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Autophagy-targeting strategies are established in various diseases including cancer, proteopathies, vascular disease, and other human diseases. (i) Applying autophagy for cancer treatment must be carefully considered based on its complex role in cancer. Characteristics of cancer such as protein abnormalities, morphology, and progressive growth can be modulated by the autophagy pathways depicted in Section 3.1. In brief, targeting autophagy in cancer can be divided into two strategies: autophagy activation and inhibition. In the autophagy activation approach, the purpose is to prevent cells from malignant transformation by maintaining cellular protection. The autophagy inhibition approach includes targeting autophagy initiation and its ability to ultimately degrade its contents. The goal of this approach is to inhibit cancer cells from exploiting autophagy for their propagation. (ii) Proteopathies are protein conformational disorders caused by the accumulation of abnormal protein aggregates such as amyloid β plaques, tau neurofibrillary tangles (NFTs), α-synuclein aggregates, and prions. The strategy for 'autophagy activation' could ameliorate pathological conditions derived from these conformational abnormality through promoting degradation of the pathological substrates as depicted in Section 3.2. (iii) In vascular disease including atherosclerosis, restenosis, intraocular neovascularization, and ischemia-reperfusion injury, autophagy plays a fundamental role in maintaining physiological homeostasis as depicted in Section 3.3. Targeting autophagy signaling such as mTOR-S6 K could improve atherosclerosis and restenosis by attenuating abnormal endothelial cell proliferation and protecting the blood brain barrier (BBB) against ROS-induced injury. ROS could negatively regulate autophagic flux, implying its role as a therapeutic target for regulating autophagy in vascular diseases. In addition, despite few clarified mechanisms, autophagy inhibition reduces VEGF protein levels, leading to an anti-intraocular neovascularization effect. (iv) Therapeutic approaches for targeting other human diseases including viral or bacterial infectious diseases and lysosomal storage diseases. Targeting strategies over autophagy pathways using specific modulators or combinational approaches with other medications are depicted in Section 3.4. In lysosomal storage disorders and bacterial infectious diseases, molecular regulators elevating autophagy turnover are promising therapeutics. In viral infections, however, this approach should be carefully determined based on how autophagy positively or negatively affects the host-virus relationship.
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Introduction
Small molecules targeting autophagy have been highly implicated as new therapeutic agents to treat diseases of interest. With the increasing demand for autophagy-targeting drugs, this review attempts to provide an efficient strategy to explore major autophagy-based human disease interventions with newly explored mechanisms using small...
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Context 1
... studies have revealed an interplay between autophagy and a variety of human diseases. In this section, major diseases such as cancer, proteopathies, vascular disease, and others are discussed ( Figure 2), followed by recent chemotherapeutic strategies that target autophagy (Table 1). ...
Citations
... For conserving cellular homeostasis, autophagy also controls cell survival pathways . To date, mammalian autophagy can be separated into three major types based on the cellular constituents that are delivered into the lysosome: macroautophagy (hereinafter referred to as autophagy), chaperone-mediated autophagy (CMA) and microautophagy (Hazari et al., 2020;Kim et al., 2020). The microautophagy pathway is the least characterized and involves the sequestration of cytoplasmic cargos directly at the surface of the lysosomal membrane; protrusion and/or membrane invagination followed by scission releases the cargo into the lysosomal lumen for subsequent degradation (Gatica et al., 2018;Lei and Klionsky, 2020). ...
Macroautophagy (hereafter referred to as autophagy), a highly conserved metabolic process, regulates cellular homeostasis by degrading dysfunctional cytosolic constituents and invading pathogens via the lysosomal system. In addition, autophagy selectively recycles specific organelles such as damaged mitochondria (via mitophagy), and lipid droplets (LDs; via lipophagy) or eliminates specialized intracellular pathogenic microorganisms such as hepatitis B virus (HBV) and coronaviruses (via virophagy). Selective autophagy, particularly mitophagy, plays a key role in the preservation of healthy liver physiology, and its dysfunction is connected to the pathogenesis of a wide variety of liver diseases. For example, lipophagy has emerged as a defensive mechanism against chronic liver diseases. There is a prominent role for mitophagy and lipophagy in hepatic pathologies including non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and drug-induced liver injury. Moreover, these selective autophagy pathways including virophagy are being investigated in the context of viral hepatitis and, more recently, the coronavirus disease 2019 (COVID-19)-associated hepatic pathologies. The interplay between diverse types of selective autophagy and its impact on liver diseases is briefly addressed. Thus, modulating selective autophagy (e.g., mitophagy) would seem to be effective in improving liver diseases. Considering the prominence of selective autophagy in liver physiology, this review summarizes the current understanding of the molecular mechanisms and functions of selective autophagy (mainly mitophagy and lipophagy) in liver physiology and pathophysiology. This may help in finding therapeutic interventions targeting hepatic diseases via manipulation of selective autophagy.
... It should be noted that each variant found in genes shared between autophagy and apoptosis (P53, BCL2, ATG5 and P14ARF) should be evaluated with caution as it could exert dual effect. Furthermore, we list genes encoding regulatory factors related to autophagy, such as transcription factors and non-coding RNA (Table 1) [66][67][68][69][70][71][72][73][74][75]. In addition, the interrelation between players of this complex network is depicted in Figure 2. Autophagy-related genes and those shared between autophagy and apoptosis could carry genetic variants that may modify the phenotypes of human disorders in which these two pathways play an important role. ...
... It should be noted that each variant found in genes shared between autophagy and apoptosis (P53, BCL2, ATG5 and P14ARF) should be evaluated with caution as it could exert dual effect. Furthermore, we list genes encoding regulatory factors related to autophagy, such as transcription factors and non-coding RNA (Table 1) [66][67][68][69][70][71][72][73][74][75]. In addition, the interrelation between players of this complex network is depicted in Figure 2. A recent study of Klaassen and co-workers described the SHANK gene family as a candidate modifier for a rare metabolic disease-phenylketonuria [76]. ...
... Microphthalmia/transcription factor E or MiT/TFE family members (MITF, TFEB, TFE3, and TFEC), nuclear factor erythroid-derived 2-like 2 (NFE2L2/NRF2), the forkhead box o (FoxO) family, the CCAAT/enhancer-binding protein (C/EBP) family, and the GATA transcription factor are the most recognized master genes of autophagy (for a comprehensive review, see Kim et al., 2020) [72]. Therefore, both variants in genes encoding for transcription factors as well as the promoter regions of genes regulated by them are worthy of investigation [73][74][75]. ...
Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype–phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype–phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients.
... Thus, autophagy can also be regarded as a self-protection mechanism of cells [129]. Autophagy has been becoming a new target of breast cancer treatment, but the role of autophagy in cancer is quite complex, which acts as a double-edged sword in the tumor treatment [130][131][132]. On the one hand, it can increase tumor cell autophagy activity, which contributes to programmed forms of cell death. ...
Triple-negative breast cancer (TNBC) is a subtype of human breast cancer with one of the worst prognoses, with no targeted therapeutic strategies currently available. Regulated cell death (RCD), also known as programmed cell death (PCD), has been widely reported to have numerous links to the progression and therapy of many types of human cancer. Of note, RCD can be divided into numerous different subroutines, including autophagy-dependent cell death, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis and anoikis. More recently, targeting the subroutines of RCD with small-molecule compounds has been emerging as a promising therapeutic strategy, which has rapidly progressed in the treatment of TNBC. Therefore, in this review, we focus on summarizing the molecular mechanisms of the above-mentioned seven major RCD subroutines related to TNBC and the latest progress of small-molecule compounds targeting different RCD subroutines. Moreover, we further discuss the combined strategies of one drug (e.g., narciclasine) or more drugs (e.g., torin-1 combined with chloroquine) to achieve the therapeutic potential on TNBC by regulating RCD subroutines. More importantly, we demonstrate several small-molecule compounds (e.g., ONC201 and NCT03733119) by targeting the subroutines of RCD in TNBC clinical trials. Taken together, these findings will provide a clue on illuminating more actionable low-hanging-fruit druggable targets and candidate small-molecule drugs for potential RCD-related TNBC therapies.
Graphical abstract
... To date, there have been a number of drugs approved by the FDA for clinical use in cancer treatment (Rapamycin derivatives, Nilotinib, Bortezomib) through modulation of autophagy and a proportion of autophagy agonists are also in clinical trials for neurodegenerative diseases (130). A large number of clinical trials are associated with everolimus-eluting stents (NCT02389946, NCT00911976, NCT00783796, NCT02681016), whose use results in better hematological reconstitution and reduced inflammation and foreign body reactions. ...
Increasing attention is now being paid to the important role played by autophagic flux in maintaining normal blood vessel walls. Endothelial cell dysfunction initiates the development of atherosclerosis. In the endothelium, a variety of critical triggers ranging from shear stress to circulating blood lipids promote autophagy. Furthermore, emerging evidence links autophagy to a range of important physiological functions such as redox homeostasis, lipid metabolism, and the secretion of vasomodulatory substances that determine the life and death of endothelial cells. Thus, the promotion of autophagy in endothelial cells may have the potential for treating atherosclerosis. This paper reviews the role of endothelial cells in the pathogenesis of atherosclerosis and explores the molecular mechanisms involved in atherosclerosis development.
... Some examples of autophagy modulating drugs approved or in clinical trials for various diseases[335][336][337][338][339] ...
Inflammatory bowel diseases (IBD) are chronic, idiopathic disorders of the gastrointestinal tract that affect mainly the young population. Disease-targeted, tolerable, cost-effective medications to treat IBD are still awaited. The discovery of the crucial involvement of the autophagy pathway in the genetic predisposition of IBD opened a novel avenue for exploration in IBD therapeutics. Autophagy is a vital process that plays a central role in maintaining cellular homeostasis and pharmacological regulation of autophagy has proven to be beneficial in several diseases. Hence, we evaluated the efficacy of P140 - a therapeutic phosphopeptide known to modulate autophagy processes in other autoimmune and inflammatory conditions - in murine models of IBD. We have demonstrated that the peptide exerts protective effects on colitis models and corrects the pathological dysfunctions in different autophagy pathways. Thus, after the era of drugs classified as "disease-modifying" therapeutics, emerging "mechanism-guided" pharmaceuticals seem to hold a lot of promises for treating inflammatory diseases.
... Autophagy is an important cellular process of self-degradation for dysfunctional or unnecessary molecules and organelles, thus dysregulation of autophagy can be involved in various diseases such as neurodegenerative diseases [1][2][3]. To understand complex process of autophagy and the related diseases, various methods have been developed, for example biochemical, chemical, and imaging assays [4][5][6][7][8]. In particular, fluorescent protein (FP)-based autophagy biosensors allow sensitive and selective monitoring of autophagy progression in live cells [9]. ...
Autophagy is an essential cellular process of self-degradation for dysfunctional or unnecessary cytosolic constituents and organelles. Dysregulation of autophagy is thus involved in various diseases such as neurodegenerative diseases. To investigate the complex process of autophagy, various biochemical, chemical assays, and imaging methods have been developed. Here we introduce various methods to study autophagy, in particular focusing on the review of designs, principles, and limitations of the fluorescent protein (FP)-based autophagy biosensors. Different physicochemical properties of FPs, such as pH-sensitivity, stability, brightness, spectral profile, and fluorescence resonance energy transfer (FRET), are considered to design autophagy biosensors. These FP-based biosensors allow for sensitive detection and real-time monitoring of autophagy progression in live cells with high spatiotemporal resolution. We also discuss future directions utilizing an optobiochemical strategy to investigate the in-depth mechanisms of autophagy. These cutting-edge technologies will further help us to develop the treatment strategies of autophagy-related diseases.
Fluorene was previously reported to have anticancer activity against human cancer cells. In this study, we examined the in vitro function of 9-methanesulfonylmethylene-2, 3-dimethoxy-9 H -fluorene (MSDF), a novel fluorene derivative, its anticancer potential in human hepatocellular carcinoma (HCC) cells and its underlying molecular mechanism. The disruption of cellular homeostasis caused by MSDF was found to promote reactive oxygen species (ROS) generation, leading to the activation of cellular apoptosis. As a survival strategy, cells undergo autophagy during oxidative stress. MSDF-induced apoptosis occurred through both receptor-mediated extrinsic and mitochondrial-mediated intrinsic routes. The development of acidic vesicular organelles and the accumulation of LC3-II protein suggest an increase in the autophagic process. Apoptosis was detected by double staining. The MAPK/ERK and PI3K/Akt signaling pathways were indeed suppressed during treatment. Along with elevated ROS generation and apoptosis, MSDF also caused anoikis and cell death by causing cells to lose contact with their extracellular matrix. ROS production was induced by MSDF and sustained by an NAC scavenger. MSDF-induced apoptosis led to increased autophagy, as shown by the suppression of apoptosis by Z-VAD-FMK. However, inhibition of autophagy by inhibitor 3-MA increased MSDF-induced apoptosis. More evidence shows that MSDF downregulated the expression of immune checkpoint proteins, suggesting that MSDF could be used in the future as an adjuvant to improve the effectiveness of HCC immunotherapy. Altogether, our results highlight the potential of MSDF as a multitarget drug for the treatment of HCC.
The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.
Background
Jujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS).
Method
Wide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining.
Results
Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC.
Conclusion
In conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.
Long noncoding RNAs (lncRNAs) are emerging regulators of vascular diseases, yet their role in diabetic vascular calcification/aging remains poorly understood. In this study, we identified a down-expressed lncRNA SNHG1 in high glucose (HG)-induced vascular smooth muscle cells (HA-VSMCs), which induced excessive autophagy and promoted HA-VSMCs calcification/senescence. Overexpression of SNHG1 alleviated HG-induced HA-VSMCs calcification/senescence. The molecular mechanisms of SNHG1 in HA-VSMCs calcification/senescence were explored by RNA pull-down, RNA immunoprecipitation, RNA stability assay, luciferase reporter assay, immunoprecipitation and Western blot assays. In one mechanism, SNHG1 directly interacted with Bhlhe40 mRNA 3'-untranslated region and increased Bhlhe40 mRNA stability and expression. In another mechanism, SNHG1 enhanced Bhlhe40 protein SUMOylation by serving as a scaffold to facilitate the binding of SUMO E3 ligase PIAS3 and Bhlhe40 protein, resulting in increased nuclear translocation of Bhlhe40 protein. Moreover, Bhlhe40 suppressed the expression of Atg10, which is involved in the process of autophagosome formation. Collectively, the protective effect of SNHG1 on HG-induced HA-VSMCs calcification/senescence is accomplished by stabilizing Bhlhe40 mRNA and promoting the nuclear translocation of Bhlhe40 protein. Our study could provide a novel approach for diabetic vascular calcification/aging.
