Apoptosis DOI 10.1007/s10495-016-1335-1
REVIEW
Natural products as modulator of autophagy with potential clinical prospects Peiqi Wang1,2 · Lingjuan Zhu1 · Dejuan Sun1 · Feihong Gan1,2 · Suyu Gao1 · Yuanyuan Yin1,2 · Lixia Chen1
© Springer Science+Business Media New York 2016
Abstract Natural compounds derived from living organisms are well deined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic beneits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases. Keywords Natural compounds · Autophagy · Disease · Drug therapy Peiqi Wang and Lingjuan Zhu have contributed equally to this work. * Lixia Chen
[email protected] 1
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
2
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Introduction Natural compounds, isolated and exploited from plants, animals and microorganisms, have been reported to be involved in the modulation of several biological processes, thus showing a great potential to be translated into clinical use. Moreover, natural compounds often hold unusual structural features which cannot be easily mimicked [1]. Therefore, such compounds may serve as an invaluable source of drug discovery for diverse diseases. However, despite the extensive attention focused on natural products, their exact regulatory mechanisms still remain to be explored. Macroautophagy (hereafter referred as autophagy) is an evolutionally conserved catabolic process that delivers cytoplasmic components to the vacuole or lysosome for degradation in eukaryotic cells [2]. By providing energy and metabolic precursors and eliminating damaged organelles or proteins, autophagy mainly acts as a homeostatic maintaining mechanism to retain cell vitality [3, 4]. Nevertheless, evidence is emerging that impaired or excessive autophagy may cause a unique cell death modality termed autophagic cell death [5–7]. Interestingly, the dual efect of autophagy has been proposed to be context dependent and related to the extent and duration of autophagy [6]. Hitherto, a great variety of natural products have been demonstrated to participate in the modulation of autophagy, correlated to either pro-survival autophagy or autophagic cell death. Since autophagy has been revealed to be implicated in the pathogenic process of multiple diseases such as cancer, neurodegenarative diseases, cardiovascular diseases, metabolic diseases, and immune diseases [2], autophagy-modulating natural compounds have become research hotspots with a wide range of clinical prospect (Fig. 1). Notably, the consideration that
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Fig. 1 Autophagy-modulating natural compounds in therapeutic treatments. As autophagy is involved in the pathophysiological process of multiple diseases, autophagy-regulating natural compounds, either through induction (marked as red) or inhibition (marked as green) of autophagy, are promising to be translated into clinical use. In cancer treatment, for example, natural compounds function by inducing autophagic cell death or inhibiting protective autophagy. Autophagy induced by natural compounds plays an important part in clearance of protein aggregates and thus ameliorate neurodegeneration, while in cardiomyocyte and vascular endothelial cells,
autophagy mainly protects against detrimental stress by maintaining energy and nutrition homeostasis. Moreover, natural compounds impede metabolic diseases such as obesity by inhibiting autophagy which may facilitate adipogenesis. Since virus and other pathogens can induce autophagy to enhance their replication in cell cultures, natural compounds may suppress autophagy to inhibit infection. On the other hand, natural compounds can also enhance both innate and adaptive immunity by promoting autophagy and therefore restrain chronic inlammation. (Color igure online)
autophagy modulation is involved in the administration of natural compounds may facilitate a better understanding of the mechanisms of natural products in treatment of autophagy-related diseases. Albeit extensively studied, natural compounds in different disease treatments have not been comprehensively
reviewed. Herein, we focus on systematically summarizing natural compounds with autophagy-regulating properties into categories against diverse diseases with diferent mechanisms, in the hope of shedding light on future therapeutic strategies using natural compounds and their derivatives for autophagy-associated diseases.
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Apoptosis
Physiological functions of autophagy Autophagy takes place at basal levels in most cells to perform homeostatic functions, and is often activated as an adaptive process in response to diferent forms of metabolic stresses such as nutrient starvation, growth factor depletion, and hypoxia [8]. This degradative process generates a deluge of free amino and fatty acids which can then be recycled to synthesize adaptive proteins. Furthermore, the amino and fatty acids released from autophagic degradation can be further processed and used by the tricarboxylic acid cycle (TCA) to maintain cellular ATP production. By maintaining macromolecular synthesis and ATP production, autophagy appears to be critical in meeting the demands of metabolic substrates, thus maintaining energy homeostasis [9]. Autophagy is also known as a pivotal quality control system, functioning through the clearance of aggregated proteins and organelles, the prevention of aggregate accumulation, and the elimination of pathogens. Although some of its functions overlap with those of the ubiquitin–proteasome system (UPS), the other major protein catabolic system, autophagy uniquely can sequester and degrade entire organelles such as mitochondria, endoplasmic reticulum (ER), and peroxisomes [2]. Since cellular diferentiation requires elimination of proteins, nucleic acids and organelles to switch into the next developmental stage, and cellular remodeling is often associated to nutrient-deprived developmental phases, autophagy is likely to be triggered during developmental remodeling [9, 10]. Moreover, autophagic machinery can also limit DNA damage and chromosomal instability as suggested in diferent experimental models, while the mechanisms may lie in the protection of checkpoint or repair proteins, turnover of centrosomes, suicient energy for proper DNA replication and repair [2]. Evidence has emerging that autophagy is implicated in the removal of maternal macromolecules during early embryogenesis. Autophagy is essential for preimplantation development of mouse embryos [11], as well as the clearance of mitochondria during erythrocyte, lymphocyte and adipocyte diferentiation [12–14]. As mentioned before, autophagy constitutes a stress adaptive mechanism under most circumstances, protecting cells against detrimental insults and defending them from pathogens. Paradoxically, autophagy has also been described to be a form of non-apoptotic programmed cell death, namely type II or autophagic cell death. In a disease context, cell death via autophagy is not simply a matter of exceeding a quantitive threshold, it also intricately interacts with apoptotic death pathways through molecular links and mutual regulating pathways [15].
With the identiication of the physiological functions of autophagy and its dual role in diferent settings, diverse experimental approaches are being used to redeine the precise character of autophagy performs in the pathology of human diseases, and thus facilitate the discover, design and utility of autophagy-regulating compounds.
Autophagy and natural compounds in diseases The wide range of physiological functions attributed to autophagy explain why alterations in autophagic process lead to cellular malfunction and consequently contribute to the pathogenesis of diverse human disorders or diseases. Due to the interplay between autophagy and diseases, natural compounds with autophagy-modulating properties, either through induction or inhibition of autophagy, are promising to be translated into clinical use. Importantly, growing evidence supports a dual role of autophagy in pathogenesis and progression of diverse diseases, reinforcing the need to evaluate autophagy critically, especially during the design and selection of autophagy-regulating therapy.
Cancer In the past decades, increasing data have suggested an intricate interaction between autophagy and cancer [2]. Some key regulators of autophagy, such as mTOR, Beclin-1, p53, PI3K, ERK and reactive oxygen species (ROS) have been incorporated in modulating cancer initiation and development [16–20] (Fig. 2). The manipulation of autophagy has been an important strategy to improve anti-tumor therapeutics, and so far emerging evidence has revealed that a large series of autophagy-modulating natural compounds exhibit therapeutic efects against various cancers (Table 1). With diferent microenvironment during cancer development, tumor is recognized as a complicated biological system. Autophagy likely acts two opposing functions depending on diferent stages of cancer [9, 98–100]. In the initial stages of tumorigenesis, autophagy mainly acts as a tumor suppressing mechanism, particularly over genome maintenance. On the contrary, autophagy plays a role in the maintenance or entry of cells into the G0 phase, which consequently prevents cell hyper-proliferation. Therefore, induction of autophagy has a great clinical prospect in cancer therapy. For instance, natural compound tetrahydrocannabinol (THC) promotes autophagic cell death via ER stress-dependent inhibition of mammalian target of rapamycin (mTOR), a pivotal mediator of autophagy repression which has been deciphered to promote tumor growth by numerous studies [74]. Resveratrol (Rsv), an intensively
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Apoptosis Fig. 2 Main autophagic pathways and representative autophagy-modulating natural compounds in cancer. Autophagy can be divided into ive steps: induction, vesicle nucleation (formation of the phagophore), vesicle elongation and completion of autophagosome, fusion with the lysosome, degradation and recycling. Numerous signaling pathwaysare implicated in autophagy have a close relationship with cancer development. Natural compounds activating (marked as red) and inhibiting (marked as green) autophagy via interaction with the key regulators of autophagy have shown their potential in the treatment of different types of cancers. (Color igure online)
studied natural phytoalexin with a variety of beneicial efects in multiple human disease models, reportedly shows a strong antioxidant activity and has recently been demonstrated to facilitate anti-tumor therapy by triggering autophagy in an mTOR dependent manner [39–42]. Moreover, through activation of NAD-dependent deacetylase Sirt1, the closest mammalian homolog of yeast Sir2, Rsv enhances the induction of starvation-induced autophagy and thus administer to anti-tumor therapy [101–103]. Quercetin, an anti-tumor lavonoid widely known for its antioxidant and anti-inlammatory properties, also induce autophagy by repressing mTOR signaling [59]. In addition to regulation over mTOR signaling, quercetin has been reported to trigger autophagy by facilitating dissociation of Beclin-1 with Bcl-2/Bcl-xL through HIF-1α-induced
13
expression of BNIP3/BNIP3L [57]. Belcin-1 functions by promoting autophagic localization and autophagosome formation by forming the PI3KCIII complex, and has been revealed as a tumor suppressor in several types of cancers [2, 104]. Meanwhile, Bcl-2 and Bcl-xL, which may inhibit autophagy activation by binding to Beclin-1, are known as proto-oncoproteins in virtue of their overexpression in human cancers [2]. As a BH3-mimetic inhibitor of Bcl-2, natural compound gossypol potently binds to Bcl-2 and Bcl-xL and releases Beclin 1 at the ER, thus preferentially inducing autophagy. Intriguingly, JNK, a member of the mitogen-activated protein kinase (MAPK) family, may induce autophagy by facilitating the dissociation between Beclin-1 and Bcl-2, and has been proposed as a tumor suppressor [105–107]. It has been reported that neoalbaconol
Terpenoid
Terpenoid
Terpenoid
Terpenoid
Ursolicacid (UA)
EM23*
Neoalbaconol (NA)
Alisol B monoacetate
Category
Terpenoid
Structure
Paclitaxel (Taxol)
Natural compound
Table 1 Autophagy-modulating natural compounds in cancer
Induction
Induction
Induction
Induction
Induction
Induction or inhibition of autophagy
Activating CaMKK/ AMPK/mTOR signaling
Inhibiting Akt signaling Activating JNK signaling (Targeting PKD1)
Activating PI3K signaling Activating JNK signaling Inhibiting Akt/mTOR signaling
–
Female C57BL/6 J mice Balb/cA nude mice
Breast cancer
–
Nasopharyngeal carci- Nude mice noma (NPC)
Cervical cancer
Colorectal cancer
Cervical cancer
–
– –
Cervical cancer Non-small lung cancer (NSCLC) Breast cancer
Activating MAPK1/3
–
Ovarian cancer
Upregulating TXNDC17 via a Beclin-1—dependent pathway Autophagic cell death Protective autophagy
–
–
–
–
–
–
Phase 3 Phase 4
Phase 4
C57BL/6 Rnf5−/−mice Phase 4
Breast cancer
Enhancing RNF5mediated SLC1A5 degradation via ER stress
[27]
[26]
[25]
[24]
[23]
[22]
[19] [1]
[17]
[21]
Clinical trial References
In vivo model(s)
Disease(s)
Mechanism(s)
Apoptosis
13
13 Terpenoid
Terpenoid
Terpenoid
Terpenoid
Cucurbitacin I (Cu I)
Cucurbitacin E (Cu E)
Oleifolioside B (OB)
Zerumbone
Induction
Induction
Induction
Induction
Induction
Terpenoid
Cucurbitacin B (Cuc B)
Induction or inhibition of autophagy Induction
Category
Terpenoid
Structure
β-Elemene
Natural compound
Table 1 (continued) Disease(s)
Autophagic cell death
Autophagic cell death
Activating AMPK/ mTOR/P70S6K signaling Inhibiting mTORC1 signaling Activating AMPK
Enhancing ROS production
Enhancing ROS production
Human hormonerefractory prostate cancer (HRPC)
Non-small cell lung cancer (NSCLC)
–
–
–
–
–
–
–
BALB/c nude (nu/nu) mice
Glioblastomamultiforme (GBM) Cervical cancer, breast cancer
– –
Breast cancer Cervical cancer, breast cancer, colon cancer, glioma
– –
–
–
Cervical cancer, breast cancer, colon cancer, glioma
[32]
[31]
[30]
[28]
[29] [28]
[28]
[26]
Clinical trial References
–
In vivo model(s)
–
Inhibiting Akt/mTOR/ Gastric cancer p70S6K signaling
Mechanism(s)
Apoptosis
Induction
Terpenoid
Terpenoid
Betulinic acid (BetA)
Andrographolide Induction
Inhibition
Terpenoid
Frondoside A (FrA)
Induction or inhibition of autophagy Induction
Category
Terpenoid
Structure
Celastrol
Natural compound
Table 1 (continued)
Prostate cancer Cervical cancer Pancreatic cancer Prostate cancer
Inhibiting AR/miR101
Enhancing ROS productionthrough cyclophilin D
Protective autophagy
Protective autophagy –
–
Liver cancer
Enhancing HIF-1α through ROS productionand Akt signaling
Liver cancer
–
– Breast cancer, cervical cancer, nonsmall lung cancer (NSCLC), colon cancer
– – Nude mice NOD SCID mice
In vivo model(s)
Disease(s)
Mechanism(s)
–
–
– – – –
–
[38]
[37]
[34] [33] [35] [36]
[33]
Clinical trial References
Apoptosis
13
13 Stilbene
Pterostilbene (PT)
Category
Stilbene
Structure
Resveratrol (Rsv)
Natural compound
Table 1 (continued)
Induction
Induction
Induction or inhibition of autophagy
Inhibiting EGFRmediated pathways Enhancing ROS production Inhibiting AKT/ mTOR/p70S6K signaling Activating MEK/ ERK1/2 signaling Inducing ER stress
–
Glioma
Male A/J mice – –
–
Lung cancer Breast cancer Bladder cancer
Fibrosarcoma
–
–
–
Oral cancer
–
–
Chronic myelogenous leukemia Breast cancer
–
–
–
–
–
–
–
–
Lung adnocarcinoma
Activating Ca2+/ AMPK/mTOR signaling Activating AMPK and JNK Non-canonical Beclin 1-independent pathway Inhibiting Akt or p70S6K Activating JNK1/2 Inhibiting Akt, ERK1/2, and p38
Phase 1
C57BL/6 J ApcMin/+ (ApcMin) mice, C57BL/6 J mice, NOD/SCID mice
[46]
[45]
[44]
[43]
[42]
[41]
[42]
[41]
[40]
[39]
Clinical trial References
In vivo model(s)
Colorectal cancer
Disease(s)
Activating AMPK
Mechanism(s)
Apoptosis
Induction
Induction
Flavonoid
Flavonoid
Flavonoid
Apigenin
Wogonin
Dimethyl cardamonin (DMC) Induction
Induction
Flavonoid
Induction
Induction or inhibition of autophagy
Icariside II (IS)
Category
Stilbene
Structure
Silvestrol
Natural compound
Table 1 (continued)
Activating PI3KCIII
Colorectal cancer
–
UV-induced skin Female SKH-1 haircancer less mice Colon cancer – Nasopharyngeal carci- – noma (NPC)
Inhibiting Akt/mTOR signaling Protective autophagy Inhibiting mTOR/ P70S6K signaling
–
ICR male mice
–
In vivo model(s)
Leukemia
Hepatoblastoma
Melanoma
Disease(s)
Inhibiting mTOR and p70S6K
Inhibiting autophagic degradation
Autophagic cell death
Mechanism(s)
[52]
[50] [51]
– –
–
[49]
[48]
[47]
[45]
–
–
–
–
Clinical trial References
Apoptosis
13
13 Flavonoid
Flavonoid
Xanthohumol (XN)
Quercetin
Category
Flavonoid
Structure
Baicalin
Natural compound
Table 1 (continued)
Induction
Induction
Induction
Induction or inhibition of autophagy Hepatocellular carcinoma (HCC)
Disease(s)
BALB/cAnN-nu athymic Mice
In vivo model(s)
Gastric cancer
Colon cancer Glioblastoma Cervical cancer, breast cancer
Inhibiting Akt/mTOR signaling through HIF-1α accumulation Autophagic cell death Protective autophagy Inhibiting mTOR through proteasome inhibition
– – –
Female BALB/c nude mice
Prostate cancer, breast – Inhibiting mTORC1 cancer expression Activating AMPK/ ULK1 signaling Inhibiting Akt signal- Bladder cancer – ing – Impairing autophago- Human epidermoid cancer, human some maturation cervical cancer through inhibition of valosin-containing protein (VCP)
Activating RelB/p52 signaling
Mechanism(s)
[56]
–
– – –
[58] [57] [59]
[57]
[55]
–
–
[54]
[53]
–
–
Clinical trial References
Apoptosis
Induction
Induction
Thiazolidinedione Polyketide
Alkaloid
OSU-CG-12
Monascuspiloin (MP)
Neferine Induction
Induction
Diketone
Tetrahydrocurcumin
Induction or inhibition of autophagy Induction
Category
Diketone
Structure
Curcumin
Natural compound
Table 1 (continued)
–
Lung cancer
Hepatocellular carcinoma (HCC)
Inhibiting PI3K/Akt/ mTOR signaling Enhancing ROS production
Autophagic cell death
–
Male nude mice (BALB/cAnN.CgFoxn1nu/CrlNarl)
Prostate cancer
Inhibiting Akt/mTOR signaling
Prostate cancer, breast – cancer
– –
Colon cancer Leukemia
Activating AMPK signaling
Athymicnude mice –
Glioma Breast Cancer
– Activating AMPK signaling Autophagic cell death Inhibiting PI3K/Akt/ mTOR/p70S6K
In vivo model(s)
Adult nude mice
Disease(s)
Inhibiting Akt/mTOR/ Glioma p70S6K signaling Activating ERK1/2 signaling
Mechanism(s)
–
[67]
[66]
[65]
–
–
[64]
[62] [63]
[59] [61]
[60]
–
Phase 2 –
Phase 3
Phase 0
Clinical trial References
Apoptosis
13
13 Induction
Induction
Alkaloid
Alkaloid
Alkaloid
Phenolic acid
Monanchocidin A (Mon A)
Berberine chloride (BBR)
Matrine
Δ9-Tetrahydrocannabinol (THC) Induction
Inhibition
Induction
Alkaloid
Induction
Induction or inhibition of autophagy
Voacamine (VOA)
Category
Alkaloid
Structure
Piperlongumine (PL)
Natural compound
Table 1 (continued) Disease(s)
Melanoma
Inhibiting Akt and Glioma mTOR via TRIB3 Hepatocellular carciInhibiting Akt/ mTORand activating noma (HCC) AMPK via TRIB3
Autophagic cell death
Phase 2 –
Male athymic nude mice
–
–
–
–
–
–
[73]
[72]
[71]
[38]
[70]
[38]
[69]
[68]
Clinical trial References
Nude mice
Athymic nude mice
–
Gastric cancer Blocking autophagic degradation by inhibiting lysosomal proteases
–
–
–
Genitourinary malignancies
Osteosarcoma
–
In vivo model(s)
Colon cancer
Autophagic cell death
Autophagic cell death
Autophagic cell death
Enhancing ROS pro- Osteosarcoma, cervical cancer duction Activating p38 signaling
Mechanism(s)
Apoptosis
Phenolic acid
Lignans
Lignans
Lignans
Oblongifolin C (OC)
Cannabisin B
Honokiol
Magnolol (Ery5)
Category
Phenolic acid
Structure
Guttiferone K (GUTK)
Natural compound
Table 1 (continued)
Induction
Induction
Induction
Inhibition
Induction
Induction or inhibition of autophagy
–
Male nude mice
Prostate cancer
–
Gastric cancer
–
–
–
–
BALB/c nude mice
Liver cancer, nasopharyngeal carcinoma (NPC), colon cancer, breast cancer Hepatoblastoma
–
–
–
–
–
–
–
Cervical cancer
[79]
[77]
[78]
[77]
[76]
[75]
[74]
Clinical trial References
In vivo model(s)
Disease(s)
Activating PI3K/Akt/ Neuroblastoma mTOR signaling and ER stress-mediated ERK1/2 signaling Inhibiting PI3K/ Non-small lung canPTEN/Akt pathway cer (NSCLC)
Inhibiting mTOR signaling Enhancing ROS production
Inhibiting Akt/mTOR signaling Enhancing ROS production Activating JNK signaling Blocking autophagosome-lysosome fusion Inhibiting lysosomalcathepsin Inhibiting Akt/mTOR signaling Inducing S phase cell cycle arrest
Mechanism(s)
Apoptosis
13
13 Induction
Induction
Quinone
Quinone
Cryptotanshinone (CTS)
Dihydrotanshinone (DHTS)
Induction
Steroid
Induction
Induction or inhibition of autophagy
Timosaponin AIII (TAIII)
Category
Steroid
Structure
Bufalin
Natural compound
Table 1 (continued)
–
– –
Hepatocellular carcinoma (HCC) Malignant glioma
Activating caspase through ROS
Colon cancer
Apoptosis-resistant cancer Colon cancer
Autophagic cell death Autophagic cell death
Human hepatoma
Activating AMPK signaling
Male NOD/SCID mice
–
–
Balb/c nu/nu mice
Breast cancer, cervical – cancer
–
–
Hepatoma
Upregulating Beclin-1 and Atg8 via JNK signaling Inhibiting Akt/mTOR signaling Activating AMPK and PERK/eIF2α/ CHOPsignaling Protective autophagy
–
–
–
–
Hepatocellular carcinoma (HCC)
ER stress through activation of IRE1 signaling
[86]
[85]
[85]
[84]
[83]
[82]
[81]
[81]
[80]
Clinical trial References
In vivo model(s)
Disease(s)
Mechanism(s)
Apoptosis
Naphthalene
Amino acid
Carbene
Cyclic peptide
Viriditoxin (VDT)
Bailomycin A1
Oplopantriol-A (OPT)
Coibamide A
Category
Naphthoic aldehyde
Structure
Gossypol
Natural compound
Table 1 (continued)
Induction
Induction
Inhibition
Induction
Induction
Induction or inhibition of autophagy
Disease(s)
Inducing autophagosome accumulation via an mTOR-independent pathway
Protective autophagy
Inhibiting vacuolar ATPase
Inducing cell cycle arrest Inhibiting Beclin-1— Bcl-2 interaction Autophagic cell death
–
Glioblastoma
–
–
–
–
Female athymic nude mice
–
–
– –
Phase 2
[96]
[95]
[94]
[93]
[92]
[90] [91]
[88] [89]
[87]
Clinical trial References
–
Female nude mice Female NCr-nu/nu nude mice – Female NCr-nu/nu nude mice –
–
In vivo model(s)
Human colorectal cancer
Epstein Barr virus (EBV)-related lymphomas
Prostate cancer
Breast cancer
Melanoma Colon cancer
Promoting Beclin-1— Prostate cancer Bcl-2/Bcl-xL dissociation by binding to Bcl-2/Bcl-xL
Mechanism(s)
Apoptosis
13
13 Disease(s)
Enhancing ROS production
Prostate cancer
Promoting autophago- Ovarian cancer some accumulation Blocking autophagic lux through inhibition of lysosomalcathepsin
Mechanism(s)
BALB/c nude mice
BALB/C athymic mice
In vivo model(s)
–
–
[97]
[95]
Clinical trial References
*2-Propenoic acid, 2-methyl-,(3aR,4S,8S,11S,11aS)-2,3,3a,4,5,8,11,11a-octahydro-8-methoxy-6,10-dimethyl-3-methylene-2-oxo-8,11-epoxy(6E)-cyclodeca[b]furan-4-ylester
Phenylpropanoid Induction
Inhibition
Induction or inhibition of autophagy
Hydroxychavicol (HC)
Category
Macrolide
Structure
Elaiophylin
Natural compound
Table 1 (continued)
Apoptosis
Apoptosis
(NA), a novel natural compound from Albatrellus confluens, may contribute to cancer cell death partially through autophagy related to JNK activation, apart from its efect on inhibition of PKD1/PI3K/Akt signaling [26]. Of note, a series of natural compounds directly targeting ROS production have also shown strong anti-tumor eicacy, through multiple signaling pathways involved in the interaction of ROS and autophagy [21]. As a recent study reported, cucurbitacins such as cucurbitacin B (Cuc B) and cucurbitacin I (Cuc I), triterpenoids isolated from herbal medicine, could inhibit tumor growth via mitochondrial ROS-induced autophagy, and among the diverse signaling involved, prolonged ERK and JNK activation following enhanced ROS contributed most to cucurbitacin-induced autophagic cell death [28]. Other natural compounds such as neferine [66], celastrol [33], piperlongumine (PL) [68], oplopantriol A (OPT) [95], and honokiol [77] can also stimulate autophagy by enhancing ROS generation. On the other hand, autophagy also represents a protective mechanism for cell survival when the cancerous phenotype is established or under stress induced by treatments [15, 108]. Herein, inhibition of autophagy may lead to new therapeutic strategies in cancer. One example lies in oblongifolin C (OC), a natural small-molecule compound extracted from Garcinia yunnanensis Hu, which inhibits autophagic lux by blocking autophagosome-lysosome fusion and suppressing the lysosomal proteolytic activity. OC was shown to eiciently sensitize nutrient-deprived cancer cells to apoptosis both in vitro and in vivo and its eicacy was potentiated in combined treatment with caloric restriction [75]. Likewise, in ovarian cancer cells, autophagy inhibitor elaiophylin has exerted a signiicant anti-tumor efect by blocking autophagic lux through lysosomal cathepsin suppression [37].
Neurodegenerative diseases In most cell types, autophagy occurs at low basal levels under normal conditions, and can only be fully activated when exposed to stress conditions [109]. In these contexts, autophagy malfunction may afect cells’ reaction to stress and thus increase cell susceptibility but is not likely to impair cell viability. On the other hand, however, because neurons are post-mitotic cells which cannot dilute misfolded proteins and damaged organelles by cellular division, efective and constitutive autophagy is required continuously to maintain neuronal homeostasis, eliminating misfolded proteins generated during routine protein turnover [110]. Once the autophagic process fails to work properly, it leads to the accumulation of intracellular aggregates and ultimately compromises cell vitality. As demonstrated in numerous studies, impaired or dysfunctional autophagy
in neurons concurs in the onset of diverse neurodegenerative diseases, while diferent neuronal subtypes show different susceptibilities to changes in autophagy. Noteworthily, neural autophagy also plays an important role in the clearance of aggregate-prone mutant proteins associated with neurodegenerative diseases. For instance, autophagy defects likely feature in the accumulation of extracellular β-amyloid (Aβ) in Alzheimer’s disease (AD), mutant huntingtin (Htt) protein in Huntington’s disease (HD), proteins mutated in spinocerebellar ataxia, mutant α-synucleins which lead to Parkinson’s disease (PD), and diferent mutant forms of tau that may cause frontotemporal dementia and other diseases [111–114]. Beyond its role in the clearance of misfolded and mutant proteins, autophagy may also halt the onset of several neurodegenerative settings including PD and AD by alleviating oxidative stress through turnover of mitochondria [115, 116]. Another important aspect about neuronal autophagy lies in the particular morphology of the neurons. Since neuron consist of a soma and neurites (axons and dendrites) and that autophagy can be formed wherever and whenever needed, the process inevitably requires retrograde transport of autophagosomes from distally located neurites to the soma. Accordingly, neuronal autophagy, and consequently neuronal viability, is particularly vulnerable to defects in traficking machinery [117]. On the other hand, although not intensively investigated, it has been delineated that activation of autophagic machinery may be detrimental in some neuronal models such as neuronal loss after a stroke [118, 119]. Therefore, autophagy-regulating natural compounds are of great potential to be utilized for treatment of neurodegenerative diseases (Table 2). As a progressively neurodegenerative disease, AD would eventually lead to irreversible loss of intellectual abilities including cognition and memory, and the Aβ-induced neurodegeneration is deemed to be the main pathological mechanism through the process. Studies in vitro and in vivo have supported that oleuropein aglycone (OLE), a natural phenol found in olive leaf, may protect neurons against Aβ-induced cytotoxicity by promoting neuronal autophagy which facilitates Aβ clearance, even at advanced stages of pathology, and therefore has beneicial efects against AD [120, 121]. Further studies have indicated that OLEmediated autophagy proceeds through mTOR inhibition, which is, at least in part, due to the activation of the Ca2+CAMKKβ-AMPK axis [121, 122]. Furthermore, arctigenin from Arctium lappa (L.) efectively ameliorates memory impairment in AD, targeting both production and clearance of Aβ. It inhibits Aβ production by down-regulating β-site amyloid precursor protein cleavage enzyme 1 (BACE1) and promotes Aβ clearance by enhancing autophagy induced by inhibition of AKT/mTOR signaling and activation of AMPK/Raptor pathway [125]. Notably, in HD models,
13
13 Induction
Induction
Flavonoid
Alkaloid
Lignans
Kaempferol
Neferine
Arctigenin
Induction
Induction
Flavonoid
Induction
Induction or inhibition of autophagy
Epigallocatechin3-gallate (EGCG)
Category
Terpenoid
Structure
Oleuropeinaglycone (OLE)
Natural compound
Table 2 Autophagy-modulating natural compounds in neurodegenerative diseases
Huntington’s disease (HD)
Inhibiting Akt/mTOR Alzheimer’s disease (AD) signaling Activating AMPK/ Raptor pathway
Activating AMPK/ mTOR signaling
Parkinson’s disease (PD)
Prion diseases
APP/PS1 mice
–
Wistarrats
–
–
–
–
–
[125]
[124]
[123]
[121]
[120]
Phase 2
Enhancing SIRT1 expression and activation Protective autophagy
[122]
–
[120, 121]
Clinical trial References
TgCRND8 mice Activating AMPK through Ca2+/ CaMKKβ activation Inhibiting mTOR/ Chronic unpredictable Male Wistar rats p70S6K mild stress (CUMS)induced cognitive dysfunctions
In vivo model(s)
–
Alzheimer’s disease (AD)
Disease(s)
TgCRND8 mice
Inhibiting mTOR
Mechanism(s)
Apoptosis
Stilbene
Stilbene
Flavonoid
Resveratrol (Rsv)
Pterostilbene (PT)
Epigallocatechin3-gallate (EGCG)
Inhibition
Induction
Induction
Induction
Induction
Terpenoid
Arglabin
Induction or inhibition of autophagy Induction
Category
Terpenoid
Structure
Ursolic acid (UA)
Natural compound
Table 3 Autophagy-modulating natural compounds in cardiovascular diseases Disease(s)
Cardiovascular complications
Restoring detrimen- Subarachnoid Hemtal autophagic lux orrhage (SAH)
Activating CaMKKβ/AMPK signaling
C57BL6J mice
Cardiovascular diseases Atherosclerosis
Adult male Kunming mice
–
–
Male Sprague–Daw- – ley rats
Ischemia/reperfusion (I/R) injury
Activating Rictor-mediated mTORC2 survival pathway at a low dose Activating AMPK and SIRT1 Activating AMPK through Ca2+/ CaMKKβ activation
–
–
–
Phase 2
Phase 2
–
Atherosclerosis
Activating cAMP/ PRKA/AMPK/ Sirt1 signaling
[144]
[145]
[148]
[144]
[145]
[74]
[141]
–
ApoE2.Ki mice and ApoE2.Ki/ Nlrp3−/− mice
[141]
–
LDLR−/− mice, C57BL/6 mice
References
Clinical trial
In vivo model(s)
Atherosclerosis
–
Atherosclerosis Increasing mRNA expression of Atg5 and Atg16L1
Mechanism(s)
Apoptosis
13
13 Diketone
Biphenyl
Curcumin
Usnic acid
Category
Flavonoid
Structure
Quercetin
Natural compound
Table 3 (continued)
Induction
Induction
Induction
Induction or inhibition of autophagy Renal ischemia/reperfusion (I/R)
Disease(s)
Protective autophagy Atherosclerosis
Oxidative stressPromoting Becrelated cardiovaslin-1—Bcl-2 cular diseases dissociation Inhibiting Ptdlns3K/ Akt/mTOR signaling Blocking FOXO1 nuclear localization
Activating AMPK/ mTOR signaling
Mechanism(s)
–
–
–
–
–
Clinical trial
C57BL/6L mice
In vivo model(s)
[154]
[150]
[153]
References
Apoptosis
Flavonoid
Flavonoid
Epigallocatechin3-gallate (EGCG)
Dihydromyricetin (DHM)
Category Terpenoid
Structure
Ursolic acid (UA)
Natural compound
Induction
Inhibition
Induction
Induction
Inhibiting ERK/ JNK-p53 signaling through down-regulation of ROS Activating AMPK signaling
–
Type 2 diabetes (T2D) Male diabetic GK rats Phase 3 (Insulin resistancerelated metabolic diseases) Type 2 diabetes (T2D) Male Sprague–Daw- – ley rats (Insulin resistancerelated metabolic diseases)
C57BL/6 mice
–
–
Clinical trial
Diabetic nephropathy Suppressing miRNA-21/PTEN/ Akt/mTOR signaling Increasing AMPK Hepatosteatosis
In vivo model(s)
High fat diet (HFD)- Phase 2 fed C57BL/6 J mice
Disease(s)
Protective autophagy Hyperlipidemia Glucose tolerance
Induction or inhibition Mechanism(s) of autophagy
Table 4 Autophagy-modulating natural compounds in metabolic diseases
[169]
[168]
[167]
[166]
[165]
References
Apoptosis
13
Apoptosis
neferine from Nelumbo nuciferahas been testiied to protect against mutant Htt protein by activating autophagy through an AMPK/mTOR signaling-dependent manner [124]. It has also been clariied that administration of autophagy-inducing natural compounds may have implications in treatment of other neurodegenerative diseases such as PD. For example, kaempferol, a lavone, induces autophagy to facilitate the clearance of damaged mitochondria and thus protects neurons against cell death in models of rotenone intoxication and other PD toxins targeting mitochondria [123].
Cardiovascular diseases Cardiomyocytes, like neurons, are post-mitotic cells with limited replicative capacity, in which quality-control systems such as autophagy are fundamental to maintain cellular homeostasis [126, 127]. Beyond its role in degrading defective proteins and organelles, basal autophagy also plays an important role in the regulation of cardiac metabolism. If dysregulated, autophagy is likely to contribute to the pathogenesis of cardiac diseases [128, 129]. When nutrient supplies are limited or cells are subject to cardiac stress, autophagy is triggered to fuel the heart through diferent routes. For instance, common cardiac disorders such as cardiac ischemia characterized by a decrease in the availability of energy substrates would result in a hypoxic/anoxic environment that elicits potent autophagy [130–135]. Furthermore, studies have corroborated that the protective efect of autophagy also resides in its function of eliminating toxic ROS [136–139]. Meanwhile, the pro-survival role of autophagy in cardiomyocytes has also been supported by several studies reporting that pharmacological activation of autophagy during mild ischemic stress is cardioprotective [132, 140], whereas autophagy inhibition enhances cell death [141, 142]. It is noteworthy that autophagy has also been deciphered to play vital roles in vascular pathophysiological processes, while more detailed molecular mechanisms still warrant further investigation [143]. Most natural compounds trigger protective autophagy to reestablish homeostatic microenvironment in injured cells to improve the post-ischemic recovery of heart (Table 3). Rsv (discussed previously), for example, can potently augment autophagy through AMPK activation to mitigate adverse post-infarction cardiac remodeling and preserve cardiac performance [144]. Even at a low concentration, Rsv has been testiied to protect cell survival, at least in part, through autophagy induction. Furthermore, the mechanic insights into this beneicial efect suggested that the activation of autophagy may be mediated through expression of Rictor, a component of mTORC2 known to function via phosphorylation of Ser
13
473 and activation of Akt [145]. Unfortunately, though rapidly and eiciently absorbed after oral administration, Rsv has low bioavailability due to its metabolism to sulfated and glucoronidated derivates, leaving there a limit in its cardiovascular protective efect [146]. Further studies suggested pterostilbene (PT), a naturally occurring analogue of Rsv, could trigger a rapid elevation in intracellular calcium ([Ca2+]i) concentration and subsequently induce AMPK-mediated autophagy. Since PT has longer half-life and higher bioavailability than Rsv in vivo, it may be a potential candidate for therapies against cardiovascular diseases such as atherosclerosis [38, 147]. Intriguingly, atherosclerosis (AS), a high-incidental cardiovascular disease, has been correlated to prolonged and excessive inlammation in the vascular wall, hence natural compounds with anti-inlammatory properties may represent promising candidate drugs to treat AS. In human umbilical vein endothelial cells (HUVECs), for example, Rsv attenuates vascular endothelial inlammation with an impactful autophagy-inducing efect mediated via the activation of cAMP-PRKA-AMPK-SIRT1 signaling pathway [148]. Arglabin, a natural inlammasome inhibitor, exerted autophagy-inducing efects in macrophages which may halt the activation of inlammasome and thus restrict inlammation and markedly reduce the median lesion areas in atherosclerosis models [149]. Curcumin, an antioxidant and anti-inlammatory polyphenol beneiting vascular endothelial cells (VECs) with its capability to neutralize ROS, has also been testiied to function by enhancing autophagy through suppression of PtdIns3K-AKT-mTOR signaling pathway, activation of Beclin-1 and prevention of FOXO1 nuclear localization [150–152]. Crucially, though, autophagy may act as a detrimental cardiac response under certain circumstances, judging by the fact that suppressed autophagy may lead to attenuated injury and increased viability after ischemia/reperfusion (I/R) in several in vitro and in vivo studies [133, 155]. Moreover, autophagic cell death has been shown to be a leading cause of the progression from compensated hypotrophy to heart failure in pressure-overloaded human heart [156]. It is believed that timing and the stress-inducing condition are critical for the switch in the efect of autophagy. In settings like reperfusion recovery, the excessive need to remove accumulated dysfunctional mitochondria and oxidatively damaged cellular structures may trigger aggressive autophagic response which would ultimately lead to maladaptation to cardiac stress [157]. Herein, suppressing autophagy may also have therapeutic implications against cardiac diseases in theory, however hitherto, inhibition of autophagy has not been reported to be exploited in cardiovascular protection mediated by natural compounds.
Alkaloid
Phenolic acid Inhibition
Amino acid
Piperlongumine (PL)
Eugenol
Bailomycin A1
Inhibition
Induction
Induction
Diketone
Induction
Induction or inhibition of autophagy
Curcumin
Category
Flavonoid
Structure
Epigallocatechin3-gallate (EGCG)
Natural compound
Table 5 Autophagy-modulating natural compounds in inlammation and infection
Hepatitis B virus (HBV) infection
Disease(s)
Inhibiting Beclin-1— Bcl2 dissociation by inhibiting ERK1/2, p38 and IKK/NF-kB signaling Protective autophagy
Protective autophagy through an mTORdependent manner
Inluenza A virus (IAV) – infection
–
–
Inluenza A virus (IAV) – infection
–
–
–
Clinical trial
–
–
Balb/C mice
–
In vivo model(s)
–
Inlammation
Inducing HMGB1 aggre- Endotoxemia and sepsis gation and subsequent degradation Inhibiting NFkB activaMycobacterium tubertion culosis (MTB)
Enhancing lysosomal acidiication
Mechanism(s)
[204]
[203]
[197]
[196]
[195]
[194]
References
Apoptosis
13
Apoptosis
Metabolic diseases It is well known that autophagy acts as an essential metabolic process that controls energy balance of both single cells and the whole organism, especially in the event of nutrient deiciency [158]. In recent years, growing evidence has suggested that dysregulation of autophagy may be implicated in metabolic disorders such as diabetes and obesity [159–161]. As an important metabolic disorder, type 2 diabetes (T2D) is characterized by combined insulin resistance and relative insulin deiciency [162]. Autophagy has been demonstrated to have a close connection with the pathology of T2D since it is important for the maintenance of insulin-producing pancreatic β-cell vitality or function, while dysregulated autophagy in insulin target tissues has been associated with altered insulin sensitivity and lipid metabolism [163, 164]. Apart from the prevention of β-cell failure, the protective role against T2D of autophagy also lies in the clearance of amyloidogenic human islet amyloid polypeptide (hIAPP), a unique hallmark of human T2D [165]. Intriguingly, obesity, a metabolic disorder directly resulted from the accumulation of white adipose tissue (WAT), has also been reported to be accompanied by changes of autophagy in adipose tissue [160, 161]. It has been proposed that autophagy may remove intracellular organelles in preadipocytes early in cell diferentiation and thus make place for lipid droplets produced during adipogenesis [166]. Further studies have proposed that autophagy is important in normal white adipogenesis, especially in the formation of the unique unilocular lipid droplet structure and mitochondria homeostasis control. In support of the positive role of autophagy obesity pathogeny, in vitro and in vivo studies have demonstrated that pharmacological or genetic inhibition of autophagy would result in increased sensitivity to insulin and high-fat diet-induced obesity [167]. With accumulating researches determining the interconnection of autophagy and metabolic disorders, autophagyregulating natural compounds have been delineated to be available for treatment of metabolic diseases (Table 4). Notably, epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, may inhibit autophagy through down-regulation of the ROS-ERK/JNK-p53 pathway, ameliorating oxidative stress and reversing mitochondrial dysfunction which may play important roles in T2D and insulin resistance [168]. Conversely, induction of autophagy has also been indicated to contribute to T2D treatment through diferent mechanisms. Natural lavonoid dihydromyricetin (DHM) was found to attenuate skeletal muscle insulin resistance (SMIR), which was important in the pathogenesis of T2D, by inducing autophagy though activation of AMPK signaling [169]. AMPK-mediated autophagy is also involved in the anti-obesity activity of
13
α-lipoic acid, though in an adverse way. It has been deciphered that α-lipoic acid deteriorated the intracellular accumulation of lipid droplets by inhibiting autophagy through prevention of autophagy-related proteins such as LC3-II and suppression of AMPK at earlier steps of adipocyte differentiation [166].
Infection, immunity, and inlammatory diseases Evidence has accumulated that autophagy is involved in both innate and adaptive immune pathways [89]. Four main roles of autophagy in immunity have been established by multiple researches: (1) direct elimination of microorganism, (2) control of inlammation, (3) control of adaptive immunity, and (4) secretion of immune mediators [170]. In the face of a pathogen, through conventional pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), mammalian cells could elicit autophagic responses which intercept microorganism invasion at diferent stages of the host-pathogen encounter [171]. Activated autophagic machinery intercepts microorganism invasion via LC3-associated phagocytosis (LAP) and xenophagy, while its antimicrobial function of autophagy may be ampliied due its cooperation with TLRs [172–174]. Paradoxically, autophagy can present a pro-infective role in some cases by suppressing type I interferon (IFN), mainly though inhibition of RIGI-like receptor RLR signaling [175, 176]. When a pathogen escapes the autophagy barriers that are controlled by conventional PRRs, it can still be captured and eliminated in the cytoplasm or even in the cytosol by sequestosome1-like receptors (SLRs), a group of specialized autophagic adapters [177–180], and other autophagy-associated factors such as ATG5 [181] and Beclin-1 [182]. Several reports suggest that basal levels of autophagy control the set point of inlammasome activation, whereas blocked autophagy increases IL-1β levels through accumulation of inlammasome agonists such as mitochondrial DNA and ROS [183]. Additionally, autophagy also controls inlammation by suppressing calpan-dependent IL-1α activation [183] and degrading pro-inlammatory signaling factors like B cell lymphoma 10 (BCL-10) [184, 185]. In adaptive immune response, autophagy may enhance major histocompability complex (MHC) class II-mediated antigen presentation to CD4+ T cells and facilitate naive T cell repertoire selection, T cell homeostasis and TH cell polarization [186–189]. Notably, in contrast to the initial promotion of MHC class II processing, autophagy also promotes the disassembly of immunological synapses, helping to downregulate the response at later stages [190]. Beyond its intracellular actions, autophagy also modulates the extracellular release of immune mediators such as ATP, IL-6, IL-8 and
Apoptosis
immunoglobulin, repressing the inlammasome under basal conditions [191–195]. Interestingly however, under stress conditions, autophagy may facilitate unconventional secretion of IL-1β and and IL-18 [196], and the understanding of the speciic role of autophagy in secretion is still in its infancy. Given the intricate interaction between autophagy and immunity processes, autophagic modulators undoubtedly have great clinical prospects in treating inlammatory disorders, autoimmune diseases and infection (Table 5). Piperlongumine (piplartine, PL), an electrophilic molecule isolated from Piper longum L., possesses excellent anti-cancer and anti-inlammatory properties. A recent paper reported that PL and its analogue PL-0N have potent efects on restriction of lipopolysaccharide (LPS)-induced inlammation, partially through induction of autophagy in an mTOR-dependent rather than Akt-dependent manner [197]. Moreover, via ROS clearance and autophagy induction, some natural products such as Rsv can ameliorate the state of oxidative stress, thus reversing restraint-induced declines of spleen index and splenocyte number. As the maintenance of splenic lymphocyte number and splenic immunity is important for normal immune function, Rsv functions to ameliorate inlammations [198, 199]. Intriguingly, autophagy could be induced by inluenza A virus (IAV) infection to facilitate viral replication, making inhibition of autophagy a promising strategy to impede infection [200]. For example, eugenol could impair IAV replication by inhibiting autophagy through deceased dissociation of Beclin-1-Bcl2 heterodimer via inhibition of ERK1/2, p38 and IKK/NF-kB signaling [201]. Likewise, a potent vacuolar ATPase inhibitor, bailomycin A1 can also impede IAV infection through autophagy suppression [202].
Conclusions Based on new understandings of pharmacological and biological activities of natural compounds, utilization of natural compounds and their derivatives has gradually become a promising avenue for potential therapeutic purposes. Natural compounds can serve as active components for medicines and have inspired a large number of currently prescribed drugs. Importantly, they may also represent lead compounds for novel drugs with improved potency and safety [115]. Autophagy, an intricate catabolic process pivotal for homeostatic maintaining, has been demonstrated to be implicated in various diseases, making autophagymodulating drug therapy of great therapeutic beneit in novel treating strategies. Hitherto, a growing body of evidence has delineated that many natural compounds exert autophagy-modulating activity and thus may contribute to treatments of diverse diseases.
Indeed, with substantial explorations, natural compounds have shown potent efects on multiple human diseases through induction of autophagy. In a great number of cancer models, natural compounds have been clariied to exert anti-tumor properties, at least in part, by promoting autophagic cell death, while in the state of neurodegeneration, natural compounds mainly stimulate autophagy for clearance of mutant or dysfunctional proteins. Furthermore, autophagy induced in anti-cardiovascular disease treatment primarily serves as homeostasis retaining system to protect cardiomyocytes or VECs, and is often related to the amelioration of inlammation. Notably, natural compounds may also enhance insulin sensitivity via autophagy induction to mitigate metabolic disorders, and some compounds can halt inlammation and immune diseases mainly by enhancing autophagy in immune cells or immune organs such as spleen. However, due to the dual role of autophagy in diferent pathophysiologic settings, autophagy can lead to unpleasant outcomes under certain circumstances, while autophagy inhibition may turn out to be propitious therapeutic strategy. Therefore, it is pivotal to weigh the therapeutic beneits of autophagy against its potential risks, and research into combinations of autophagy-modulating natural compounds with other agents may help to restrict the undesirable side efects or therapy-resistance caused by autophagy. In fact, autophagy-inhibiting natural compounds may protect against diseases as single agents or improve the eicacy of conventional therapies. Autophagy is widely accepted to be connected to the resistance of anti-cancer therapies, therefore, natural compounds inhibiting protective autophagy may be utilized to improve anti-tumor efects in combined treatment or as single agents. Moreover, autophagy induced by certain cells like adipocytes or pathogens is involved in the pathogenesis of some diseases such as obesity and infection, making natural products inhibiting autophagy beneicial for disease amelioration. So far, autophagy-regulating natural compounds intensively explored are conined to ahandful of categories such as terpenes, alkaloids, lavones and stilbenes, thus more attention could be addressed at the autophagy-modulating properties of these compounds. Meanwhile, it is still not fully clariied how these studied natural compounds interact with autophagic targets to induce or inhibit autophagy. Hence, further insight of autophagy modulation by natural compounds may make a great contribution to facilitating a better understanding of the molecular mechanisms of natural compounds and thus propel the development of natural compounds in clinical use. Acknowledgements We acknowledge support from the National Natural Science Foundation of China (NSFC) (Grant Number 31270399 and Grant Number 81603275), Key Projects of the
13
Apoptosis National Science and Technology Pillar Program (Grant Number 2012BAI30B02), Fund of the Educational Department of Liaoning Province (Grant Number L2011177), Liaoning Baiqianwan Talents Program (Grant Number 2013921043), Liaoning Province Natural Science Foundation (Grant Number 201602689), Scientiic Research Foundation for the Returned Overseas Chinese Scholars of Shenyang Pharmaceutical University (Grant Number GGJJ2015103), and 2015 Career Development Program for Young and Middle-aged Teachers of Shenyang Pharmaceutical University (Grant Number ZQN2015015). Compliance with ethical standards Conlict of interest interests.
The authors declare that they have no competing
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