precaution and treatment of Staphylococcus aureus-associated pneumonia. It is well-established that Nod-like receptor (NLR) family pyrin domain containing-3 (NLRP3) inflammasome is a caspase-1-triggering multiprotein complex that plays an essential role in the progression of inflammatory diseases via regulating the release of cytokines. The previous report demonstrated that resveratrol improved S. aureus-induced pneumonia in mice by significantly decreasing the mRNA and protein expression of Caspase-1, NLRP3 and apoptosis-associated speck-like protein (ASC) (Wu & Huang, 2017) . It has been well documented that NF-kB expression and relative NLRP3 targets are regulated by p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinases 1 and 2(JNK1/2) and activator protein 1 (AP-1) signaling pathways in various cell types.

Interestingly, further studies have indicated that resveratrol not only suppressed the S. aureus-upregulated phosphorylation of c-Src, platelet-derived growth factor receptor (PDGFR), p38 MAPK, JNK1/2 and AP-1, but also inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) in human lung epithelial cells ( 

COPD is a lung disease characterized by continuous and irreversible respiratory symptoms, including dyspnea, cough, nasal congestion, more sputum, chest tightness and persistent inflammation. It is well established that mucus hypersecretion caused by chronic airway and lung parenchyma inflammation is a common feature in COPD. The main reason for excessive mucus includes CS exposure, acute and chronic bacterial infection or viral infection. Epidemiological data indicated that COPD was a leading cause of death, accounting for more than 3 million in 2012, and it will become the third leading cause of death worldwide by 2020 (Kim & Criner, 2013) . Hence, the identification and evaluation of novel therapeutic targets for the treatment of COPD are urgent.

Pulmonary rehabilitation is a treatment that ameliorates the psychological and physical condition of patients with COPD by uniting exercise regimen and education about self-care. It is generally accepted that pulmonary rehabilitation is an effective therapy for patients with COPD and improve their health-related quality of life. However, present treatments are not capable of completely suppressing inflammation and delaying disease progression associated with COPD. Sirtuin1 (SIRT1) is an NAD + -dependent type III histone/protein deacetylase that regulates cellular senescence, inflammation and stress resistance. Recently, there are several studies illuminated that resveratrol is an activator of S1RT1 and might mitigate COPD by activating the SIRT1 pathway (Fig. 1) . AMP-activated protein kinase (AMPK) is associated with the regulation of energetic metabolism, insulin resistance and inflammation. Qi et al. indicated that the expression of AMPK was markedly reduced, which led to the dysfunction of muscle metabolism in COPD rats. They also found that SIRT1 stimulated AMPK expression under the moderate concentration of resveratrol (Qi et al., 2014) . These studies suggest that resveratrol-induced SIRT1 serves as superoxide dismutase 1 (SOD1) and SOD2 and further protects against oxidative stress . A previous study showed that resveratrol reduced oxidative damage in mice by activating nuclear SIRT1 and triggering ROS detoxifying enzyme, SOD2 (Sebori, Kuno, Hosoda, Hayashi, & Horio, 2018) . Wang et al further reported that resveratrol prevented oxidative stress in COPD module rats by upregulating the expression of SIRT1 and PGC-1α (Wang, Li, Li, Miao, & Xiao, 2017 

Asthma is a common disease caused by chronic inflammation of the lower respiratory Exposure to indoor and outdoor pollutants, innate immune activation is a significant determinant of asthma severity. Previous studies showed that resveratrol frustrated airway inflammation and airway hyperreactivity (AHR) induced by OVA in several murine models of asthma (Fig. 2) . It has been reported that OVA-specific IgE, IgG2a, and Th2 inflammatory cytokines, such as IL-4 and IL-5, were effectively decreased by resveratrol treatment. Moreover, resveratrol also significantly suppressed mucus hypersecretion, AHR, and eosinophilia (Lee et al., 2009) . In OVA-induced mouse model, resveratrol was found to markedly reduce the serum levels of IL-5, IL-13 and TGF-β, decrease total cell counts of CD3 + CD4 + , CD3 + CD8 + and CD3 + CD4 + IL-4 (Th2 cells) in lungs through downregulating miR-34a and subsequent inducing FOXP3, a critical mediator of T regulatory cell (Treg) functions (Alharris et al., 2018) .

Concurrently, another study demonstrated that resveratrol prevented the progression of asthma through upregulating phosphatase and tensin homolog (PTEN) and SIRT1 signaling pathway. Furthermore, PTEN overexpression reduced the area of smooth muscle, inner airway wall and mucous glands, and further improved asthma, which was prevented by SIRT1 inhibitor and shRNA (Chen et al., 2015) . Transforming Besides, emerging studies reported the therapeutic effects of resveratrol in the treatment of asthma in other mouse models. Respiratory syncytial virus (RSV)

infections cause lower respiratory tract infections of children and also play an important role in old people with asthma. Recent studies have indicated that RSV-mediated airway inflammation and AHR were alleviated by resveratrol via regulating TLR3 expression and suppressing the TRIF signaling pathway in mice (Zang et al., 2011) . Insulin signaling transmission in the lungs plays an essential role in obesity-associated asthma exacerbations. Recently, researchers found that after resveratrol treatment, OVA-challenged pulmonary eosinophil infiltration and insulin resistance in obese mice were markedly abrogated. Resveratrol also significantly increased the phosphorylated AMPK expression, reduced the expression of p47phox and TNF-α and prevented ROS production in lung tissues of obese mice (Andre et al., 2016) .

Furthermore, another study demonstrated that resveratrol administration improved allergic airway inflammation and obesity-associated asthma exacerbations by restoring insulin-induced phosphorylation of Akt, insulin receptor substrate 1 (IRS-1) and insulin receptor β (IRβ), decreasing JNK and NF-κB signaling pathways in lung tissues of obese mice (Andre et al., 2017) .

IPF is a chronic and fibrotic lung disease characterized by progressive scarring of the lungs and is the pathological hallmark of usual interstitial pneumonia.

Excessive deposition of ECM proteins further leads to the destruction of lung structure and function, disrupted gas exchange and ultimately fatal outcome. IPF is associated with an inevitable recession in lung function, later, superimposed complications lead to the rapid exacerbation of clinical courses in IPF patients.

Two anti-fibrotic medications, pirfenidone and nintedanib are sanctioned for the treatment of patients with mild to moderate IPF over the last 5 years (Tran & Suissa, 2018 ).

An increasing number of studies have been affirmed that resveratrol treatment is an ideal method to alleviate IPF (Fig. 3) . TGF-β1 is shown to regulate mRNA and protein expression of α-SMA through the Smad2/3 pathway and also promote the phosphorylation of Akt and ERK1/2 signaling pathways (Heldin & Moustakas, 2016).

Fagone et al. investigated the effects of resveratrol on TGF-β-induced activation of human pulmonary fibroblasts into myofibroblasts. They found that resveratrol repressed TGF-β-induced collagen production, lung fibroblast proliferation and inhibited the mRNA and protein levels of α-SMA through inhibiting the phosphorylation of ERK1/2 and Akt and restoring PTEN expression (Fagone et al., 2011) . Further studies demonstrated that resveratrol treatment downregulated TGF-β1 levels, decreased the activities of SOD and CAT and ameliorated pulmonary fibrosis in the LPS-induced mouse model via suppression of TGF-β1/Smad2/3/4 signaling pathway (Zhang et al., 2015) .

In addition, miR-21 was significantly induced in bleomycin ( Furthermore, several clinical and experimental studies indicate that the incidence and severity of IPF are influenced by cellular alterations and age.

Genetically, epigenetic methylations and general genetic mutations accumulated over a person's lifespan, while the expression of miRNA changed from birth to adulthood.

These age-related alterations may result in gene deregulation, activated oxidative stress and accumulation of dysfunctional organelles, resulting in the development of lung disease. It has been well established that several proteases, cytokines and growth factors were secreted by injured epithelial cells, which further promoted the migration, activation and proliferation of fibroblasts and finally contributed to lung injury (Zhao, Wang, Qiu, Liu, & Yao, 2020) . Resveratrol has been reported to be involved in the regulation of lifespan, health maintenance and age-associated disorders (Li et al., 2018) . Additionally, resveratrol is a potential method for slowing aging-related exacerbation of lung function and structure by keeping AEC2

integrity (Navarro et al., 2017) .

From ancient times until now, P. cuspidatum is one of the most effective and frequently used herbal medicine in traditional Chinese prescriptions and is prescribed for the treatment of lung diseases. A variety of clinic reports and experimental studies have been investigated the medicinal properties of crude extracts from P. cuspidatum. However, among the major and most representative ingredients isolated from P. cuspidatum, there is seldom a report highlight the importance of resveratrol in the treatment of acute or chronic lung diseases. In the present review, we comprehensively reviewed these findings. The oxidative stress and inflammation in alveolar macrophages play a key role in the pathogenesis and progression of lung disease. As a natural product isolated from various fruits and herbs, resveratrol elevated alveolar macrophage infiltration, alleviated the oxidative stress progression and improved the inflammation process by regulating MAPK/IκB/NF-κB, HMGB1/TLR4/NF-κB and SIRT1/PGC-1α pathway, which further protected the lung from external stimuli. On the other hand, resveratrol also inhibited the release of many cytokines and suppressed lung inflammation in mice by significantly decreasing the levels of Caspase-1, NLRP3 and ASC, regulating p38 MAPK/JNK1/2/AP-1 and ERK1/2/MyD88 signaling pathways. It also exerted protective effects on lung diseases by significantly suppressing mucus hypersecretion, AHR, and eosinophilia.

More intriguingly, resveratrol was reported to inhibit fibroblast activation and lung fibrosis by directly reducing TGF-β/Smad2/3/4 pathway or interacting with several miRNAs.

There are several factors lead to lung diseases, such as CS, air pollution and aging. Indeed, age is a significant and inevitable risk factor for chronic diseases, especially for lung diseases, which is often overlooked in clinical practice. In summary, lung disease is one of the most important health issues that directly affect the life quality of patients and antibiotics are the commonly used drugs in the treatment of lung disease clinically. However, the long-term use of antibiotics is causing many inevitable side effects. Besides that, current pharmacological treatments are still inadequate to reduce the progression and mortality of lung disease worldwide. Notably, traditional Chinese prescriptions have substantial therapeutic effects with rare side effects on several chronic diseases, including lung diseases. Compared with conventional treatments, bioactive natural ingredients derived from natural herbs may provide additional benefits in the prevention of lung diseases, including pneumonia, COPD, asthma and IPF, and represent an important source of novel drug screening and development. Resveratrol is a potential and beneficial drug candidate, which has drawn a great deal of attention due to its potent anti-microbial, neuroprotective, anti-aging, cardioprotective and anti-cancer activities. Further extensive evaluation of the bioactivities of resveratrol, identification of specific molecular-target as well as structure-activity relationship is urgently needed. Further pharmacology research will contribute to the development of resveratrol or traditional Chinese prescriptions containing resveratrol not only as a potential health supplement but also as health-promoting medicines in the near future.

Dr. X. Li conceived the original idea. Dr. X. Li and Ms. B. Ma wrote the manuscript.

Ms. B. Ma revised figures and Table 1 .

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Niu et al., 2005) 

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