Author’s Accepted Manuscript Autophagy modulators from traditional Chinese medicine: mechanisms and therapeutic potentials for cancer and neurodegenerative diseases Sheng-Fang Wang, Ming-Yue Wu, Cui-Zan Cai, Min Li, Jia-Hong Lu

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S0378-8741(16)31473-8 JEP10527

To appear in: Journal of Ethnopharmacology Received date: 15 June 2016 Revised date: 19 October 2016 Accepted date: 21 October 2016 Cite this article as: Sheng-Fang Wang, Ming-Yue Wu, Cui-Zan Cai, Min Li and Jia-Hong Lu, Autophagy modulators from traditional Chinese medicine: mechanisms and therapeutic potentials for cancer and neurodegenerative diseases, Journal of Ethnopharmacology, This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Autophagy modulators from traditional Chinese medicine: mechanisms and therapeutic potentials for cancer and neurodegenerative diseases Sheng-Fang Wang1, Ming-Yue Wu1, Cui-Zan Cai1, Min Li2*, Jia-Hong Lu1* 1

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 2 School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong. * Corresponding author.

Abstract Ethnopharmacological relevance Traditional Chinese medicine (TCM), an ancient yet still alive medicinal system widely used in East Asia, has played an essential role in health maintenance and diseases control, for a wide range of human chronic diseases like cancers and neurodegenerative diseases. TCM-derived compounds and extracts attract wide attention for their potential application as therapeutic agents against above mentioned diseases. Aim of review Recent years the enthusiasm in searching for autophagy regulators for human diseases has yielded many positive hits. TCM-derived compounds as important sources for drug discovery have been widely tested in different models for autophagy modulation. Here we summarize the current progress in the discovery of natural autophagy regulators from TCM for the therapeutic application in cancer and neurodegenerative disease models, aiming to provide the direct link from traditional use to new pharmacological application. Methods The present review collected the literature published during the recent 10 years which studied the effect of TCM-derived compounds or extracts on autophagy regulation from PubMed, Web of Science, Google Scholar and Science Direct. The names of chemical compounds studied in this article are corresponding to the information in journal plant list. Results In this review, we give a brief introduction about the autophagy and its roles in cancer and neurodegenerative disease models and describe the molecular mechanisms of autophagy modulation. We also make comprehensive lists to summarize the effects and underlying mechanisms of TCM-derived autophagy regulators in cancer and neurodegenerative disease models. In the end of the review, we discuss the current strategies, problems and future direction for TCM-derived autophagy regulators in the treatment of human diseases. Conclusions A number of data from in vivo and in vitro models indicated TCM derived compounds and extract hold great potential for the treatment of human diseases including cancers

and neurodegenerative diseases. Autophagy, as a novel and promising drug target involved in a wide range of human disease, can be modulated by many TCM derived agents, indicating autophagy modulation may be an important mechanism underlying the therapeutic effect of TCM in treating diseases. Furthermore, we look forward to seeing the discovery of ideal autophagy modulators from TCM with considerably higher selectivity for the treatment of human diseases. Keywords: Autophagy, TCM, cancer, neurodegenerative diseases

Chemical compounds studied in this article Berberine (PubChem CID: 2353); Piperine (PubChem CID: 638024); Matrine (PubChem CID: 91466); Baicalin (PubChem CID: 64982); Fucoidan (PubChem CID: 9812534); Celastrol (PubChem CID: 122724); Quercetin (PubChem CID: 5280343); Resveratrol (PubChem CID: 91745415); Wogonin (PubChem CID: 5281703); Curcumin (PubChem CID: 969516) 1. Introduction Autophagy is a lysosome-mediated bulk degradation process that occurs in all eukaryotic cells from yeasts to mammals(Karakaş and GÖZÜAÇIK, 2014). There are three types of autophagy: chaperone-mediated autophagy, microautophagy and macroautophagy. Different kinds of autophagy differ in their formation processes and related functions (Karakaş and GÖZÜAÇIK, 2014; Mizushima et al., 2008; Weckman et al., 2015). Generally, the term “autophagy” refers to macroautophagy, henceforth in this paper we will use the shorter term “autophagy” accordingly. Autophagy starts from the expansion of double membrane structure called phagophore which extends to engulf various intracellular cargos, including Golgi, mitochondrion, superfluous and damaged organelles and cytosolic protein aggregates to form vesicle called autophagosome. Two ubiquitin like conjugation systems namely ATG5-ATG12 conjugation system and Atg8/LC3 lipidation system play essential roles during the initiation and expansion of autophagosome(Choi et al., 2013; Mizushima et al., 2008; Parzych and Klionsky, 2014), then the autophagosome fuses with lysosome to form autolysosome where the cargos are degraded to release amino acids, nucleotides, ATP and fatty acids into cytosol for the maintenance of basic metabolism(Levine and Kroemer, 2008; Mizushima, 2007; Weckman et al., 2015). Recent studies have shown that autophagy played a role in recycling iron complexes(White, 2015); sustaining the stability of chromosome(Mathew et al., 2007; Schmeisser et al., 2014); counteracting apoptosis; regulating immunity and host defense(Crotzer and Blum, 2009). It is widely accepted that autophagy mainly serves as a stress-adaption and survival mechanism. Autophagy is not only involved in physiological condition but also implicated in a wide spectrum of pathological condition(Weckman et al., 2015). For example, mice with autophagy defects were shown to develop neurodegenerative diseases, tumor, chronic inflammation, steatohepatitis and muscle damage(Levine et al., 2011; Mizushima and Komatsu, 2011). Some autophagy-related diseases have been summarized in the following table 1.

Recent years the enthusiasm in searching for autophagy regulators for human diseases has yielded many positive hits. TCM-derived compounds as important sources for drug discovery have been widely tested in different models for autophagy. Here we summarize the current progress in the discovery of natural autophagy regulators from TCM for the therapeutic application in cancer and neurodegenerative disease models.

Figure 1 Autophagy regulation in cancer and neurodegenerative disease.

2. Autophagy and human diseases 2.1 Molecular mechanisms of autophagy regulation Autophgy is a complex process composed of cargo recognition and selectivity, autophagosome formation, vesicle fusion and autolysosome forms(He and Klionsky, 2009). Different autophagy genes play different roles in the formation of autolysosome. Mammalian two Atg1 homologues(ULK1 and ULK2), Atg13 and FIP200 formed ULK complexes (ULK-Atg13-FIP200), which plays an essential role in the initiation of autophagy, mainly manifested in receiving signal of nutrient condition, recruiting downstream Atg proteins to participate in autophagosome formation(Mizushima, 2010), which was regulated by m-TORC1 under nutrient-deficient condition(Hara et al., 2008; Jung et al., 2009). When m-TORC1 was inhibited by rapamycin, ULK was activated to phosphorylate FIP200 to induce autophagy(Jung et al., 2009). AMPK also acted during this process to induce autophagy to keep cell survival during starvation(Egan et al., 2011). Beclin1-PI3KC3 complex is another essential autophagy complex for autophagosome formation, which mainly plays role in nucleation and initial phagophore membrane formation. In yeast, Beclin1-PI3KC3 complex involved Atg14-Beclin1-PI3KC3, while in mammalian, Beclin1-PI3KC3 complex is composed of Atg14L-Beclin1-PI3KC3, which contributed to the autophagosome formation(Itakura et al., 2008; Mizushima, 2010). There has been reported silencing of human Atg14 in Hela cells inhibited autophagosome formation(Itakura et al., 2008). Beclin1-PI3KC3 complex was

involved in PAS targeting of a number of Atg proteins to regulate autophagosome and maturation in mammalian cells(Obara et al., 2008; Strømhaug et al., 2004). What is more, Atg14-Beclin1-PI3KC3 complex recruits two inter-related UBL conjugation systems to the phagophore to regulate the membrane elongation and autophagosome expansion(He and Klionsky, 2009). Two UBL proteins Atg12 and LC3/Atg8 undergoing conjugation in a similar manner as ubiquitin play a critical role during the autophagosome formation. In the activation of Atg7, Atg12 attached to Atg5 and further interacted with protein Atg16 to form Atg12-Atg5-Atg16 complex(Mizushima et al., 1999) having novel activities as E3 like enzyme function, which facilitates another UBL protein conjugation Atg8/LC3 to target at phosphatidylethanolamine to form other conjugation systems like Atg8/LC3-PE(Hanada et al., 2007). When confronted with the stresses like nutrient deficient or stimuli, Atg12-Atg5-Atg16 complex responsible for Atg8/LC3 lipidation and conjugation locating to both sides of phagophore to regulate autophagy induction(Fujita et al., 2008; Geng and Klionsky, 2008; Kirisako et al., 1999). During the process, there exists a “molecular switch” to mediate the turn-on and turn-off of autophagy. Beclin1 interacts with Vps34/PI3KCIII through its highly evolutionary conserved domain, which is responsible for Beclin1 to regulate autophagy to inhibit tumoregenesis(AdiϋHarel et al., 2010; Furuya et al., 2005). Besides, other proteins like UVRAG and Bcl-2 family proteins through the interaction with Beclin1 to regulate autophagy(Erlich et al., 2007; Liang et al., 2006; Zalckvar et al., 2009). Mammalian target of rapamycin (m-TOR) is a negative regulator of autophagy(He and Klionsky, 2009). Several kinases including AMPK and PI3K-I/AKT regulate autophagy pathway via interaction with m-TOR directly or non-directly. PI3K-I/AKT and p70S6 respectively play roles in the upstream and downstream of m-TOR(Gleason et al., 2007; Steelman et al., 2011). Under the stimulation of growth factors, PI3K-I/AKT activates cell proliferation mechanisms, which promotes m-TOR activity and suppresses autophagy pathway. Tumor suppressor proteins like TSC1/TSC2 also promote autophagy to inhibit cancer via the suppression of m-TOR pathway(Inoki et al., 2003). p62, a central regulator of autophagy and cell death, is aberrantly activated in many types of cancer. It has been demonstrated that autophagy deficiency leaded to p62 accumulates, which were critical for tumorigenesis in vivo and in vitro(Komatsu et al., 2007; Mathew et al., 2009b). Conversely, p62 deficiency inhibited tumorigenesis in lung cancer(Duran et al., 2008). The aggregates were absent when the mice lacked both genes Atg7 and p62 at the same time which revealed p62 functioned in the formation of aggregates(Moscat and Diaz-Meco, 2009). Interestingly, under the condition of nutrient deficiency, p62 provided a safeguard mechanism to maintain cell survival via the interaction with TORC1 to induce autophagy(Moscat and Diaz-Meco, 2012). Recent studies have revealed the ability of p62 to mediate autophagy-dependent cancer suppression was related to ROS suppression and NRF2 activation by the interaction of Keap1 and p62(Jaramillo and Zhang, 2013; Komatsu et al., 2010). NRF2, an essential regulator in cell defense and survival pathways, can protect cell from toxicants and carcinogens by promoting the expression of cytoprotective genes, which indicated NRF2 can not only protect normal cells but also cancer cells from chemotherapeutic(Jaramillo and Zhang, 2013). Additionally, the tumor suppressor protein p53 also has been shown to regulate autophagy in a bi-direction manner(Maiuri et al., 2009).

2.2 Autophagy and cancer During different stages of cancer development, autophagy plays completely different roles. For example, Beclin1, an essential genes involved in the formation process of autophagy, which was loss in 40%-75% of sporadic human breast cancers(Opipari et al., 2004), later Beclin1 was proven to be a tumor suppressor gene(Liang et al., 1999). It was indicated that autophagy was up-regulated in RAS-transformed cancer cells to promote cancer cell growth, survival, tumorigenesis, invasion, and metastases(Guo et al., 2011; Lock et al., 2014; Lock et al., 2011; Yang, S. et al., 2011). Accumulating data revealed that autophagy exerted complex effects on cancer and served as a double-edged sword in the process of cancer development. In the early stage of tumorigenesis, autophagy gene Beclin1 knockout mice showed an increased incidence of spontaneous tumors, over-expression of Beclin1 inhibited development of tumor(Liang et al., 1999). Furthermore, mice with Atg5 and Atg7 deletion developed liver adenomas(Qu et al., 2003; Yue et al., 2003). When exposed to the condition of metabolic stress (i.e. damaged and excessive organelles, damaged DNA and ROS production), the incidence of cancers increases dramatically(Mathew et al., 2009a). Autophagy-defective cells with p62/SQSTM 1 knockout prevented against ROS and the DNA damage response(Mathew et al., 2009b). The relationship between defective autophagy and p62/SASTM 1 accumulation in tumorigenesis was also indicated in a study p62/SASTM 1 knockout mice were prevented from RAS-induced lung carcinomas(Duran et al., 2008). It has been reported that the autophagy gene PARK2(Fujiwara et al., 2008) and transcription factor NRF2(White, 2012) play significant role during this process. During the formation of cancer accompanied by autophagy incompetence, cells were reported to be more prone to undergo necrotic cell death, resulting in the extracellular release of cellular contents and inflammatory responses, which are related to the formation of cancer(Karakaş and GÖZÜAÇIK, 2014). Another anti-tumor mechanism of autophagy may be the activation of senescence which is activated in normal cells in response to cancer to restrict normal cell growth and proliferation(Young et al., 2009). Additionally, autophagy was implicated in event that modulated immune surveillance via its role in antigen presentation, T cells and B cells maturation, inflammation as well as necrosis(Carneiro and Travassos, 2013; Münz, 2009; Ma et al., 2013; Viry et al., 2014), which are associated with the release of pro-inflammatory HMGB1(Tang et al., 2010). p53, a cancer suppressor gene, has been linked to autophagy regulation in a double phase manners in recent studies (D’Amelio and Cecconi, 2009; Feng et al., 2005; Tasdemir et al., 2008b). Together, these findings establish a role for autophagy as a mechanism of tumor suppression. Relevant studies also revealed established cancer cells have higher metabolic demands due to a high proliferation rate. There is no doubt that cancer cells are sensitive to confront with hypoxemia, insufficiency of growth factors and nutrition resulting from insufficient vascularization(Choi et al., 2013), damaged stimuli and proteasome inhibition(White, 2012). These stressful stimuli activate autophagy served as tumor-survival mechanism via degradation some intracellular substances to maintain cellular biosynthesis and ATP level. This was firstly indicated in the study that autophagosomes were rich in the hypoxic tumor regions, defects of autophagy genes led to cancer cells death in hypoxic tumor regions(Mathew et al., 2007). It was

also indicated that autophagy was up-regulated in RAS-transformed cancer cells and promoted their growth, survival, tumorigenesis, invasion, and metastasis(Guo et al., 2011; Lock et al., 2014; Lock et al., 2011; Yang, S. et al., 2011), which led to the concept that RAS-driven cancers may be “autophagy addicted”(Guo et al., 2011; Guo et al., 2013b; Yang, S. et al., 2011). The strong evidence supporting the concept came from in vivo models of cancer in which autophagy sustained tumor metabolism, maintained mitochondrial quality and mitochondrial function, controlled reactive oxygen production and allowed nutrient recycling(Guo et al., 2013a). Instead, suppression of autophagy in tumor cells such as RAS-driven cancer cell inhibited cells growth(Yang, Z.J. et al., 2011). Furthermore, autophagy also assisted cancer cells to resist anoikis, a special type of apoptosis, and activated cell to detach from the basal lamina, a property that facilitates tumor cells evasion from primary sites, invasion, and spread(Fung et al., 2008). Recently, a concept called dormancy related to autophagy emerged to enable cancer cells to resist chemotherapy or radiation(Gewirtz, 2009), this can intervene clinical treatment of cancer due to the tumor concurrence and progression(Lu, Z. et al., 2008). It should be noted that the inhibition of autophagy in tumor cells may improve the efficacy of anticancer drug. Consequently, owing to complex mechanisms of autophagy and relationship between cancer and autophagy, further studies should be carried out to find out the right strategies for using autophagy modulator as novel cancer treatment approach.

2.3 Autophagy and neurodegenerative diseases Neurodegenerative diseases are age-dependent diseases which are caused by the loss of neurons and spinal marrows, leading to functional disorders of brain. The basic pathological characteristics of neurodegenerative diseases commonly include the intracellular accumulation of aggregate-prone proteins, as well as the damaged protein degradation systems(Goedert et al., 2010; Jellinger, 2010) including ubiquitin-proteasome system and autophagy pathway. The pathogenic insults result in neurotoxicity like axonal transport blockage and transcriptional interruption in brain(Millecamps and Julien, 2013; Ravikumar and Rubinsztein, 2004). As for nerve cells, known as post-mitotic cells, which means dysfunctional organelles and cellular wastes can’t be diluted by a way of cell division(Kesidou et al., 2013; Martinez-Vicente, 2015; Nixon, 2013). Consequently, nervous system indeed needs an inter-degradation system to clear intracellular misfolded protein aggregates. As the popular research finding showed, autophagy acted as the clearance mechanism to degrade mutant proteins to keep homeostasis. So autophagy plays an essentially adaptive role in neurodegenerative diseases. For further investigating the exact role of autophagy in neurodegenerative diseases, transgenic animals with deletion of autophagy genes like Atg5, Atg7 or Becin1 have been established and many neurodegeneration-like phenotypes have been obviously observed. Decreased neuronal autophagy resulted in neurodegeneration and disruption of lysosomes in the early AD(Hara et al., 2006; Pickford et al., 2008). Further, the protective role of autophagy in central nervous system was convincingly demonstrated by the studies using genetic or chemical modulators of autophagy to alleviate symptoms related to neurodegenerative diseases in mouse models(Ravikumar et al., 2004; Schaeffer et al., 2012). As we known, the synaptic protein α-synuclein accumulations were the hallmark of PD, which was associated with the alteration of autophagy pathway.

There has been reported the expression of Beclin1 activated autophagy to decrease the level of α-synuclein and ameliorate associated neuritic alteration in vivo and in vitro(Spencer et al., 2009). Recent study revealed TFEB, a significant transcriptional regulator of the autophagy-lysosome pathway was closely associated with PD pathogenesis(Decressac et al., 2013). Over-expression of TFEB contributed to neuro-protection via the clearance of α-synuclein while delayed activation of TFEB deteriorated the PD progression(Decressac et al., 2013). Chemical modulators like rapamycin, an inhibitor of certain m-TOR, provided a neuro-protective role in vitro and in vivo model of PD through the blockage of some actions like p70S6K activation to suppress neuron death in PD(Jefferies et al., 1997). Mammalian target of rapamycin(m-TOR) was reported to attenuate Htt mutant accumulations and cell death in cell model of Huntington disease(Sarkar et al., 2009), as well as in a fly model of Huntington disease(Ravikumar et al., 2004). Additionally, autophagy regulator derived from TCM, Trehalose has been reported to be a m-TOR-independent autophagy activator to enhance the clearance of mutant Huntingtin and mutant α-synuclein to prevent cells against subsequent pro-apoptotic insults via autophagy induction(Sarkar et al., 2007a). l

Autophagy and Alzheimer’s disease (AD)

Alzheimer’s disease is characterized by two key histopathological hallmarks: senile plaque (SP) composed of amyloid beta peptides generating from APP through the degradation function of β-secretase and λ-secretase, and neurofibrillary tangles made up of phosphorylated tau protein associated with the formation and stabilization of microtube. Earlier studies have suggested autophagic vacuoles were observed abundantly in AD brain(Cheung and Ip, 2011; Son et al., 2012). Autophagy genes including Beclin1 dysfunction has been linked to the pathogenesis of AD. A convincing research evidence indicated the impairment of autolysosome acidification, cathepsin activation or retrograde transport were closely related to AD, which were caused by the failure of PS-1-dependent targeting of v-ATPase subunit to lysosomes(Lee et al., 2010; Son et al., 2012). All these data indicated the impairment of autophagolysosome formation and maturation may contribute to the gradual accumulation of Aβ and lead to AD in the end. On the contrary, recently compelling evidence indicates that Aβ is generated from autophagic vacuoles, suggesting that autophagy activation in AD brains may exacerbate AD pathogenesis by increasing Aβ levels(Nixon, 2007; Nixon et al., 2005; Yu et al., 2005).


Autophagy and Parkinson’s disease (PD)

PD is a neurodegenerative disorder featured by the selective death of dopaminergic neurons in substantia nigra and the accumulation of cytoplasmic inclusions called Lewy bodies, containing α-synuclein and ubiquitin. The accumulation of α-synuclein can be degraded via autophagy pathway(Crews et al., 2010). However, α-synuclein accumulation in cytoplasm has been shown to impair macroautophagy(Winslow et al., 2010) and CMA(Vogiatzi et al., 2008), which means accumulation of α-synuclein could in turn deteriorate the function of autophagy. Recent research also reported the PD-related proteins like DJ-1, an important regulator of redox signal pathway(Kahle et al., 2009), as well as PINK1 interacts with Beclin1 promoted autophagy process to intervene the pathogenic events of PD(Michiorri et al., 2010). Another pathological

characteristic of PD involves in mitochondrial dysfunction. PD-related genes like PINK1 and Parkin play essential roles in promoting basal autophagy and normal mitochondrial balance by mediating mitophagy, a subtype of autophagy for mitochondria turnover. PINK1 mutations abrogated mitophagy and resulted in the accumulation of damaged mitochondria(Geisler et al., 2010b). Recent data showed VDAC1 and p62/SQSTM1 also contributed to the PINK1/Parkin-mediated clearance of mitochondria(Geisler et al., 2010a).


Autophagy and Huntington’s disease(HD)

Huntington’s disease is a progressive neurodegenerative disease caused by the abnormal repeats of CAG in huntingtin gene, which encodes an expanded polyglutamine stretch at the N-terminus of Htt protein. The expansion of polyQ in Htt protein beyond 36 has complete penetrance in development of HD. These protein aggregates in neurons rely on autophagy pathway to degrade themselves in order to maintain the homeostasis. The features of altered autophagy were first observed in postmortem brain of HD(TELLEZ-NAGEL et al., 1974). Furthermore, the research on fly and mouse models of Huntington showed the sequestration of m-TOR induced autophagy and accelerated the clearance for Htt proteins(Ravikumar et al., 2004; Shintani and Klionsky, 2004). Recent study reported some new small molecules enhancers (SMER) cleared Htt proteins to reduce toxicity in HD models via autophagy induction(Sarkar et al., 2007b). Recent study also indicated the inefficient engulfment of cytosolic components by autophagosome is responsible for the Htt slower turnover, functional decay and accumulations in HD cells(Martinez-Vicente et al., 2010). In addition, the sequestration of Beclin1, a gene essential for autophagy, can reduce the function of degradation of Htt proteins, which means that induction of autophagy pathway plays a significant role in HD alleviation 2.4 Autophagy and cardiovascular diseases and cerebrovascular diseases Autophagy has been reported to be associated with many cardiovascular diseases and cerebrovascular diseases, including stroke, hypertension, atherosclerosis and cardiomyopathy(De Meyer and Martinet, 2009; Mei et al., 2015; Wen et al., 2008; Zhu et al., 2007). On the one hand, autophgy pathway is adaptive in a model of proteotoxic cardiomyopathy, which not only has been confirmed in vivo and in vitro model, but also in clinical patients. For instance, deficiency in LAMP2, which is essential to autophagosome-lysosome fusion leads to Danon’s disease(Nishino et al., 2000). Autophagic activity was also shown to provide cardio protection in vivo mode with desmin-related cardiomyopathy(Tannous et al., 2008). What’ more, it has been clued that autophagy may stabilize atherosclerotic plaques through preventing macrophage apoptosis and plaque necrosis and by preserving efferocytosis(Liao et al., 2012). However, excessive autophagy leads to autophagic cell death to deteriorate human diseases, which has been revealed in stroke and atherosclerosis(Wen et al., 2008). 2.5 Autophagy and immune system diseases Autophagy contributes to the regulation of innate and adaptive immune responses. It has been clued many pathogens including bacteria, viruses and parasites can targeted

to autophagosomes for degradation. Furthermore, an increasing number of data uncovered deletion of specific autophagy genes caused susceptibility to infection or even led to immune diseases. For example, metazoan specific autophagy-related gene EPG5 mutations lead to autophagy defective and causes Vici syndrome(Cullup et al., 2013). Other autopahgy-related genes like NOD2, IRGM and ATG16L1 variants cause autophagy defects and leads to the impairment of bacterial handing and bacterial capture which increased the risk of Crohn’disease(Kuballa et al., 2008; Parkes et al., 2007). Thus, targetting at the regulation of autophagy by the enhancement of strategies to target intracellular pathogens to autophagosomes or by the inhibition of microbial virulence factors that block host autophagy defenses can present novel strategies for the treatment of immune system diseases.

Table 1 Autophagy associated human diseases On the initiation of cancer Autophagy modulates immune surveillance to play a role in anticancer

(Viry et al., 2014)

Metabolic stresses, mitochondrial dysfunction and DNA damages result in cancer due to defective autophagy

(Mathew et al., 2009a)

Activation of the PI3K/Akt pathway leads to decreased autophagy via m-TOR activation


(Guertin and Sabatini, 2007)

Bcl-2 over-expression inhibits autophagy through interaction with Beclin1 to inhibit cancer cell apoptosis

(Maiuri et al., 2007)

Activation of p53 in the condition of stresses leads to the autophagy induction to function as a tumor suppressor

(Tasdemir et al., 2008a)

Beclin1 acts as a tumor suppressor by activating autophagy On the progression of cancer

(Liang et al., 1999)

Autophagy confers survival advantages on cancer cells owing to high proliferation rate and demand for sufficient nutrition

(Degenhardt et al., 2006)

Autophagy assists cancer cells with

dormancy and resist anoikis, which help tumor cell evasion from primary sites, invasion, and spread Autophagy is induced in RAS-transformed cancer cells to accelerates growth and invasion

(Fung et al., 2008)

(Guo et al., 2011)

Alzheimer’ disease

ß-amyloid aggregates and hyperphosphorylated tau can be degraded by autophagy pathway

(Nixon, 2007)

Autophagy activation increases the level of ß-amyloid

Parkinson’ disease

Neurodegene rative diseases

Autophagy degrades α-synuclein mutants α-synuclein over-expressions inhibit autophagy

Huntington’ disease

Mutant Htts are degraded through autophagy induction

(Cheung and Ip, 2011)


Autophagy degrades Tau aggregations

(Schaeffer et al., 2012)

Amyotrophi c lateral sclerosis

TDP-43 and SOD1 are involved in autophagy dysfunction

Prion disease

Prions and PrPSc can be degraded by autophagy Dysfunctional or old organelles can be cleared by autophagy pathway

Stroke Cardiovascul ar diseases and cerebrovascu lar diseases

(Cheung and Ip, 2011; Winslow et al., 2010)

Autophagy leads to autophagic cell death to deteriorate stroke

(Chen et al., 2012; Hetz et al., 2009)

(Xu et al., 2016) (Adhami et al., 2007; Wen et al., 2008)

Hypertensio n

Excessive autophagy eliminates cellular elements to provoke cell death and contributes to hypertension-related heart disease

(Mei et al., 2015; Zhu et al., 2007)

Atheroscler osis

Damaged intracellular components and defective mitochondria can be

(De Meyer and Martinet, 2009; Liao et al., 2012; Mei et

degraded by basal autophagy

al., 2015)

Excessive autophagy causes autophagic cell death in plaque cells

Cardiomyop athy

Phosphatase 4 over-expression and AKT-m-TOR up-regulation in cardiomyopathy lead to defected autophagy

(De Meyer and Martinet, 2009; Mei et al., 2015)

Autophagy machinery leads to cell death

Immune system diseases

Systemic lupus erythematos us

Autophagy defects lead to autoimmunity and inflammation associated with SLE

(Pierdominici et al., 2012)

Vici syndrome

Metazoan specific autophagy-related gene EPG5 mutations lead to autophagy defective and causes Vici syndrome

(Cullup et al., 2013)

Infectious Disease

Crohn’s disease

Intracellular bacteria, viruses and protozoans can be removed from host cells by autophagy

(Mizushima et al., 2008)

Autopahgy-related genes NOD2, IRGM and ATG16L1variants cause autophagy defects and leads to the impairment in bacterial handing and the decrease in rates of bacterial capture

(Kuballa et al., 2008; Parkes et al., 2007)

3. Autophagy regulators from TCM for human diseases .3.1 Autophagy regulators from TCM for cancer Autophagy is a catabolic degradation process involving degradation of intracellular cargos via lysosomal machinery, especially under the condition of adverse stresses and other signals such as starvation, growth factor deprivation and chemical stimuli. Autophagy process aims at degrading intracellular dysfunctional components to supply amino acids and essential energy to maintain normal cellar homeostasis. Dysfunction of autophagy has been implicated in various human diseases including pathogenic infection, cancer and neurodegenerative diseases. Human diseases have been showed in the table 1. As we know that cancer is a multi-factorial disease which needs multi-target treatments. In addition, drug toxicity and resistance on chemotherapy posed a great challenge to cancer treatment. Chinese medicine herbs

have been widely used in the treatment of cancer in East Asian and have been regarded as new sources of drug discovery library. Recent years, many studies have been performed to analyze the effect of TCM extracts or compounds on autophagy for anti-cancer purpose. Quercetin, an anti-oxidant flavonoid widely distributes in fruits and vegetables, has been reported to inhibit tumor through the induction of cancer cell cycle arrest and promotion of apoptotic cell death(Wang, K. et al., 2011). Interestingly, Quercetin induces autophagy through the modulation of Akt-m-TOR signal pathway, which played a protective role in gastric cells(Psahoulia et al., 2007; Wang, K. et al., 2011). Berberine is an isoquinoline derivative alkaloid isolated from various medicinal herbs, such as Coptis chinensis Franch. with plenty of pharmacological properties to treat a number of diseases such as cancer, diabetes, metabolic syndrome and obesity(Cordell et al., 2001). Compared with radiation therapeutic alone, the therapy combining proper concentration of Berberine with radiation together achieved a much better effect in anti-tumor in A549 cells and in animal models(Peng et al., 2008). Berberine also induced autophagic cell death and apoptosis in HepG2 and MHCC97-l cells by the activation of Beclin-1 as well as the inhibition of the m-TOR signaling pathway(Wang et al., 2010). Recent study revealed that Berberine induced HCC cells death via down-regulation of the expression of CD147 which might play an important role in the inhibition of autophagy and autophagic cell death in HCC cells(Hou et al., 2011). Other Chinese medicinal herbs like Resveratrol, a natural phytoalexin derived from fruits and vegetables, resulted in cancer cell autophagic cell death via multiple pathways including JNK-mediated p62/SQSTM1 expression, AMPK activation and Beclin1 independent pathway(Puissant et al., 2010; Scarlatti et al., 2008). Plumbagin, a quinonoid isolated from the root of Plumbago zeylanica L., inhibited the activity of PI3K/AKT/m-TOR pathway and autophagy in MDAMB-231 and MCF-7 cells to inhibit the proliferation of cancer cells in vitro and in vivo(Kuo et al., 2006). More complete information regarding autophagy regulators from TCM have been listed in the following table 2.

Table 2 Autophagy regulators from TCM for cancer

TC M age nts

Al kal oid s

Autopha gy regulator s from TCM

Main TCM herbs/specie s origin


Treatmen t for gastrointe stinal Nelumbo illnesses, nucifera Gae skin rtn. diseases, nervous exhaustio n, fewer

Evodiami ne

Treatmen t for inflamma tion related disorders

Cycloviro buxine D


Euodia rutic arpa (A. Juss.) Benth.

Traditio nal uses

Buxus micro Treatmen phylla var.ja t for ponica (Müll cardiovas .Arg.) cular Rehder & diseases E.H.Wilson Treatmen t for inflamma Coptis tion, chinensis cancer Franch. and higer fever

Eff ect on au to ph ag y

Mecha nisms

Disea se mode l

Phar macol ogical effect s


Deple tion of (Lu, antiox Y. et idant, al., GSH 2008; and Poorni ROS ma et Anti-p al., rolifer 2013) ation Activ ation of ER (Ada calciu ms et al., m chann 2004; Liu et el al., Induct ion of 2013a ) cell apopt osis

PI3K/A kt/m-T OR and ROS↓

A549 cells

Calciu m/JNK ↑

U87MG cells


MCF7 cells

Induct ion of cell death


HepG 2/MH CC97 -L cells

Induct ion of (Wang autop et al., hagic 2010) cell death

(Lu et al., 2014)

Treatmen t for gastrointe stinal Nelumbo Isoliensini illnesses, nucifera Gae skin ne rtn. disease, nervous exhaustio n, fewer Treatmen t for gastrointe stinal Liensinin Nelumbo illnesses, e nucifera Gae skin rtn. disease, nervous exhaustio n, fewer Treatmen t for blood pressure, platelet Menispermu aggregati Dauricine m dauricu-m on, DC. inflamma tory response and arrhythmi a Cepharant hine

Stephania ce phalantha Hayata

Treatmen t for fever


Autoph agosom e-lysos ome fusion↓



Hela cells

Induct ion of autop hagic cell death

(Law et al., 2014; Lu, Y. et al., 2008)

MDA -MB231 cells

Enhan cemen t of doxor ubicin -medi ated apopt osis

(Lu, Y. et al., 2008; Zhou et al., 2015)

Hela cells

Induct (Law ion of et al., autop 2014; hagic Parikh cell et al., death 2011)

Hela cells

Induct ion of autop hagic cell death

(Chea et al., 2007; Law et al., 2014)

L-securini ne



Voacamin e

Securinega s uffruticosa (Pall.) Rehder

Camellia sin ensis (L.) Kuntze

Piper nigru m L.

Peschiera fu chsiaefolia ( A. DC.) Miers

Treatmen t for rheumati c disease, quadriple gia, paralysis following infectious disease and children's malnutriti on Treatmen t for central nervous effects, diuretic stimulati on, drowsine ss and headache Anti-micr obia,antiinflamma tory and antioxida nt effects

Treatmen t for malaria

AMPLSW48 TSC20 m-TOR cells ↓

Arre st of cell cycle G1 phase

(Xia et al., 2011)

Beclin1 -depen dent

SH-S Y5Y cells

Induct ion of cell apopt osis

(Ku et al., 1999; Saiki et al., 2011)


LNCa Anti-p P/PCrolifer 3 ation cells

(Ouya ng et al., 2013)

(Mesc hini et al., 2008; Mesch Induct ini et MDR ion of al., osteos autop 2007; arcom hagic Schwi a cells cell kkard death and van Heerd en, 2002)


Dihydroc apsaicin

Camptoth ecin


Pancratist atin

Peganum ha rmala L.

Capsicum a nnuum L.

Camptothec a acuminata Decne.

Treatmen t for asthma, jaundice, lumbago and other human ailments Treatmen t for atthritis, rheumatis m, stomach ache, skin rashe, inflamma tion and oxidant Anti-tum or and anti-micr obial effects

Anti-infla mmatory, Sophora flav anti-fibro escens Aiton tic and anti-canc er effects

Hymenocalli s littoralis (Jacq.) Salisb.

Anti-viral , anti-bacte rial and antineopl astic effects

Autop hagic cell death

(Abe et al., 2011)


HCT1 Induct 16/M ion of CF-7c cell ells death

(Oh et al., 2008; Zimm er et al., 2012)


MCF7 cells

Induct ion of cell death delay

(Abed in et al., 2007; Li et al., 2008)

Beclin1 -depen dent

Anti-p rolifer ation Induct Huma (Dai ion of et al., n autop hepat 2009; hagic oma Zhang cell et al., G2 death 2010) cells and cell apopt osis

p38 MAPK ↓

A549 Cells

DU14 Induct 5 cell ion of (Griffi n et with autop al., p53 hagic 2011) mutan cell ts death

Fangchin oline

Diuretic, anti-phlo Stephania tet gistic and randra anti-rheu S.Moore matic effects

Salidrosid e

Rhodiola sa chalinensis Boriss.

Stimulati on of nervous system, eliminati on of fatigue and resistance of anoxia


Anti-canc er, anti-infla Fucus vesicu mamator losus L. y and anti-oxid ant effects

Flavokaw ain B

Treatmen t for the problem of digestive system, relieve symptom s of bronchiti s, measles, rubella and cholera

Sac cha rid es

Fla vo

Alpinia pricei Hayat a

Induct ion of autop hagic cell death

(Joshi et al., 2008; Wang, N. et al., 2011)

UMU C3 cells

Cell death

(Li, T. et al., 2007; Liu et al., 2012)

PI3K/A kt/m-T OR↓

AGS cells

Induct ion of autop hagic cell death and apopt osis

(Park, H.S. et al., 2011)


Growt HCT1 h 16 inhibit cells ion

(Kuo et al., 2010; Yang et al., 2008)

p53/ses trin2/A MPKdepend ent

Hepat ocellu lar carcin oma

noi ds


Silybum mar ianum (L.) Gaertn.


Apocynum v enetum L. Poacynum h endersonii( Hook.f.) Woodson



Kaempfer ol

Solanum nig rum L.

Treatmen t for chronic liver disease, diabetes and hypercho leste-rle mia Treatmen t for inflamma tion, anxiety, clearance of heat and sooth nerves Treatmen t for inflamma tion and liver disorders

Rhus succed anea L.

Antioxid ant and anti-infla mma-tory effects

Dodonaea vi scosa (L.) Jacq.

Treatmen t for sore throat, wounds, fever, malaria, angina, cold, arthritis, sinusitis flu and skin diseases

HIF-1a ↑

Beclin1 -depen dent↑

Akt/mTOR/p 70S6K ↓

ROS-d epende nt mitoch ondria dysfunc tion

Akt-de pendent ↓

(Jiang , K. et al., 2015; Tama yo and Diam ond, 2007)

MCF 7cells

Induct ion of autop hagic cell death

AGS/ MKN 28 cells

Protec (Frueh tion auf; agains Wang, t K. et apopt al., osis 2011)

NCIH460 cells

Induct ion of cell death

(Lin et al., 2008; Park et al., 2013)

PC3 cells

Induct ion of autop hagic cell death

(Suh et al., 2010)

Hela cells

Block age of apopt otic cell death

(Filo meni et al., 2010; Teffo et al., 2010)



Timosapo nin A-III Sa po nin s

Ginsenosi de F2

Treatmen t for inflamma tion, hypertens Scutellaria b ion, aicalensis cardiovas Georgi cular diseases and bacterial and viral infections Treatmen t for inflamma tion, hypertens Scutellaria b ion, cardiovas aicalensis cular Georgi diseases and bacterial and viral infections Use as an antipyreti c, anti-infla mmatory, Anemarrhen antidiabet a ic, asphodeloid anti-plate let es Bge aggregato r and antidepre ssant effects Treatmen t for hypodyna Panax mia, ginseng lassitude C.A.Mey. and anorexia

m-TOR / P70S6 K↓

m-TOR C1/2↓


NPC cells

Ameli oratio n of apopt otic cell death

(Cho w et al., 2012; Li-We ber, 2009)

T24 cells

Induct ion of autop hagic cell death

(Li-W eber, 2009; Lin et al., 2013)

HeLa cells

Block age of apopt otic cell death

(Kang et al., 2010; Sy et al., 2008)

Breast CSCs

Block age of apopt otic cell death

(Mai et al., 2012; Xiang et al., 2008)

Jujubosid eB

Ziziphus juju ba var. spino sa (Bunge) Hu ex H.F.Chow

Akebiasa ponin PA

Dipsacus as peroidesC.Y. Cheng & T.M.Ai


Ophiopog onin B


Dioscorea zingiberensis C.H. Wright

Ophiopogon japonicus (T hunb.) Ker Gawl.

Dioscorea zingiberensis C.H. Wright

Treatmen t for insomnia, anxiety, inflamma tory and neurodeg eneration Anti-oxid ant, anti-infla mmation, osteoprot ective effects Treatmen t for anthrax, ryeumati c heart disease and rheumato id arthritis Treatmen t for chronic inflamma tory diseases, cardiovas cular diseases Treatmen t for anthrax, ryeumati c heart disease and rheumato id arthritis

AGS/ HCT 16 cell

Block age of apopt otic cell death

(Xu, M.-Y. et al., 2014)

AGS cells

Induct ion of autop hagic cell death

(Xu et al., 2013)


FaDu cells

Inhibi tion of cell growt h

(Xie et al., 2014)

ERK1/ 2↑

NClH157 cells and NClH460 cells

Inhibi tion of cell growt h

(Chen et al., 2013; Kou et al., 2005)

A549/ H129 9 cells

Block (Hsieh age of et al., apopt 2013) otic (Xie cell et al., death 2014)

AKT-d epende nt↓

Atg-7/ Beclin1 depend ent↑

Saikosapo nin-d



Ter pe noi ds

Bupleurum chinense DC.

Treatmen t for liver diseases

Treatmen t for sprains, bruises, Arnica painful montana L. swellings , wounds and inflamma tion Treatmen t for fever, chills, edema, carbuncle Trichosanthe and s kirilowii inflamma Maxim. tion and stimulati on of blood circulatio n Treatmen t for respirator y infection, bacterial dysentery , diarrhea and fever

Androgra pholide

Andrographi s paniculata (Burm. f.) Nees

Cucurbita cin B

Use as an anti-infla mma-tory Trichosanthe , s kirilowii anti-diab Maxim. etic and abortifaci ent

Induct HeLa/ ion of MCF- autop 7 hagic cells cell death

(Chia ng et al., 2003; Wong et al., 2013)

Autop hagic cell death

(Knue sel et al., 2002; Lim et al., 2012)

Apopt otic cell death

(Chen , 2001; Giord ano et al., 2014)

Blocka HeLa Enhan ge of cells/ cemeautopha MCF- nt of gosome 7 cisplat -lysoso cells/ inme MDA -medi fusion↓ -MBated P53 231 apopt indepen cells osis dent

(Zhou et al., 2012)


Autop hagic cell death

(Zhan g et al., 2012)



A275 0 cell


HepG 2 cell and H129 9 cells

Hela cells

pol yp he nol s


Treatmen t for fever, chills, edema, carbuncle Trichosanthe and s kirilowii inflamma Maxim. tion and stimulati on of blood circulatio n


Antithro Magnolia off mbotic icinalis var.b antibacter iloba Rehder ial and & anxiolyti E.H.Wilson c effects

[6]-Ginge rol

Zingiber offi cinale Rosco e

Resveratr ol

Polygonum c uspidatum Si ebold & Zucc.

Magnolia off icinalis var. Magnolol biloba Rehd er & E.H.Wilson

Treatmen t for catarrh, rheumatis m, nervous diseases, gingivitis , toothache , asthma, stroke, constipati on and diabetes Use as a painkiller , antipyreti c, diuretic Treatmen t for cough, diarrhea, allergic rhinitis and tumor

(Chen , 2001; Krosc h et al., 2013)


SH-S Y5Y cells

Induct ion of autop hagic cell death

NF-κB p65↓

DBT RG-0 5MG GBM cells

Autop hagic and apopt otic cell death

(Chan g et al., 2013)

Hela cells

Induct ion of autop hagic cell death

(Ali et al., 2008; Chakr aborty et al., 2012)

DU14 5 cells

Induct ion of autop hagic cell death

(Hao et al., 2012; Li et al., 2013)

H460 cells

Induct ion of autop hagic cell death

(Li, H.-b. et al., 2007)


Intracel lular calcium ↑

ROS/E RK/JN K depend ent↑

Marchanti n

Marchantia polymorpha L.

Anti-bact erial and anti-infec tion effect

Plumbagi n

Anti-canc er and Plumbago ze anti-bacte ylanica L. rial effects

a-Mangos tin

Treatmen t for trauma, Garcinia ma diarrhea, ngostana L. skin infection and wounds

Ot her s

Oblongifo lin C

Garcinia yu nnanensis Hu

Treatmen t for cancer

PC-3 cells

autop hagic cell death

(Gibb ons, 2005; Jiang, H. et al., 2013)

MDA MB-2 31 MCF7 cells SIRT1/ nude S6K/m- mice TOR↓ inject ed with MDA -MB231 cells

Induct ion of autop hagic cell death

(Kuo et al., 2006)

m-TOR -depen dent↓

CML cells

Block age of apopt otic cell death

(Chen , J.-J. et al., 2014)

Hela cells

Elimi nation of tolera nce of cancer cells to nutrie nt starva tion

(Lao et al., 2014)

Blocka ge of autopha gosome -lysoso me fusion↓



Sulforaph ane

Immunos timulator y, anti-bacte rial Allium infection, sativum L. anti-diab etes and cancer preventio n Treatmen t for throat sore, burns, cut Arnebia and skin diseases guttata such as Bunge macular eruption, measles a nd carbuncle s Protectiv e effect against Rassica oler chemical tumors acea var. ital and ica Plenck anti-oxid ative effect

Water Antinocic extracts of eptive Terminalia b Terminali and ellirica (Gae a bellirica anti-bacte rtn.) Roxb. (Gaertn.) rial Roxb. effects

PI3K/A kt/m-T OR↓

Hep G2 cells

Induct (Bore k, ion of autop 2001; hagic Chu et al., cell death 2012)

ROS/A kt↓

BXP C-3 huma n pancr eatic cance r cells

Cell growt h inhibit ion

(Lu et al., 2011; Shi and Cao, 2014)

PC-3/ LNCa P cell

Block age of apopt otic cell death

(Herm an-An tosiew icz et al., 2006)

Hep G2 cells

Autop hagic and apopt otic cell death

(Padhi , 2014)

Beclin1 /Atg5↑

ERK1/ 2↑

,Anti-hyp olipidemi c, anti-infla Methylen mmatory, e chloride anti-viral extracts of Lycii Radicis effects Lycii Cortex. * Treatmen Radicis t for Cortex. upper respirator y system diseases Ethanol extracts of Cinnamomu Treatmen Cinnamo t for m camphora mum cam hysteria (L.) J.Presl phora (L.) J.Presl Extracts of A. Anticanc Asparagus c Asparagu er and ochinchinens s cochinc anti-infla is (Lour.) hinensis ( mma-tory Merr. Lour.) effects Merr. Antitumo r, Extracts anti-infla of Solanum nig mmation Solanum rum L. and nigrum L. hepatopr otect-ion Treatmen t for rheumatis m, Acetonic arthritis, bile duct extracts Buxus sempe of Buxus s infections rvirens L. empervire , ns L. diarrhea, fever and skin ulceratio n



Block age of apopt otic cell death

(Kim et al., 2011; Park et al., 2012)

HT10 Anti-p 80 fibros rolifer arcom ation a cells

(KIM et al., 2013)

NCIH460 cells

PI3K/A kt↓

HepG 2 cells

ERK1/ 2 indepen dent

HepG 2 cells


MCF7 cells

Autop hagic and apopt otic cell death Auto phagi c and apopt otic cell death

Autop hagic and apopt otic cell death

(Park, M. et al., 2011)

(Lin et al., 2007)

(AitMoha med et al., 2011)

Methanol extracts of Poncirus t rifoliata ( L.) Raf.

Extracts of Solanum nigrum L.

Poncirus trif oliata (L.) Raf.

Solanum nig rum L.

Treatmen t for gastrointe stinal disorders and pulmonar y diseases Treatmen t for skin disorders, wound, fevers, eye diseases

PI3K/m -TOR↓

HSC4 cells

PI3K/A kt/m-T OR↓

AU56 5 cells

Anti-p rolifer ation

(Han et al., 2015)

Autop hagic cell death

(Huan g et al., 2010)

The the name of herbs/species in the original articles were confirmed with the names in plant list. * Lycii Radicis Cortex could not be found in the plant list.

3.2 Autophagy regulators from TCM for neurodegenerative diseases Neurodegenerative diseases are pathologically characterized by mitochondrial dysfunction, the loss of neural function and the accumulation of mutated and misfolded protein aggregates. For instance, AD exhibits the pathological characteristics including Aβ deposition and tau protein accumulations; PD displays the characteristics of α-synuclein accumulations in cytoplasm(Martinet et al., 2009). Two major protein degradation pathways exist in eukaryotic cells: ubiquitin-proteasome system is responsible for the clearance of short-lived proteins, autophagy-lysosome pathway is mainly responsible for regulating and recycling the long-lived proteins and organelles(Levine and Klionsky, 2004; Mizushima et al., 2008). Coincided with autophagy function, autophagy pathway can be responsible for the degradation of intracellular excessive misfolded proteins and dysfunctional mitochondria to maintain the survival of neurons(He and Klionsky, 2009; Martinet et al., 2009). It has been widely recognized that Chinese medical herbs extracts and herbal compounds have been popularized in treatment for human diseases like heart diseases, cancers and neurodegenerative diseases due to their properties of lower side effects and multi-target effects. There has been quite a lot of studies revealed that Resveratrol, a natural compound derived from red grape, exhibited the properties of anti-aging and anti-inflammatory(Alarcón de la Lastra and Villegas, 2005). In the model of HEK293 and N2a cells stably transfected with human APP695 and PS1 transgenic mice model of AD, Resveratrol decreased the extracellular Aβ accumulation and increased cytosolic calcium levels via m-TOR dependent autophagy pathway(Vingtdeux et al., 2010). Resveratrol also enhanced the degradation of a-synuclein in PC12 cell lines over-expressed α-synuclein, protected SY5Y cell lines from rotenone-induced apoptosis through the activation of AMPK/SIRT1 and autophagy induction(Wu et al., 2011). Trehalose, a disaccharide composed of two glucose molecules, was demonstrated to induce autophagy to clear autophagy substrates like mutant huntingtin and the α-synuclein via mTOR-independent pathway and protected the cells against pro-apoptotic insults via mitochondrial pathway(Sarkar

et al., 2007b). Additionally, Trehalose induced autophagy pathway to play a role in another type of neurodegeneration named Prion disease(Aguib et al., 2009). Recently, it was demonstrated that Trehalose can also alleviated dopaminergic and tau pathology in parkin deleted mice and tau over-expressed mice through autophagy activation(Rodríguez-Navarro et al., 2010). Wogonin, as an active ingredient of Scutellaria baicalensis Georgi, has been reported to play a role in neural protection by promoting the degradation of Aβ in SH-SY5Y cell stably expressed APP through m-TOR-dependent autophagy pathway(Zhu and Wang, 2015). Isorhynchophylline, a natural alkaloid derived from Chinese herbal medicine Uncaria rhynchophylla (Miq.) Miq.ex Havil, promoted the degradation of α-synuclein in N2a, SH-SY5Y, PC12 cells as well as in primary cortical neurons via the autophagy-lysosome pathway through a manner independent of the m-TOR pathway but dependent on the function of Beclin1(Lu et al., 2012). Herbal compounds like modified Yaoldahanso-tang protected NGF-differentiated PC12 cell lines from MPP-induced injury via the Beclin1-dependent pathway(Bae et al., 2011). More detailed and complete information regarding autophagy-modifying property of TCM compounds and extracts have been list in table 3.

Table 3 Autophagy regulators from TCM for neurodegenerative diseases Autop Eff TC hagy ect Pharm Main TCM Traditi M regula on Mecha Disease acologi herbs/species onal Ref. age tors aut cal nism model uses origin nts from oph effects TCM agy Treatm ent for N2a cardiov (Lu Uncaria cells Clearan ascular et Isorhy m-TOR over-ex rhynchophylla ce of and al., nchop ↑ -indepe pressing α-synuc (Miq.) Miq. ex neurolo 2012 hylline ndent α-synucl lein Havil gical ) ein disease Alk s aloi Antiam (Wa ds oebic, Mitigati ng et Piperi MN9D anti-ast al., on of ne and cells Beclin1 hmatic, neurona 2015 Piper piperlo ↑ -depend injured anti-dia ) l longum L. ngumi by ent betic, apoptos (Zav nine rotenone anti-inf eri is lammat et

ory, anti-ca ncer and anti-car diovasc ular effects Treatm ent for Nelumbo anxiety Neferi nucifera and ne Gaertn. aging disease s Treatm ent for inflam Methy Delphinium br mation llycac and ownii Rydb. onitine aging disease s Treatm ent for cancer, inflam Euodia Evodia mation, rutaecarpa mine obesity (Juss.) Benth. and Alzhei mer’s disease Treatm ent for bacteri al Coptis Berber diarrhe chinensis ine a and Franch. pneum ococcal infectio n Treatm ent for Uncaria headac Coryn rhynchophylla he, (Miq.) oxine dizzine Miq.ex Havil. ss, tremor

al., 2010 )

PC12 cells over-ex pressing Htt mutants

(Wo Clearan ng et ce of al., Htt 2015 mutants )


SH-SY5 Y cells injured with Aβ25-3 5

(Zhe Alleviat ng et ion of al., toxic 2014 effect )

m-TOR ↓

U87-M G Astrocyt es cells treated with CPZ

Inducti (Liu on of et protecti al., ve 2013 autopha b) gy

m-TOR ↑

Calciu m↑

HEK29 3 cells transfect ed with Htt Transge nic mice expresse d Htt N2aSwe dAPP cells Mice over-ex pressing APP

(Jian Degrad g, ation W. Htt et mutant al., aggrega 2015 tions )

Clearan ce of APP/C TF

(Dur airaj an et al., 2013 ; Hou

and convul sive disorde rs Ervatamia mic Conop rophylla (Pit.) Kerr hylline

Salvig enin

Naring in

Flav onoi ds

Wogo nin

Luteol in

Treatm ent for diabete s and cancer

Treatm ent for Salvia sahendi skin ca Boiss. & disease Buhse s and cancers Anti-in flamma tory, anti-car cinoge nic, Citrus grandis (L.) Osbeck lipid-lo wering and anti-ox idant effects Anti-in flamma tory, anti-vir Scutellaria al, baicalensis anti-ba Georgi cterial and anti-ca ncer effects Treatm ent for inflam Solanum nigru mation and m L. liver disorde rs

et al., 2005 )


PC12 cells treated with MPP+

(Sas Clearan aza ce of wa protein et aggrega al., tions 2015 ) (Raf Inhibiti atian on of et apoptos al., is 2012 )

SH-SY5 Y cells injured by H2O2

Mice Reducti seizures m-TOR on of -induced /p70SK autopha by /GSK↓ gy Kainic stresses acid

(Jeo ng et al.)

SH-SY5 Y-APP/ BACE1 cells

Clearan ce of Aβ

(Zhu and Wan g, 2015 )

Mice with brain traumati c injury

(Xu, Anti-inf J. et lammati al., 2014 on )

m-TOR /p70S6 K↓

Kaem pferol

Onjisa ponin B

Sap onin s

Treatm ent for sore throat, wound s, fever, malaria Dodonaea visc , osa var. angus angina, tifolia (L.f.) cold, Benth. arthriti s, sinusiti s flu and skin disease s Treatm ent for anxiety , heart palpitat ion and hepatic ischem Polygala ia-repe tenuifolia rfusion Willd. and improv ement of learnin g and memor y

Improv ement Centella Madec of assosi asiatica˄L.˅ memor de y and Urb. learnin g Ginsen Use as oside Panax ginseng antioxi compo C.A.Mey. dant, und K anti-agi

Akt-de pendent ↓

PC12 cells over-ex Clearan (Wu ce of pressing et α-synuc Htt al., mutant lein/hun 2013 tingtin and ) a-synucl mutants ein mutants

Hela cells

(Filo meni et Blocka al., ge of 2010 apoptoti ; c cell Teff death o et al., 2010 )

Beclin1 depend ent


Mice NG10815 neural cells treated with Aβ25– 35 Astrocyt es treated with Aβ

Prevent ion against inflam mation

(Du et al., 2014 )

Clearan ce of Aβ

(Gu o et al., 2014

ng agent and cogniti on enhanc er Trehal ose

Claviceps purpurea (Fr.) Tul.

Cell protecti on from stresses

Treatm ent for inflam mation, Curcu Curcuma cancer min longa L. and cardiov ascular disease s Treatm ent for fever, chills, edema, carbun Tripterygium cle and Celastr wilfordii Hook inflam ol . f. mation and stimula tion of Ter blood pen circulat oids ion Use as an antispa smodic , tonic, Paeoni Paeonia lactifl astring florin ora Pall. ent and analges ic Treatm ent for neurod


COS-7 cells transfect ed with Htt

(Sar Clearan kar ce of et hunting al., tin 2007 mutants a)

SH-SY5 m-TOR Y cells indepen over-ex dent pressing A53T

(Jian g, Clearan T.-F. ce of et α-synuc al., lein 2013 )

(Den Prevent g et ion SH-SY5 al., from Y cells 2013 m-TOR injury injured ) ↓ Clearan by (Che ce of rotenone n, α-synuc 2001 lein )

Sac char ides


PC12 cells injured by MPP+/a cid

Inhibiti (Cao on of et LAMP2 al., expressi 2010 on )

Cucur bitacin E

poly Resver phe atrol nols

Ecballium elat erium (L.) A.Rich.

Polygonum cu spidatum Sieb old & Zucc.

egener ative disease s Anti-tu mor, anti-inf lammat ory, and anti-ox idant propert ies Use as a painkill er, antipyr etic, diuretic


PC12 cells treated with MPP+

(Are l-Du Decreas beau e of et neurona al., l death 2014 )


HEK29 3/ N2a cells transfect ed with APP+ APP/PS 1 transgen ic mice

Increas (Vin e of gtde calcium ux et levels al., Clearan 2010 ce of ) Aβ

* The the name of herbs/species in the original articles were confirmed with the names in plant list.

4. Discussion Autophagy dysfunction has been linked to a wide range of human diseases. Cancer and neurodegenerative diseases are the two most well characterized autophagy-related diseases. A large body of evidence showed that the induction of autophagy is a survival mechanism via degradation of dysfunctional proteins and damaged organelles to promote the restoration of healthy metabolism and homeostasis. Autophagy plays a role in suppressing tumorigenesis by preventing chronic damage-induced cells transformation, as well as in preventing neurodegeneration through promoting clearance of mutant protein aggregates and damaged mitochondria. TCM has long been used to treat human diseases including cancer and neurodegenerative diseases. There have been a growing number of reports indicating TCM-derived agents have properties to counteract cancer and neurodegeneration through modulating autophagy pathway. Simply, these autophagy modulators can be divided into two groups: autophagy inducers and autophagy inhibitors. Some autophagy inducers including Resveratrol, Corynoxine B, Trehalose and Isoliensinine, have been shown to enhance the clearance of mutant proteins associated with neurondegenerative diseases via mTOR-dependent or independent manner to promote neuronal survival(Chen, L.-L. et al., 2014; Lu et al., 2012; Sarkar et al., 2007a). Meanwhile some other autophagy inducers like Berberine, Dauricine and Fucoidan were shown to induce autophagic cell death in cancer cells, via m-TOR or Beclin1-dependent (Law et al., 2014; Park, H.S. et al., 2011; Peng et al., 2008). Autophagy inhibitors like Liensinine, Oblongifolin C and Andrographolide were shown to sensitize the cancer cells to

chemotherapy or starvation induced cell death, by blocking the maturation stage of autophagy(Lao et al., 2014; Zhou et al., 2012; Zhou et al., 2015). Generally, inducing autophagy is a widely accepted strategy against neurodegeneration; while for cancer, both autophagy inducers and autophagy inhibitors have been shown to be effective in suppressing cancer cells growth or promoting cancer cells death. When going through the literatures, it is very common to see that the evidence to support the autophagy induction activity is not strong because many studies only detected the LC3-II blot to indicate the activation of autophagy. However, LC3-II level alone is not enough to indicate autophagy flux as the LC3-II is the substrate of autophagy which increases even stronger when autophagy maturation is blocked. It is thus highly recommended to use multiple indicators like p62 or RFP-GFP-LC3 reporter system and tool compounds like CQ or baflomycin to confirm the autophagy modulation activity. It has to be noted that the precise molecular mechanisms and signaling pathways by which TCM-derived agents manipulating autophagy remains largely unclear, and the therapeutic potential of these agents have seldom been verified in animal models. The future work would be to explore the detailed mechanisms by which autophagy is modulated and to confirm the diseases-modifying activity of TCM-derived agents through in vivo models.

Recent studies on autophagy regulation pathway have provided significant insights for the discovery of autophagy modulator as therapeutic agents. Ideal autophagy modulators are expected to have considerably higher selectivity to stimulate autophagy formation complexes like ULK1 complex, Beclin1-VPS34 or two ubiquitin-like conjugation systems. To achieve the goal of long-term modulation of autophagy, transcriptional activation of autophagy by targeting transcript factors or nuclear receptor like TFEB can be a good strategy. Furthermore, promoting the recognition of substrate and autophagosome by modulating activities of autophagy adaptor molecules via phosphorylation can achieve higher selectivity. However, there are still many unanswered questions regarding the pharmacological modulation of autophagy as therapeutic strategy against human diseases: how can we achieve the selective induction or inhibition of autophagy in specific tissue or cell type? How to control the intensity and duration of autophagy flux during chemical stimulation? How to evaluate and monitor the autophagy modulation activity of compounds in animal models or in human being? We hope these questions can be addressed in the future to make the autophagy modulators become feasible and effective therapeutic agents for human diseases including neurodegenerative diseases and cancer.

Acknowledgement This work was supported by the SRG2014-00027-ICMS-QRCM from university of Macau, the opening fund of the State Key Laboratory of Quality Research in Chinese Medicine, University of Macau (2014-2016-011), FDCT_022/2015/A1, FDCT_092-2015-A3 from Macau government, NSFC-31500831 from Chinese government awarded to Jia-Hong Lu; FRG I/15-16/042, FRG II/15-16/034, RC-IRMS/ 15-16/04 from Hong Kong Baptist University, GRF/HKBU12100914 and HMRF12132091 from Hong Kong Government awarded to Min Li.

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Graphical Abstract

Electrocardiograms of bottlenose dolphins (Tursiops truncatus) out of water: habituated collection versus wild postcapture animals.

Electrocardiography (ECG) was performed on captured free-ranging bottlenose dolphins (Tursiops truncatus) during a health assessment exercise and comp...
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