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1.
Regulation of Autophagy in Cardiovascular Diseases by Natural Products.
Gu, S, Li, X
Advances in experimental medicine and biology. 2020;:731-736
Abstract
Several major cardiovascular diseases, such as heart failure (HF) and atherosclerosis (AS), have been linked to autophagy dysfunction. The influence of autophagy on the occurrence and development of cardiovascular diseases has two sides. Generally, the induction of autophagy at a low level can provide energy and nutrients for cells through degradation of damaged organelles, protect cardiomyocytes and vascular endothelial cells, and stabilize atherosclerotic plaques. However, excessive autophagy may damage cardiomyocytes and vascular endothelial cells and even cause cell death. Therefore, the study on the role and mechanism of autophagy in the pathogenesis of cardiovascular diseases may not only provide new targets for the treatment of cardiac remodeling, myocardial ischemia and reperfusion injury, atherosclerosis and heart failure, but also provide clues for the developing new drugs on prevention and treatment of clinical cardiovascular diseases. In this chapter, we reviewed the research progress on resveratrol, curcumin, epigallocatechin-3-gallate, and cordyceps sinensis on their recent research progress for cardiovascular diseases. Regulating autophagy may be an effective strategy for the treatment of cardiovascular diseases in the future.
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2.
MCOLN1/TRPML1 inhibition - a novel strategy used by Helicobacter pylori to escape autophagic killing and antibiotic eradication therapy in vivo.
Capurro, MI, Prashar, A, Jones, NL
Autophagy. 2020;(1):169-170
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Abstract
Inhibition of host macroautophagy/autophagy is one of the strategies used by several intracellular pathogens, including H. pylori, to escape killing. Here we discuss our recent work that revealed the novel mechanism by which the vacuolating cytotoxin A (VacA) produced by H. pylori inhibits lysosomal and autophagic killing. We discovered that VacA impairs the activity of the lysosomal calcium channel MCOLN1/TRPML1 leading to the formation of enlarged, dysfunctional lysosomes and autophagosomes that serve as an intracellular niche, which allows the bacteria to escape eradication therapy.
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The Prospects of Therapeutic Potential and Drug Development Targeting Autophagy in Cancer.
Bao, J, Liu, B, Wu, C
Advances in experimental medicine and biology. 2020;:663-679
Abstract
Autophagy is a self-protection mechanism of cells. Cells can degrade damaged organelles and macromolecules in this way to guarantee the growth and development of cells. In recent years, more and more researches have found that autophagy also plays a certain role in the occurrence and development of tumors. The dual role of autophagy in the development of tumors includes inhibiting the development of tumors; meanwhile, under the condition of insufficient nutrition, autophagy degrades organelles to reduce oxidative stress and provide nutrition and energy for tumor cells so as to protect tumor cells. The regulation of autophagy depends on the development of the tumor, and the corresponding autophagy inducers or inhibitors are constantly emerging, which provides a new direction for tumor treatment.
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Inhibition of HIF1A-AS1 promoted starvation-induced hepatocellular carcinoma cell apoptosis by reducing HIF-1α/mTOR-mediated autophagy.
Hong, F, Gao, Y, Li, Y, Zheng, L, Xu, F, Li, X
World journal of surgical oncology. 2020;(1):113
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is still a major health burden in China considering its high incidence and mortality. Long non-coding RNAs (lncRNAs) were found playing vital roles in tumor progression, suggesting a new way of diagnosis and prognosis prediction, or treatment of HCC. This study was designed to investigate the role of HIF1A-AS1 during the progression of HCC and to explore its related mechanisms. METHODS The expression of HIF1A-AS1 was detected in 50 paired carcinoma tissues and adjacent normal tissues by quantitative real-time PCR assay. HCC cell apoptosis was induced by nutrient-deficient culture medium and detected by Cell Counting Kit-8 and flow cytometer assays. HIF1A-AS1 inhibition in HCC cells was accomplished by small interfering RNA transfection. RESULTS HIF1A-AS1 was overexpressed in HCC tissues and was associated with tumor size, TNM stage, and lymph node metastasis. Compared with the low HIF1A-AS1 group, the high HIF1A-AS1 group had a shorter overall survival and a worse disease-free survival. HIF1A-AS1 expression was significantly higher in HCC cell lines (7721 and Huh7) than that in normal hepatocyte cell line L02 under normal culture condition. However, under nutrient-deficient condition, HIF1A-AS1 expression was significantly increased in both HCC and normal hepatocyte cell lines and was increased with the prolongation of nutrient-free culture. Inhibition of HIF1A-AS1 promoted starvation-induced HCC cell apoptosis. Furthermore, inhibition of HIF1A-AS1 could also reduce starvation-induced HCC cell autophagy. The expression of HIF-1α and phosphorylated mTOR was significantly decreased in HCC cells after HIF1A-AS1 inhibition. CONCLUSIONS HIF1A-AS1, overexpressed in HCC and associated with HCC prognosis, could regulate starvation-induced HCC cell apoptosis by reducing HIF-1α/mTOR-mediated autophagy, promoting HCC cell progression.
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Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy.
Micale, L, Morlino, S, Biagini, T, Carbone, A, Fusco, C, Ritelli, M, Giambra, V, Zoppi, N, Nardella, G, Notarangelo, A, et al
Biochimica et biophysica acta. Molecular basis of disease. 2020;(6):165742
Abstract
Transforming growth factor beta-activated kinase 1 (TAK1) is a highly conserved kinase protein encoded by MAP3K7, and activated by multiple extracellular stimuli, growth factors and cytokines. Heterozygous variants in MAP3K7 cause the cardiospondylocarpofacial syndrome (CSCFS) which is characterized by short stature, dysmorphic facial features, cardiac septal defects with valve dysplasia, and skeletal anomalies. CSCFS has been described in seven patients to date and its molecular pathogenesis is only partially understood. Here, the functional effects of the MAP3K7 c.737-7A > G variant, previously identified in a girl with CSCFS and additional soft connective tissue features, were explored. This splice variant generates an in-frame insertion of 2 amino acid residues in the kinase domain of TAK1. Computational analysis revealed that this in-frame insertion alters protein dynamics in the kinase activation loop responsible for TAK1 autophosphorylation after binding with its interactor TAB1. Co-immunoprecipitation studies demonstrate that the ectopic expression of TAK1-mutated protein impairs its ability to physically bind TAB1. In patient's fibroblasts, MAP3K7 c.737-7A > G variant results in reduced TAK1 autophosphorylation and dysregulation of the downstream TAK1-dependent signaling pathway. TAK1 loss-of-function is associated with an impaired TGFβ-mediated α-SMA cytoskeleton assembly and cell migration, and defective autophagy process. These findings contribute to our understanding of the molecular pathogenesis of CSCFS and might offer the rationale for the design of novel therapeutic targets.
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Autophagy in metabolic syndrome: breaking the wheel by targeting the renin-angiotensin system.
Menikdiwela, KR, Ramalingam, L, Rasha, F, Wang, S, Dufour, JM, Kalupahana, NS, Sunahara, KKS, Martins, JO, Moustaid-Moussa, N
Cell death & disease. 2020;(2):87
Abstract
Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasis of several organs, including liver, heart, pancreas, and adipose tissue. While studies have been conducted in these research areas, the pathogenesis and mechanisms of MetS remain debatable. Lines of evidence show that physiological systems, such as the renin-angiotensin system (RAS) and autophagy play vital regulatory roles in MetS. RAS is a pivotal system known for controlling blood pressure and fluid balance, whereas autophagy is involved in the degradation and recycling of cellular components, including proteins. Although RAS is activated in MetS, the interrelationship between RAS and autophagy varies in glucose homeostatic organs and their cross talk is poorly understood. Interestingly, autophagy is attenuated in the liver during MetS, whereas autophagic activity is induced in adipose tissue during MetS, indicating tissue-specific discordant roles. We discuss in vivo and in vitro studies conducted in metabolic tissues and dissect their tissue-specific effects. Moreover, our review will focus on the molecular mechanisms by which autophagy orchestrates MetS and the ways future treatments could target RAS in order to achieve metabolic homeostasis.
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Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress.
Ashrafizadeh, M, Tavakol, S, Ahmadi, Z, Roomiani, S, Mohammadinejad, R, Samarghandian, S
Phytotherapy research : PTR. 2020;(5):911-923
Abstract
Regulated cell death (RCD) guarantees to preserve organismal homeostasis. Apoptosis and autophagy are two major arms of RCD, while endoplasmic reticulum (ER) as a crucial organelle involved in proteostasis, promotes cells toward autophagy and apoptosis. Alteration in ER stress and autophagy machinery is responsible for a great number of diseases. Therefore, targeting those pathways appears to be beneficial in the treatment of relevant diseases. Meantime, among the traditional herb medicine, kaempferol as a flavonoid seems to be promising to modulate ER stress and autophagy and exhibits protective effects on malfunctioning cells. There are some reports indicating the capability of kaempferol in affecting autophagy and ER stress. In brief, kaempferol modulates autophagy in noncancerous cells to protect cells against malfunction, while it induces cell mortality derived from autophagy through the elevation of p-AMP-activated protein kinase, light chain-3-II, autophagy-related geness, and Beclin-1 in cancer cells. Noteworthy, kaempferol enhances cell survival through C/EBP homologous protein (CHOP) suppression and GRP78 increment in noncancerous cells, while it enhances cell mortality through the induction of unfolding protein response and CHOP increment in cancer cells. In this review, we discuss how kaempferol modulates autophagy and ER stress in noncancer and cancer cells to expand our knowledge of new pharmacological compounds for the treatment of associated diseases.
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Regulation of Autophagy in Neurodegenerative Diseases by Natural Products.
Liu, S, Li, X
Advances in experimental medicine and biology. 2020;:725-730
Abstract
Neurodegenerative diseases mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD). It is now found that these diseases may be related to autophagic dysfunction. The mechanism is due to abnormalities in autophagy, which lead to abnormal or misfolded proteins accumulating in the cytoplasm, nucleus, and extracellular inclusion bodies, causing neuronal organelle damage and synaptic dysfunction. Since these diseases are much complex, the effect of monotherapy is not significantly affected. There is still a need to strengthen the study of anti-neurodegenerative drugs. Natural products should be a good source for the new drug discovery since most of natural products are multiple-target compounds. In this chapter, we reviewed some progress on studying resveratrol, curcumin, tripterine, and paeoniflorin. These natural products can eliminate abnormal protein aggregates by regulating autophagy, and thereby these compounds are promising to be used in prevention and treatment of neurodegenerative diseases in the future.
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Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K.
Petroni, G, Bagni, G, Iorio, J, Duranti, C, Lottini, T, Stefanini, M, Kragol, G, Becchetti, A, Arcangeli, A
Cell death & disease. 2020;(3):161
Abstract
We have studied how the macrolide antibiotic Clarithromycin (Cla) regulates autophagy, which sustains cell survival and resistance to chemotherapy in cancer. We found Cla to inhibit the growth of human colorectal cancer (CRC) cells, by modulating the autophagic flux and triggering apoptosis. The accumulation of cytosolic autophagosomes accompanied by the modulation of autophagic markers LC3-II and p62/SQSTM1, points to autophagy exhaustion. Because Cla is known to bind human Ether-à-go-go Related Gene 1 (hERG1) K+ channels, we studied if its effects depended on hERG1 and its conformational states. By availing of hERG1 mutants with different gating properties, we found that fluorescently labelled Cla preferentially bound to the closed channels. Furthermore, by sequestering the channel in the closed conformation, Cla inhibited the formation of a macromolecular complex between hERG1 and the p85 subunit of PI3K. This strongly reduced Akt phosphorylation, and stimulated the p53-dependent cell apoptosis, as witnessed by late caspase activation. Finally, Cla enhanced the cytotoxic effect of 5-fluorouracil (5-FU), the main chemotherapeutic agent in CRC, in vitro and in a xenograft CRC model. We conclude that Cla affects the autophagic flux by impairing the signaling pathway linking hERG1 and PI3K. Combining Cla with 5-FU might be a novel therapeutic option in CRC.
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Maysin plays a protective role against α-Synuclein oligomers cytotoxicity by triggering autophagy activation.
Leri, M, Vasarri, M, Palazzi, L, Barletta, E, Nielsen, E, Bucciantini, M, Degl'Innocenti, D
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2020;:111626
Abstract
Parkinson's disease (PD) is a widespread neurodegenerative disorder characterized by the progressive loss of neurons. The accumulation of aggregated forms of the α-Synuclein (Syn) protein is the main cause of neurotoxicity in PD by disrupting cellular homeostasis until neuronal death. Scientific research is constantly looking for natural products as preventive agents against the progression of several neurodisorders due their safety and non-toxic nature. Neuroprotective phytochemicals include Maysin (Mys), the most abundant C-glycosilflavone in corn silk. In this work, the Mys protective role against damage by Syn amyloid aggregates - oligomers and fibrils - was investigated in SH-SY5Y human neuroblastoma cells obtaining novel and interesting information concerning the Mys molecular mechanism of action. Mys showed effectiveness in preventing the typical toxic events induced by Syn amyloid aggregates, i.e. oxidative stress and imbalance of intracellular calcium homeostasis. Mys exhibited a cytoprotective role, especially against Syn oligomers injury, activating an autophagic degradative process, thus playing a key role on several features of amyloid neurotoxicity. Therefore, Mys could be proposed for the first time to the scientific community as an interesting novel natural compound that might allow to develop alternative strategies to prevent the damage of Syn oligomers involved in Parkinson's disease.