Cell Death & Disease
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2020
·Vol. 11
·期 2
·1-18
·
IF 6.304
Zhuang Xu-Xu,Wang Sheng-Fang,Tan Yuan,Song Ju-Xian,Zhu Zhou,Wang Zi-Ying,Wu Ming-Yue,Cai Cui-Zan,Huang Zhi-Jian,Tan Jie-Qiong,Su Huan-Xing,Li Min,Lu Jia-Hong
Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
研究领域:
神经科学
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分子生物学
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药理学
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Chen Zhao,Zheng Xing,Xinbo Wei,Guoyu Liao,Depeng Yang,Haifeng Liu,Yubo Fan
Critical limb ischemia (CLI) is the terminal stage of peripheral arterial disease (PAD), always leading to a high risk of amputations and deaths. While the majority of strategies only focus on recanalization of patients, these methods are unsatisfactory due to limited therapeutic effect and surgical damage. Herein, a multifunctional engineered-extracellular vesicles (EVs)/hydrogel system is designed for facilitating angiogenesis and protecting the ischemic muscle tissue via a non-surgical delivery strategy. The EVs released from endothelial progenitor cells (EPCs), an emerging stem cell therapy candidate, were used to play the pro-angiogenesis role. Transcription factor EB (TFEB), a master regulator of autophagy, was utilized to genetically modify the EVs for building TFEB-engineered EVs (TFEB-EVs) to reduce the impairment of muscle. Moreover, a thermal-/pH-responsive hydrogel (FPD), prepared by F127, polyethylenimine (PEI), and oxidized dextran, served as a sensitive controlled-release carrier and improved the stability of TFEB-EVs in vivo , simultaneously. Our results exhibited that TFEB-EVs/FPD significantly strengthened neovascularization, alleviated muscle damage, and protected the limb function of CLI mice. Overall, TFEB-EVs/FPD offered a convenient, safe, and non-surgical approach for rescuing CLI.
研究领域:
生物医学工程
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再生医学
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组织工程
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分子生物学
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药学
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高影响因子
Autophagy
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2019
·
IF 11.059
Bin Ye,Quan Wang,Haixia Hu,Yilin Shen,Cui Fan,Penghui Chen,Yan Ma,Hao Wu,Mingliang Xiang
Macroautophagy/autophagy dysfunction is associated with many neurodegenerative diseases. TFEB (transcription factor EB), an important molecule that regulates lysosomal and autophagy function, is regarded as a potential target for treating some neurodegenerative diseases. However, the relationship between autophagy dysfunction and spiral ganglion neuron (SGN) degeneration and the role of TFEB in SGN degeneration has not yet been established. Here, we showed that in degenerated SGNs, induced by sensory epithelial cell loss in the cochlea of mice following kanamycin and furosemide administration, the lipofuscin area and oxidative stress level were increased, the nuclear-to-cytoplasmic TFEB ratio was decreased, and the late stage of autophagic flux was impaired. After autophagy dysfunction was partially ameliorated with an MTOR inhibitor, which promoted TFEB translocation into the nucleus from the cytoplasm, we found that the lysosomal deficits were significantly relieved, the oxidative stress level was reduced, and the density of surviving SGNs and auditory nerve fibers was increased. The results in the present study reveal that autophagy dysfunction is an important component of SGN degeneration, and TFEB may be a potential target for attenuating SGN degeneration following sensory epithelial cell loss in the cochlea of mice.Abbreviations: 3-NT: 3-nitrotyrosine; 4-HNE: 4-hydroxynonenal; 8-OHdG: 8-hydroxy-2ʹ-deoxyguanosine; ABR: auditory brainstem response; APP: amyloid beta (A4) precursor protein; CLEAR: coordinated lysosomal expression and regulation; CTSB: cathespin B; CTSD: cathespin D; SAMR1: senescence-accelerated mouse/resistance 1; SAMP8: senescence-accelerated mouse/prone 8; MAPK1/ERK2: mitogen-activated protein kinase 1; MTOR: mechanistic target of rapamycin kinase; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscope; TFEB: transcription factor EB
研究领域:
神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Food Bioscience
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2026
·
IF 6.2
Shiqin Gong,Ziqi Li,Fang Liu,Yi Xiao
High-sugar diets are associated with multiple health risks, such as obesity, metabolic disorders, and cardiovascular diseases. To mitigate the adverse effects of high sugar intake on biological health, aspartame (ASP) is widely used as one of the sugar substitutes. In this study, we used Caenorhabditis elegans ( C. elegans ) as the model to reveal the specific mechanism by which ASP affects healthy lifespan. Our results showed that ASP (1, 10, 100 μmol/L) significantly extended the lifespan of C. elegans and improved health indicators in dose dependent manner, including reduced lipofuscin accumulation and enhanced motility, but did not influence the fertility of worms. Furthermore, by screening the classic signaling pathways, we discovered ASP extended healthspan via mechanistic target of rapamycin complex 1 (mTORC1) pathway. In addition, we found that ASP inhibited mTORC1 activity to promote the nuclear translocation of helix-loop-helix protein 30 (HLH-30), the nematode homolog of transcription factor EB (TFEB), and subsequently upregulated autophagy-related genes such as autophagy-related gene 5 ( atg-5 ), beclin 1 ( bec-1 ), LC3, GABARAP, GATE-16 family member 1 ( lgg-1 ) and LC3, GABARAP, GATE-16 family member 2 ( Lgg-2 ). This ultimately activated the autophagy process, thereby delaying aging. This finding elucidates that ASP induces autophagy to enhance healthspan in C. elegans dependent on the mTORC1/TFEB pathway, offering a novel approach for anti-aging research.
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MOLECULAR IMMUNOLOGY
·
2026
·
IF 3.7
Jiaqi Li,Shuang Chen,Jialiang Suo,Yuanbiao Ma,Zhengxin Lu,Shenlin Cai,Haoyu Chen,Zhiyu Chen,Zhewen Deng,Chenglun Tang,Qi Zhang,Bo Ma
COR improves renal injury in diabetic mice by restoring podocyte viability. • COR restores autophagic flux to relieve PA‑induced podocyte injury. • TFEB serves as the pivotal regulator through which COR restores autophagic flux • COR activates TFEB by inhibiting mTORC1 and blocking K48-ubiquitination. Currently, effective therapeutic strategies to halt the irreversible decline of renal function in diabetic nephropathy (DN) are limited. This study aimed to investigate the renoprotective effects of Cordycepin (COR), a bioactive adenosine analog derived from Cordyceps militaris , in a mouse model of DN and to elucidate its underlying mechanisms. In a type II diabetic mouse model induced by a high-fat diet and streptozotocin, COR treatment attenuated hyperglycemia and renal dysfunction, ameliorated glomerular injury, and restored the expression of Nephrin, a critical slit-diaphragm protein in podocytes. In vitro , in palmitic acid (PA)-induced podocyte injury, COR treatment elevated cell viability and upregulated Nephrin expression dose-dependently. Mechanistically, COR restored impaired autophagic flux under diabetic conditions by improving autophagosome maturation, autophagosome-lysosome fusion, and lysosomal degradation, as demonstrated by the normalized profile of autophagy markers (LC3-II/I, p62, Beclin-1, LAMP1). This pro-autophagic activity was essential for its protection, which was abolished by 3-MA and enhanced by rapamycin. Subsequently, we identified transcription factor EB (TFEB) as the central mediator of COR's action. COR dually regulates TFEB through two synchronized pathways: it inhibits the mTORC1 axis to promote TFEB nuclear translocation and transcriptional activity, while simultaneously suppressing K48-linked polyubiquitination to prevent its proteasomal degradation, and enhancing its stability. TFEB was essential for restoring autophagic flux and podocyte integrity, with overexpression reversing and knockdown exacerbating PA‑induced injury. In summary, our findings demonstrate that COR alleviates DN by coordinately enhancing the activity and stability of TFEB. This work reveals a novel dual-targeting mechanism and proposes a promising therapeutic strategy for diabetic nephropathy.
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JOURNAL OF PHARMACEUTICAL SCIENCES
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2026
·
IF 3.9
Xinyi He,Xu Jiang,Huazhong Lin,Kexin Zhang,Xuewen Yu,Jiaxin Bi,Lu Zhang,Yingying Liang,Lijuan Chen,Mumin Shao
Breast malignant phyllodes tumor (MPT) is a fibroepithelial neoplasm characterized by high recurrence rates. Currently, no effective therapeutic agents are available, and surgery remains the mainstay of treatment for MPT. Niclosamide ethanolamine (NEN), an antiparasitic agent, has recently demonstrated broad-spectrum antitumor activity against various solid malignancies. This study aimed to evaluate the antitumor efficacy of NEN against MPT and elucidate the underlying molecular mechanisms. The effects of NEN on MPT cell proliferation and migration were assessed using CCK-8, wound healing, and Transwell migration assays. Ultrastructural alterations following NEN treatment were examined by transmission electron microscopy. Bioinformatics analyses, quantitative real-time PCR (qPCR), Western blotting, and immunofluorescence staining were employed to investigate the molecular mechanisms underlying NEN-mediated modulation of autophagy and lysosomal function. NEN significantly inhibited MPT cell proliferation and migration. Transmission electron microscopy revealed the accumulation of numerous autolysosomal structures in NEN-treated cells. Mechanistically, NEN suppressed mTOR phosphorylation, promoted nuclear translocation of transcription factor EB (TFEB), and induced lysosomal biogenesis. However, lysosomal function was compromised, as evidenced by elevated luminal pH, impaired cathepsin D maturation, and lysosomal membrane permeabilization, ultimately resulting in autophagic flux blockade at the degradation stage. Furthermore, lysosomal cathepsin leakage activated the mitochondrial apoptotic pathway, culminating in caspase-3-dependent apoptosis. NEN effectively kills MPT cells by inducing "lysosomal biogenesis–function uncoupling." This study is the first to reveal a novel anti-MPT mechanism that targets the mTOR-TFEB-lysosome axis and disrupts lysosomal homeostasis, providing a potential drug candidate for the treatment of MPT.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 15
·11899
·
IF 5.6
Peixin Wang,Chenqiong Zhao,Hanjing Zhou,Xiaona Huang,Hanqi Ying,Songying Zhang,Yibin Pan,Haiyan Zhu
Dysregulated biological behaviors of trophoblast cells can result in recurrent spontaneous abortion (RSA)—whose underlying etiology still remains insufficient. Autophagy, a conserved intracellular physiological process, is precisely monitored throughout whole pregnancy. Although the exact mechanism or role remains elusive, epigenetic modification has emerged as an important process. Herein, we found that a proportion of RSA patients exhibited higher levels of autophagy in villus tissues compared to controls, accompanied with impaired histone deacetylase (HDAC) expression. The purpose of this study is to explore the connection between HDACs and autophagy in the pathological course of RSA. Mechanistically, using human trophoblast cell models, treatment with HDAC inhibitor (HDACI)-trichostatin A (TSA) can induce autophagy by promoting nuclear translocation and transcriptional activity of the central autophagic regulator transcription factor EB (TFEB). Specifically, overactivated autophagy is involved in the TSA-driven growth inhibition of trophoblast, which can be partially reversed by the autophagy inhibitor chloroquine (CQ) or RNA interference of TFEB. In summary, our results reveal that abnormal acetylation and autophagy levels during early gestation may be associated with RSA and suggest the potential novel molecular target TFEB for RSA treatment.Keywords:recurrent spontaneous abortion;autophagy;epigenetic modification;acetylation;histone deacetylase inhibitor (HDACI);transcription factor EB;nuclear translocation;pathological course
研究领域:
妇产科学
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分子生物学
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表观遗传学
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Autophagy
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2020
·
IF 9.77
Dan Li,Rong Shao,Na Wang,Nan Zhou,Kaili Du,Jiahui Shi,Yihan Wang,Zhuangzhuang Zhao,Xin Ye,Xiaoli Zhang,Haoxing Xu
Oxidative stress underlies a number of pathological conditions, including cancer, neurodegeneration, and aging. Antioxidant-rich foods help maintain cellular redox homeostasis and mitigate oxidative stress, but the underlying mechanisms are not clear. For example, sulforaphane (SFN), an electrophilic compound that is enriched in cruciferous vegetables such as broccoli, is a potent inducer of cellular antioxidant responses. NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2), a transcriptional factor that controls the expression of multiple detoxifying enzymes through antioxidant response elements (AREs), is a proposed target of SFN. NFE2L2/NRF2 is a target gene of TFEB (transcription factor EB), a master regulator of autophagic and lysosomal functions, which we show here to be potently activated by SFN. SFN induces TFEB nuclear translocation via a Ca2+-dependent but MTOR (mechanistic target of rapamycin kinase)-independent mechanism through a moderate increase in reactive oxygen species (ROS). Activated TFEB then boosts the expression of genes required for autophagosome and lysosome biogenesis, which are known to facilitate the clearance of damaged mitochondria. Notably, TFEB activity is required for SFN-induced protection against both acute oxidant bursts and chronic oxidative stress. Hence, by simultaneously activating macroautophagy/autophagy and detoxifying pathways, natural compound SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases.Abbreviations: ANOVA: analyzes of variance; AREs: antioxidant response elements; Baf-A1: bafilomycin A1; BHA: butylhydroxyanisole; CAT: catechin hydrate; CCCP: carbonyl cyanide m- chlorophenylhydrazone; CLEAR: coordinated lysosomal expression and regulation; DCFH-DA: 2ʹ,7ʹ-dichlorofluorescin diacetate; FBS: fetal bovine serum; GFP: green fluorescent protein; HMOX1/HO-1: heme oxygenase 1; KD: knockdown; KEAP1: kelch like ECH associated protein 1; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MCOLN1/TRPML1: mucolipin 1; ML-SA1: mucolipin-specific synthetic agonist 1; ML-SI3: mucolipin-specific synthetic inhibitor 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: nuclear factor: erythroid 2 like 2; NPC: Niemann–Pick type C; PBS: phosphate-buffered saline; PPP2/PP2A: protein phosphatase 2; Q-PCR: real time polymerase chain reaction; ROS: reactive oxygen species; RPS6KB1/S6K1/p70S6K: ribosomal protein S6 kinase B1; SFN: sulforaphane; TFEB: transcription factor EB; WT, wild-type
研究领域:
细胞生物学
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分子生物学
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药理学
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营养学
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One Health Advances
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2026
·Vol. 4
·期 1
·32
·
IF 5
Ni Baihai,Du Jiayu,Li Zimeng,Jian Pingan,Chen Mingshan,Li Jinlong,Li Xuenan
One common plasticizer is di(2-ethylhexyl) phthalate (DEHP). We use it a lot in our daily lives, and prolonged exposure to it can be harmful to living things. One form of selective autophagy that can break down damaged lysosomes is called lysophagy. Conversely, excessive occurrence of lysophagy can in turn cause lysosomal damage. Here, we show that DEHP stimulates the transient receptor potential mucoLipin 1-transcription factor EB (TRPML1-TFEB) pathway, drives excessive lysophagy, resulting in lysosomal dysfunction and kidney injury in mice. One carotenoid with strong antioxidant qualities is lycopene (LYC). It is frequently employed to offset the effects of DEHP. Interestingly, our results showed that LYC can reduce kidney damage caused by DEHP in mice. Inhibiting the TRPML1-TFEB pathway's activation and reducing lysophagy are two of the mechanisms of action. In summary, LYC significantly alleviates DEHP-induced injury in mouse renal tubular epithelial cells by inhibiting TRPML1-TFEB pathway-mediated lysophagy. LYC successfully reduced the damage caused by mono(2-ethylhexyl) phthalate in human renal proximal tubular epithelial cells, confirming this effect in vitro. This study establishes a critical link between LYC treatment and lysophagy as well as lysosomal dysfunction in DEHP-induced mouse renal tubular epithelial cells. This study offers novel mechanistic perspectives on DEHP-induced nephrotoxicity and the renal protection conferred by LYC. Graphical
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Toxics
·
2026
·Vol. 14
·期 5
·430
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IF 4.9
Haobo Qu,Xiaoyu Zhao,Yifan Wang,Sichao Mao,Xingxiang Chen,Kehe Huang,Xinyi Xu
Cadmium (Cd) is a persistent environmental pollutant that poses a significant health risk to humans and animals, with acute exposure known to induce kidney injury. Fucoidan (Fc), a natural bioactive polysaccharide derived from brown algae, exhibits diverse biological activities; however, its potential to protect against Cd-induced kidney damage and the underlying mechanisms remain unclear. In this study, we investigated the effects of Fc on Cd-induced renal injury in vitro and further explored the role of transcription factor EB (TFEB) in regulating autophagy in its protective mechanism. Our results demonstrate that in Cd-exposed porcine kidney cells (PK-15), Fc suppressed the expression of renal inflammatory factors (TNF-α, IL-1β) and kidney injury markers (NGAL, NTN-1, KIM-1), reduced reactive oxygen species (ROS) production, and downregulated apoptosis-related proteins (cleaved caspase-3 and cleaved caspase-9). Mechanistically, Fc upregulated TFEB protein expression, enhanced the levels of lysosomal function-related proteins (Cathepsin B, CTSB; Cathepsin D, CTSD), and reversed Cd-induced autophagic flux blockade. Importantly, TFEB silencing abolished the protective effects of Fc. Collectively, these findings suggest that Fc exerts renoprotective effects against Cd-induced injury by restoring autophagic flux, a process that involves TFEB.
Keywords: fucoidan; cadmium; autophagy; TFEB
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EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Xiaohong Liu,Xiaoyu Li,Shan Su,Yujia Yuan,Wen Liu,Min Zhu,Qing Zheng,Xin Zeng,Fudong Fu,Yanrong Lu,Younan Chen
Lipotoxicity caused by excess free fatty acids , particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.
研究领域:
肝病学
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细胞生物学
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分子生物学
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高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2026
·Vol. 44
·期 4
·e70214
·
IF 3.5
Jia-Wei Sun,Yin-Kang Chen,Liang Ji,Jian Zhao,Fu-Jun Wang
Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy. Summary This study reveals a novel strategy to combat cancer by repurposing an endogenous anti-apoptotic protein into a potent therapeutic agent. We demonstrate that apocytochrome C (APO-Cyt C), when combined with the natural compound sodium aescinate (SA), triggers cancer cell death through excessive autophagy rather than conventional apoptotic pathways. The discovery that this combination induces lethal autophagy by synergistically targeting both mTOR signaling and lysosomal function provides important insights for overcoming drug resistance. These findings highlight the promising therapeutic potential of combining mTOR inhibitors with lysosome-targeting saponins, establishing a new paradigm for cancer treatment through coordinated regulation of autophagic processes.
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