Journal articles on the topic 'Autophagy dysfunction'
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1
Lee, Jisun, Samantha Giordano, and Jianhua Zhang. "Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling." Biochemical Journal 441, no. 2 (December 21, 2011): 523–40. http://dx.doi.org/10.1042/bj20111451.
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Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role.
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Spaulding, HR, C. Ballmann, JC Quindry, MB Hudson, and JT Selsby. "Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models." JRSM Cardiovascular Disease 8 (January 2019): 204800401987958. http://dx.doi.org/10.1177/2048004019879581.
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Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.
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Miceli, Caterina, Yohan Santin, Nicola Manzella, Raffaele Coppini, Andrea Berti, Massimo Stefani, Angelo Parini, Jeanne Mialet-Perez, and Chiara Nediani. "Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/8067592.
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Age-associated diseases such as neurodegenerative and cardiovascular disorders are characterized by increased oxidative stress associated with autophagy dysfunction. Oleuropein aglycone (OA), the main polyphenol found in olive oil, was recently characterized as an autophagy inducer and a promising agent against neurodegeneration. It is presently unknown whether OA can have beneficial effects in a model of cardiac stress characterized by autophagy dysfunction. Here, we explored the effects of OA in cardiomyocytes with overexpression of monoamine oxidase-A (MAO-A). This enzyme, by degrading catecholamine and serotonin, produces hydrogen peroxide (H2O2), which causes oxidative stress, autophagic flux blockade, and cell necrosis. We observed that OA treatment counteracted the cytotoxic effects of MAO-A through autophagy activation, as displayed by the increase of autophagic vacuoles and autophagy-specific markers (Beclin1 and LC3-II). Moreover, the decrease in autophagosomes and the increase in autolysosomes, indicative of autophagosome-lysosome fusion, suggested a restoration of the defective autophagic flux. Most interestingly, we found that the ability of OA to confer cardioprotection through autophagy induction involved nuclear translocation and activation of the transcriptional factor EB (TFEB). Our data provide strong evidence of the beneficial effects of OA, suggesting its potential use as a nutraceutical agent against age-related pathologies involving autophagy dysfunction, including cardiovascular diseases.
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Dong, Qianqian, Wenjuan Xing, Feifei Su, Xiangyan Liang, Fei Tian, Feng Gao, Siwang Wang, and Haifeng Zhang. "Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy." Cellular Physiology and Biochemistry 43, no. 1 (2017): 293–307. http://dx.doi.org/10.1159/000480410.
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Aims: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. Methods: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP–RFP–LC3. Results: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. Conclusion: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.
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Chen, Yan, Chengxing Xia, Chunwei Ye, Feineng Liu, Yitian Ou, Ruping Yan, Haifeng Wang, and Delin Yang. "MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction." Open Life Sciences 17, no. 1 (January 1, 2022): 710–25. http://dx.doi.org/10.1515/biol-2022-0082.
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Abstract Bladder cancer (BC) is one of the most common malignancies involving the urinary system. Our previous study demonstrated that cobra venom membrane toxin 12 (MT-12) could effectively inhibit BC cell growth and metastasis and induce apoptosis. However, the specific molecular mechanism remains unknown. In this study, we explored whether MT-12 inhibits BC cell proliferation by inducing autophagy cell death through mitochondrial dysfunction. As a result, MT-12 inhibited proliferation and colony formation in RT4 and T24 cells. In the BC xenograft mouse model, autophagy inhibitor 3-MA alleviated the inhibitory effect of MT-12 on tumor growth. In addition, immunostaining revealed downregulated autophagy in MT-12-treated RT4 and T24 cells. We also found that MT-12 led to dysfunctional mitochondria with decreased mitochondrial membrane potential, mtDNA abundance, and increased ROS production, ultimately inducing autophagic apoptosis via the ROS/JNK/P53 pathway. MT-12 inhibits BC proliferation in vitro and in vivo by enhancing autophagy. MT-12 induces mitochondrial dysfunction and decreases autophagy, leading to increased ROS production, which in turn activates the JNK/p53 pathway, leading to BC apoptosis.
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Gukovskaya, Anna S., and Ilya Gukovsky. "Autophagy and pancreatitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 9 (November 1, 2012): G993—G1003. http://dx.doi.org/10.1152/ajpgi.00122.2012.
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Acute pancreatitis is an inflammatory disease of the exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. Recent findings from experimental models and genetically altered mice summarized in this review reveal that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis and that one cause of autophagy impairment is defective function of lysosomes. We propose that the lysosomal/autophagic dysfunction is a key initiating event in pancreatitis and a converging point of multiple deranged pathways. There is strong evidence supporting this hypothesis. Investigation of autophagy in pancreatitis has just started, and many questions about the “upstream” mechanisms mediating the lysosomal/autophagic dysfunction and the “downstream” links to pancreatitis pathologies need to be explored. Answers to these questions should provide insight into novel molecular targets and therapeutic strategies for treatment of pancreatitis.
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Kang, Liang, Qian Xiang, Shengfeng Zhan, Yu Song, Kun Wang, Kangcheng Zhao, Shuai Li, Zengwu Shao, Cao Yang, and Yukun Zhang. "Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration." Oxidative Medicine and Cellular Longevity 2019 (December 30, 2019): 1–27. http://dx.doi.org/10.1155/2019/7810320.
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Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.
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Ko, Su-Hyuk, Gilberto Gonzalez, Zhijie Liu, and Lizhen Chen. "Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy." International Journal of Molecular Sciences 21, no. 22 (November 13, 2020): 8559. http://dx.doi.org/10.3390/ijms21228559.
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Autophagy is a conserved pathway that plays a key role in cell homeostasis in normal settings, as well as abnormal and stress conditions. Autophagy dysfunction is found in various neurodegenerative diseases, although it remains unclear whether autophagy impairment is a contributor or consequence of neurodegeneration. Axonal injury is an acute neuronal stress that triggers autophagic responses in an age-dependent manner. In this study, we investigate the injury-triggered autophagy response in a C. elegans model of tauopathy. We found that transgenic expression of pro-aggregant Tau, but not the anti-aggregant Tau, abolished axon injury-induced autophagy activation, resulting in a reduced axon regeneration capacity. Furthermore, axonal trafficking of autophagic vesicles were significantly reduced in the animals expressing pro-aggregant F3ΔK280 Tau, indicating that Tau aggregation impairs autophagy regulation. Importantly, the reduced number of total or trafficking autophagic vesicles in the tauopathy model was not restored by the autophagy activator rapamycin. Loss of PTL-1, the sole Tau homologue in C. elegans, also led to impaired injury-induced autophagy activation, but with an increased basal level of autophagic vesicles. Therefore, we have demonstrated that Tau aggregation as well as Tau depletion both lead to disruption of injury-induced autophagy responses, suggesting that aberrant protein aggregation or microtubule dysfunction can modulate autophagy regulation in neurons after injury.
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Azuelos, Ilan, Boris Jung, Martin Picard, Feng Liang, Tong Li, Christian Lemaire, Christian Giordano, Sabah Hussain, and Basil J. Petrof. "Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction." Anesthesiology 122, no. 6 (June 1, 2015): 1349–61. http://dx.doi.org/10.1097/aln.0000000000000656.
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Abstract Background: Mechanical ventilation (MV) is associated with atrophy and weakness of the diaphragm muscle, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Autophagy is a lysosomally mediated proteolytic process that can be activated by oxidative stress, which has the potential to either mitigate or exacerbate VIDD. The primary goals of this study were to (1) determine the effects of MV on autophagy in the diaphragm and (2) evaluate the impact of antioxidant therapy on autophagy induction and MV-induced diaphragmatic weakness. Methods: Mice were assigned to control (CTRL), MV (for 6 h), MV + N-acetylcysteine, MV + rapamycin, and prolonged (48 h) fasting groups. Autophagy was monitored by quantifying (1) autophagic vesicles by transmission electron microscopy, (2) messenger RNA levels of autophagy-related genes, and (3) the autophagosome marker protein LC3B-II, with and without administration of colchicine to calculate the indices of relative autophagosome formation and degradation. Force production by mouse diaphragms was determined ex vivo. Results: Diaphragms exhibited a 2.2-fold (95% CI, 1.8 to 2.5) increase in autophagic vesicles visualized by transmission electron microscopy relative to CTRL after 6 h of MV (n = 5 per group). The autophagosome formation index increased in the diaphragm alone (1.5-fold; 95% CI, 1.3 to 1.8; n = 8 per group) during MV, whereas prolonged fasting induced autophagosome formation in both the diaphragm (2.5-fold; 95% CI, 2.2 to 2.8) and the limb muscle (4.1-fold; 95% CI, 1.8 to 6.5). The antioxidant N-acetylcysteine further augmented the autophagosome formation in the diaphragm during MV (1.4-fold; 95% CI, 1.2 to 1.5; n = 8 per group) and prevented MV-induced diaphragmatic weakness. Treatment with the autophagy-inducing agent rapamycin also largely prevented the diaphragmatic force loss associated with MV (n = 6 per group). Conclusions: In this model of VIDD, autophagy is induced by MV but is not responsible for diaphragmatic weakness. The authors propose that autophagy may instead be a beneficial adaptive response that can potentially be exploited for therapy of VIDD.
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Luo, Li, Yonghong Liang, Yuanyuan Fu, Zhiyuan Liang, Jinfen Zheng, Jie Lan, Feihai Shen, and Zhiying Huang. "Toosendanin Induces Hepatocyte Damage by Inhibiting Autophagic Flux via TFEB-Mediated Lysosomal Dysfunction." Pharmaceuticals 15, no. 12 (December 3, 2022): 1509. http://dx.doi.org/10.3390/ph15121509.
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Toosendanin (TSN) is a triterpenoid from the fruit or bark of Melia toosendan Sieb et Zucc, which has clear antitumor and insecticidal activities, but it possesses limiting hepatotoxicity in clinical application. Autophagy is a degradation and recycling mechanism to maintain cellular homeostasis, and it also plays an essential role in TSN-induced hepatotoxicity. Nevertheless, the specific mechanism of TSN on autophagy-related hepatotoxicity is still unknown. The hepatotoxicity of TSN in vivo and in vitro was explored in this study. It was found that TSN induced the upregulation of the autophagy-marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) and P62, the accumulation of autolysosomes, and the inhibition of autophagic flux. The middle and late stages of autophagy were mainly studied. The data showed that TSN did not affect the fusion of autophagosomes and lysosomes but significantly inhibited the acidity, the degradation capacity of lysosomes, and the expression of hydrolase cathepsin B (CTSB). The activation of autophagy could alleviate TSN-induced hepatocyte damage. TSN inhibited the expression of transcription factor EB (TFEB), which is a key transcription factor for many genes of autophagy and lysosomes, such as CTSB, and overexpression of TFEB alleviated the autophagic flux blockade caused by TSN. In summary, TSN caused hepatotoxicity by inhibiting TFEB-lysosome-mediated autophagic flux and activating autophagy by rapamycin (Rapa), which could effectively alleviate TSN-induced hepatotoxicity, indicating that targeting autophagy is a new strategy to intervene in the hepatotoxicity of TSN.
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Li, Siying, Wenjuan Wang, Ting Niu, Hui Wang, Bin Li, Lei Shao, Yimu Lai, et al. "Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/748524.
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The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
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Hwang, Hui-Yun, Yoon Sun Cho, Jin Young Kim, Ki Na Yun, Jong Shin Yoo, Eunhyeong Lee, Injune Kim, and Ho Jeong Kwon. "Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment." Cancers 12, no. 3 (February 27, 2020): 543. http://dx.doi.org/10.3390/cancers12030543.
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Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors are shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets, we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC–MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.
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Dong, Qianqian, Wenjuan Xing, Feng Fu, Zhenghua Liu, Jie Wang, Xiangyan Liang, Xuanxuan Zhou, et al. "Tetrahydroxystilbene Glucoside Inhibits Excessive Autophagy and Improves Microvascular Endothelial Dysfunction in Prehypertensive Spontaneously Hypertensive Rats." American Journal of Chinese Medicine 44, no. 07 (January 2016): 1393–412. http://dx.doi.org/10.1142/s0192415x16500786.
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Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension.
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Herzog, Christian, Cheng Yang, Alexandrea Holmes, and Gur P. Kaushal. "zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function." American Journal of Physiology-Renal Physiology 303, no. 8 (October 15, 2012): F1239—F1250. http://dx.doi.org/10.1152/ajprenal.00659.2011.
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Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.
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El-Khider, Faris, and Christine McDonald. "Links of Autophagy Dysfunction to Inflammatory Bowel Disease Onset." Digestive Diseases 34, no. 1-2 (2016): 27–34. http://dx.doi.org/10.1159/000442921.
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Introduction: Autophagy is a cellular stress response that plays key roles in physiological processes, such as adaptation to starvation, degradation of aberrant proteins or organelles, anti-microbial defense, protein secretion, and innate and adaptive immunity. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including inflammatory bowel disease (IBD). Genetic studies have identified multiple IBD-associated risk loci that include genes required for autophagy, and several lines of evidence demonstrate that autophagy is impaired in IBD patients. How dysfunctional autophagy contributes to IBD onset is currently under investigation by researchers. Key Messages: Dysfunctional autophagy has been identified to play a role in IBD pathogenesis by altering processes that include (1) intracellular bacterial killing, (2) anti-microbial peptide secretion by Paneth cells, (3) pro-inflammatory cytokine production by macrophages, (4) antigen presentation by dendritic cells, (5) goblet cell function, and (6) the endoplasmic reticulum stress response in enterocytes. The overall effect of dysregulation of these processes varies by cell type, stimulus, as well as cellular context. Manipulation of the autophagic pathway may provide a new avenue in the search for effective therapies for IBD. Conclusion: Autophagy plays multiple roles in IBD pathogenesis. A better understanding of the role of autophagy in IBD patients may provide better subclassification of IBD phenotypes and novel approaches to disease management.
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Vijayan, Vinoy, and Patrik Verstreken. "Autophagy in the presynaptic compartment in health and disease." Journal of Cell Biology 216, no. 7 (May 17, 2017): 1895–906. http://dx.doi.org/10.1083/jcb.201611113.
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Synapses are functionally distinct neuronal compartments that are critical for brain function, with synaptic dysfunction being an early pathological feature in aging and disease. Given the large number of proteins needed for synaptic function, the proliferation of defective proteins and the subsequent loss of protein homeostasis may be a leading cause of synaptic dysfunction. Autophagic mechanisms are cellular digestion processes that recycle cellular components and contribute to protein homeostasis. Autophagy is important within the nervous system, but its function in specific compartments such as the synapse has been unclear. Evidence from research on both autophagy and synaptic function suggests that there are links between the two and that synaptic homeostasis during aging requires autophagy to regulate protein homeostasis. Exciting new work on autophagy-modulating proteins that are enriched at the synapse has begun to link autophagy to synapses and synaptic dysfunction in disease. A better understanding of these links will help us harness the potential therapeutic benefits of autophagy in combating age-related disorders of the nervous system.
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Gorostieta-Salas, Elisa, Daniel Moreno-Blas, Cristian Gerónimo-Olvera, Bulmaro Cisneros, Felipe A. Court, and Susana Castro-Obregón. "Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain." Oxidative Medicine and Cellular Longevity 2021 (August 13, 2021): 1–22. http://dx.doi.org/10.1155/2021/6682336.
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Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson–Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.
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Morleo, Manuela, and Brunella Franco. "The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle." Cell Stress 5, no. 3 (March 8, 2021): 33–36. http://dx.doi.org/10.15698/cst2021.03.244.
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The autophagy-lysosomal pathway is one of the main degradative routes which cells use to balance sources of energy. A number of proteins orchestrate the formation of autophagosomes, membranous organelles instrumental in autophagy. Selective autophagy, involving the recognition and removal of specific targets, is mediated by autophagy receptors, which recognize cargos and the autophagosomal membrane protein LC3 for lysosomal degradation. Recently, bidirectional crosstalk has emerged between autophagy and primary cilia, microtubule-based sensory organelles extending from cells and anchored by the basal body, derived from the mother centriole of the centrosome. The molecular mechanisms underlying the direct role of autophagic proteins in cilia biology and, conversely, the impact of this organelle in autophagy remains elusive. Recently, we uncovered the molecular mechanism by which the centrosomal/basal body protein OFD1 controls the LC3-mediated autophagic cascade. In particular, we demonstrated that OFD1 acts as a selective autophagy receptor by regulating the turnover of unc-51-like kinase (ULK1) complex, which plays a crucial role in the initiation steps of autophagosome biogenesis. Moreover, we showed that patients with a genetic condition caused by mutations in OFD1 and associated with cilia dysfunction, display excessive autophagy and we demonstrated that autophagy inhibition significantly ameliorates the renal cystic phenotype in a conditional mouse model recapitulating the features of the disease (Morleo et al. 2020, EMBO J, doi: 10.15252/embj.2020105120). We speculate that abnormal autophagy may underlie some of the clinical manifestations observed in the disorders ascribed to cilia dysfunction.
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Maixner, Nitzan, Sapir Bechor, Zlata Vershinin, Tal Pecht, Nir Goldstein, Yulia Haim, and Assaf Rudich. "Transcriptional Dysregulation of Adipose Tissue Autophagy in Obesity." Physiology 31, no. 4 (July 2016): 270–82. http://dx.doi.org/10.1152/physiol.00048.2015.
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There is growing interest in understanding how dysregulated autophagy may contribute to pathogenesis of disease. Most frequently, disease states are associated with diminished autophagy, mostly attributed to genetic variation in autophagy genes and/or to dysfunctional posttranscriptional mechanisms. In human adipose tissue (AT), in obesity, expression of autophagy genes is upregulated and autophagy is likely activated, associating with adipose dysfunction. This review explores the emerging role of transcriptional mechanisms regulating AT autophagy in obesity.
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Qin, Mengqi, Zhi Xie, Ting Cao, Zhiruo Wang, Xiaoyu Zhang, Feifei Wang, Wei Wei, et al. "Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress." Cells 11, no. 17 (August 25, 2022): 2645. http://dx.doi.org/10.3390/cells11172645.
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Müller glial cells (MGCs) are a group of glial cells in the retina that provide essential support to retinal neurons; however, the understanding of MGC apoptosis and autophagy remains limited. This study was aimed at investigating the role of autophagy in MGCs under normal and oxidative conditions, and identifying the underlying mechanisms. In addition, the sirtuin 4 (SIRT4)-mediated signaling pathway was observed to regulate the autophagic process in MGCs. To assess the effect of autophagy on MGC mitochondrial function and survival, we treated rMC-1 cells—rat-derived Müller glial cells—with rapamycin and 3-methyladenine (3-MA), and found that MGC death was not induced by such treatment, while autophagic dysfunction could increase MGC apoptosis under oxidative stress, as reflected by the expression level of cleaved caspase 3 and PI staining. In addition, the downregulation of autophagy by 3-MA could influence the morphology of the mitochondrial network structure, the mitochondrial membrane potential, and generation of reactive oxygen species (ROS) under oxidative stress. Moreover, SIRT4 depletion enhanced autophagosome formation, as verified by an increase in the LC3 II/I ratio and a decrease in the expression of SQSTM1/p62, and vice versa. The inhibition of AMPK phosphorylation by compound C could reverse these changes in LC3 II/I and SQSTM1/p62 caused by SIRT4 knockdown. Our research concludes that MGCs can endure autophagic dysfunction in the absence of oxidative stress, while the downregulation of autophagy can cause MGCs to become more sensitized to oxidative stress. Simultaneous exposure to oxidative stress and autophagic dysfunction in MGCs can result in a pronounced impairment of cell survival. Mechanically, SIRT4 depletion can activate the autophagic process in MGCs by regulating the AMPK–mTOR signaling pathway.
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Doerr, Vivian, Ryan N. Montalvo, Oh Sung Kwon, Erin E. Talbert, Brian A. Hain, Fraser E. Houston, and Ashley J. Smuder. "Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction." Antioxidants 9, no. 3 (March 23, 2020): 263. http://dx.doi.org/10.3390/antiox9030263.
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Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration.
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Zhang, Chi, Daosheng Luo, Tingting Li, Qiyun Yang, Yun Xie, Haicheng Chen, Linyan Lv, et al. "Transplantation of Human Urine-Derived Stem Cells Ameliorates Erectile Function and Cavernosal Endothelial Function by Promoting Autophagy of Corpus Cavernosal Endothelial Cells in Diabetic Erectile Dysfunction Rats." Stem Cells International 2019 (September 9, 2019): 1–13. http://dx.doi.org/10.1155/2019/2168709.
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Aims. Cavernosal endothelial dysfunction is one of the factors in developing diabetic erectile dysfunction (DED), but the mechanism of cavernosal endothelial dysfunction is unclear. The present study is aimed at determining the contribution of autophagy in cavernosal endothelial dysfunction of DED rats and explaining the therapeutic effect of urine-derived stem cells (USCs). Methods. After rat corpus cavernosal vascular endothelial cells (CCECs) were isolated and cultured in vitro, CCECs were treated with advanced glycation end products (AGEs) to mimic the diabetic situation. Autophagy flux, proliferation, and apoptosis of CCECs were determined by mRFP-GFP-LC3 adenovirus infection combined with fluorescence observation and western blot analysis. USCs were isolated from the urine of six healthy male donors, and coculture systems of USCs and CCECs were developed to assess the protective effect of USCs for CCECs in vitro. The contribution of autophagy to the cellular damage in CCECs was evaluated by the autophagic inhibitor, 3-methyladenine (3-MA). Then, DED rats were induced by streptozotocin (50 mg/kg) and screened by apomorphine test (100 μg/kg). In DED rats, USCs or PBS as vehicle was administrated by intracavernous injection (n=15 per group), and another 15 normal rats served as normal controls. Four weeks after injection, erectile function was evaluated by measuring the intracavernosal pressure (ICP) and mean arterial pressure (MAP). Cavernosal endothelial function and autophagic activity were examined by western blot, immunofluorescence, and transmission electron microscopy. Results. In vitro, AGE-treated CCECs displayed fewer LC3 puncta formation and expressed less LC3-II, Beclin1, and PCNA but expressed more p62 and cleaved-caspase3 than controls (p<0.05). Coculture of USCs with CCECs demonstrated that USCs were able to protect CCECs from AGE-induced autophagic dysfunction and cellular damage, which could be abolished by 3-MA (p<0.05). DED rats showed lower ratio of ICP/MAP, reduced expression of endothelial markers, and fewer autophagic vacuoles in the cavernosal endothelium when compared with normal rats (p<0.05). Intracavernous injection of USCs improved erectile function and cavernosal endothelial function of DED rats (p<0.05). Most importantly, our data showed that the repaired erectile function and cavernosal endothelial function were the result of restored autophagic activity of the cavernosal endothelium in DED rats (p<0.05). Conclusions. Impaired autophagy is involved in the cavernosal endothelial dysfunction and erectile dysfunction of DED rats. Intracavernous injection of USCs upregulates autophagic activity in the cavernosal endothelium, contributing to ameliorating cavernosal endothelial dysfunction and finally improving the erectile dysfunction induced by diabetes.
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Fujitani, Yoshio, Takashi Ueno, and Hirotaka Watada. "Autophagy in health and disease. 4. The role of pancreatic β-cell autophagy in health and diabetes." American Journal of Physiology-Cell Physiology 299, no. 1 (July 2010): C1—C6. http://dx.doi.org/10.1152/ajpcell.00084.2010.
Full textAbstract:
Autophagy is an evolutionarily conserved machinery for degradation and recycling of various cytoplasmic components such as long-lived proteins and organelles. In pancreatic β-cells, as in most other cells, autophagy is also important for the low basal turnover of ubiquitinated proteins and damaged organelles under normal conditions. Insulin resistance results in upregulation of autophagic activity in β-cells. Induced autophagy in β-cells plays a pivotal role in the adaptive expansion of β-cell mass. Nevertheless, it is not clear whether autophagy is protective or detrimental in response to cellular stresses in β-cells. In this review, we describe the crucial roles of autophagy in normal function of β-cells and discuss how dysfunction of the autophagic machinery could lead to the development of diabetes mellitus.
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Song, Young Mi, Sun Ok Song, Young-Hye You, Kun-Ho Yoon, Eun Seok Kang, Bong Soo Cha, Hyun Chul Lee, Ji-Won Kim, and Byung-Wan Lee. "Glycated Albumin Causes Pancreatic β-Cells Dysfunction Through Autophagy Dysfunction." Endocrinology 154, no. 8 (August 1, 2013): 2626–39. http://dx.doi.org/10.1210/en.2013-1031.
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Abstract Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein–microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500μM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic β-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.
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Chuang, Shih-Yi, Chih-Hung Lin, and Jia-You Fang. "Natural Compounds and Aging: Between Autophagy and Inflammasome." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/297293.
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Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper.
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Yuan, Yujia, Younan Chen, Tianqing Peng, Lan Li, Wuzheng Zhu, Fei Liu, Shuyun Liu, et al. "Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition." Clinical Science 133, no. 15 (August 2019): 1759–77. http://dx.doi.org/10.1042/cs20190672.
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Abstract Macrophage polarization toward the M1 phenotype and its subsequent inflammatory response have been implicated in the progression of diabetic complications. Despite adverse consequences of autophagy impairment on macrophage inflammation, the regulation of macrophage autophagy under hyperglycemic conditions is incompletely understood. Here, we report that the autophagy–lysosome system and mitochondrial function are impaired in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated RAW 264.7 cells. Mitochondrial dysfunction promotes reactive oxygen species (ROS) production and blocks autophagic flux by impairing lysosome function in macrophages under hyperglycemic conditions. Conversely, inhibition of mitochondrial ROS by Mito-TEMPO prevents HG-induced M1 macrophage polarization, and its effect is offset by blocking autophagic flux. The role of mitochondrial ROS in lysosome dysfunction and M1 macrophage polarization is also demonstrated in mitochondrial complex I defective RAW 264.7 cells induced by silencing NADH:ubiquinone oxidoreductase subunit-S4 (Ndufs4). These findings prove that mitochondrial ROS plays a key role in promoting macrophage polarization to inflammatory phenotype by impairing autophagy–lysosome system, which might provide clue to a novel treatment for diabetic complications.
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Iida, Tomoya, Yoshihiro Yokoyama, Kohei Wagatsuma, Daisuke Hirayama, and Hiroshi Nakase. "Impact of Autophagy of Innate Immune Cells on Inflammatory Bowel Disease." Cells 8, no. 1 (December 22, 2018): 7. http://dx.doi.org/10.3390/cells8010007.
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Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy. In Crohn’s disease, many associations with autophagy-related genes, such as ATG16L1, IRGM, NOD2, and others, have been reported. Abnormalities in the ATG16L1 gene, in particular, have been reported to cause autophagic dysfunction, resulting in enhanced production of inflammatory cytokines by macrophages as well as abnormal function of Paneth cells, which are important in intestinal innate immunity. In this review, we provide an overview of the autophagy mechanism in innate immune cells in inflammatory bowel disease.
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Zhang, Guiting, Chao He, Qianqian Wu, Guoying Xu, Ming Kuang, Ting Wang, Liangjie Xu, Hong Zhou, and Wei Yuan. "Impaired Autophagy Induced by oxLDL/β2GPI/anti-β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction." Oxidative Medicine and Cellular Longevity 2021 (June 14, 2021): 1–20. http://dx.doi.org/10.1155/2021/6662225.
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Endothelial cell dysfunction plays a fundamental role in the pathogenesis of atherosclerosis (AS), and endothelial autophagy has protective effects on the development of AS. Our previous study had shown that oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex could promote the expressions of inflammatory cytokines and enhance the adhesion of leukocytes to endothelial cells. In the present study, we aimed to assess the effects of oxLDL/β2GPI/anti-β2GPI complex on endothelial autophagy and explore the associated potential mechanisms. Human umbilical vein endothelial cells (HUVECs) and mouse brain endothelial cell line (bEnd.3) were used as models of the vascular endothelial cells. Autophagy was evaluated by examining the expressions of autophagic proteins using western blotting analysis, autophagosome accumulation using transmission electron microscopy, and RFP-GFP-LC3 adenoviral transfection and autophagic flux using lysosome inhibitor chloroquine. The expressions of phospho-PI3K, phospho-AKT, phospho-mTOR, and phospho-eNOS were determined by western blotting analysis. 3-Methyladenine (3-MA) and rapamycin were used to determine the role of autophagy in oxLDL/β2GPI/anti-β2GPI complex-induced endothelial cell dysfunction. We showed that oxLDL/β2GPI/anti-β2GPI complex suppressed the autophagy, evidenced by an increase in p62 protein, a decrease in LC3-II and Beclin1, and a reduction of autophagosome generation in endothelial cells. Moreover, inhibition of autophagy was associated with PI3K/AKT/mTOR and eNOS signaling pathways. Rapamycin attenuated oxLDL/β2GPI/anti-β2GPI complex-induced endothelial inflammation, oxidative stress, and apoptosis, whereas 3-MA alone induced the endothelial injury. Our results suggested that oxLDL/β2GPI/anti-β2GPI complex inhibited endothelial autophagy via PI3K/AKT/mTOR and eNOS signaling pathways and further contributed to endothelial cell dysfunction. Collectively, our findings provided a novel mechanism for vascular endothelial injury in AS patients with an antiphospholipid syndrome (APS) background.
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Liu, Yulan, Hong Xiang, Wenfang Xiong, Jie Ouyang, Hengdao Liu, Shaoli Zhao, Jie Xiao, et al. "Glucolipotoxicity induces endothelial cell dysfunction by activating autophagy and inhibiting autophagic flow." Diabetes and Vascular Disease Research 19, no. 3 (May 2022): 147916412211025. http://dx.doi.org/10.1177/14791641221102513.
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Objectives This study aims to determine the role and mechanism of autophagy in endothelial cell dysfunction by glucolipotoxicity. Methods Human umbilical vein endothelial cells (HUVECs) were treated with high glucose and high palmitic acid. The number of autophagosomes was evaluated by monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM). The expression of autophagy-related proteins (LC3 and P62) was assessed by Western blotting. Capillary tube-like formation was evaluated on Matrigel. Reactive oxygen species (ROS) production was detected by DCFH-DA. Cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Phosphorylation of AMPK, mTOR, and ULK1 was also analyzed by Western blotting. Results We found that glucolipotoxicity induced autophagy initiation and hindered autophagosomes degradation. Moreover, glucolipotoxicity increased the production of intracellular ROS, decreased the ability of tubular formation, and increased cell apoptosis. However, endothelial cell dysfunction was alleviated by 3-methyladenine, an early-stage autophagy inhibitor. Additionally, glucolipotoxicity promoted the phosphorylation of AMPK and ULK1 and inhibited the phosphorylation of mTOR. Conclusions Glucolipotoxicity initiates autophagy through the AMPK/mTOR/ULK1 signaling pathway and inhibits autophagic flow, leading to the accumulation of autophagosomes, thereby inducing apoptosis and impairing endothelial cell function.
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Choi, Suyun, and Hyeyoung Kim. "The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy." International Journal of Molecular Sciences 21, no. 16 (August 12, 2020): 5775. http://dx.doi.org/10.3390/ijms21165775.
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Autophagy is an evolutionarily conserved process that degrades damaged organelles and recycles macromolecules to support cell survival. However, in certain disease states, dysregulated autophagy can play an important role in cell death. In pancreatitis, the accumulation of autophagic vacuoles and damaged mitochondria and premature activation of trypsinogen are shown in pancreatic acinar cells (PACs), which are the hallmarks of impaired autophagy. Oxidative stress mediates inflammatory signaling and cytokine expression in PACs, and it also causes mitochondrial dysfunction and dysregulated autophagy. Thus, oxidative stress may be a mediator for autophagic impairment in pancreatitis. Lycopene is a natural pigment that contributes to the red color of fruits and vegetables. Due to its antioxidant activity, it inhibited oxidative stress-induced expression of cytokines in experimental models of acute pancreatitis. Lycopene reduces cell death through the activation of 5′-AMP-activated protein kinase-dependent autophagy in certain cells. Therefore, lycopene may ameliorate pancreatitis by preventing oxidative stress-induced impairment of autophagy and/or by directly activating autophagy in PACs.
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Margeta, Marta. "Autophagy Defects in Skeletal Myopathies." Annual Review of Pathology: Mechanisms of Disease 15, no. 1 (January 24, 2020): 261–85. http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032618.
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Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies; the observed autophagy defects differ from disease to disease but have been shown to involve all steps of the autophagic cascade (from induction to lysosomal cargo degradation) and to impair both bulk and selective autophagy. To highlight the molecular and cellular mechanisms that are shared among different myopathies with deficient autophagy, these disorders are discussed based on the nature of the underlying autophagic defect rather than etiology or clinical presentation.
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Liu, Xiaojuan, Manhui Zhu, Yuanyuan Ju, Aihong Li, and Xiaolei Sun. "Autophagy dysfunction in neuropathic pain." Neuropeptides 75 (June 2019): 41–48. http://dx.doi.org/10.1016/j.npep.2019.03.005.
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Hua, Yichao, Min Shen, Christine McDonald, and Qingping Yao. "Autophagy dysfunction in autoinflammatory diseases." Journal of Autoimmunity 88 (March 2018): 11–20. http://dx.doi.org/10.1016/j.jaut.2017.10.012.
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Cherra 3rd, Salvatore J., and Charleen T. Chu. "Autophagy in neuroprotection and neurodegeneration: a question of balance." Future Neurology 3, no. 3 (May 2008): 309–23. http://dx.doi.org/10.2217/14796708.3.3.309.
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A central issue in developing therapies for neurodegenerative diseases involves understanding why adaptive responses to stress or injury fail to prevent synaptic dysfunction and neuronal cell death. Macroautophagy is a major, evolutionarily conserved response to nutrient and bioenergetic stresses, which has the capacity to remove aggregated proteins and damaged organelles such as mitochondria. This has prompted intense interest in autophagy-related therapies for Huntington’s, Alzheimer’s, Parkinson’s, stroke and other neurological diseases. However, excessive or imbalanced induction of autophagic recycling can actively contribute to neuronal atrophy, neurite degeneration and cell death. Oxidative-, aging- and disease-related increases in demand for autophagy, coupled with declining axonal trafficking, lysosomal degradation or biosynthetic efficiencies promote increased susceptibility to a harmful state of autophagic stress. A more complete understanding of dysfunction along the entire spectrum of autophagic recycling, from autophagosome formation through clearance and regeneration of new cellular components, is necessary to restore balance to the system, promote neuronal health and maximize therapeutic potentials.
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Yuan, Xi-Ming, Nargis Sultana, Nabeel Siraj, Liam J. Ward, Bijar Ghafouri, and Wei Li. "Autophagy Induction Protects against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress." Journal of Cell Death 9 (January 2016): JCD.S37841. http://dx.doi.org/10.4137/jcd.s37841.
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7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.
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Seibler, Philip, Lena F. Burbulla, Marija Dulovic, Simone Zittel, Johanne Heine, Thomas Schmidt, Franziska Rudolph, et al. "Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells." Brain 141, no. 10 (August 30, 2018): 3052–64. http://dx.doi.org/10.1093/brain/awy230.
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Abstract Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.
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Chen, Zhilong, Chen Li, Anwen Yuan, Ting Gu, Feng Zhang, Xiujun Fan, Xiaosong Wu, Xingyao Xiong, and Qing Yang. "α-Solanine Causes Cellular Dysfunction of Human Trophoblast Cells via Apoptosis and Autophagy." Toxins 13, no. 1 (January 18, 2021): 67. http://dx.doi.org/10.3390/toxins13010067.
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The trophoblast, an embryonic tissue, exerts a crucial role in the processes of implantation and placentation. Toxins in food can cause malfunction of trophoblasts, resulting in apoptosis, oxidative stress, and abnormal angiogenesis. α-solanine, a steroidal glycoalkaloid, has antitumor properties on several cancer cells. However, its effect on human trophoblasts has not been elucidated. In this study, human extravillous trophoblast HTR-8/SVneo cells were exposed to α-solanine. Cellular functions including proliferation, migration, invasion, tube formation, and apoptosis were assessed. To monitor autophagic flux, trophoblasts were transfected with a mCherry-GFP-LC3B vector using lentiviral transduction, and expression of autophagy-related biomarkers including Beclin 1, Atgl3, and microtubule-associated protein 1 light chain-3 (MAP1-LC3) were detected. The results show that application of 20 μM α-solanine or above inhibited the cell viability, migration, invasion, and tube formation of the human trophoblast. Cell cycle was arrested at S and G2/M phases in response to 30 μM α-solanine. α-solanine induced apoptosis of HTR-8/SVneo cells and triggered autophagy by increasing the autophagic gene expression and stimulating the formation of autophagosome and autophagic flux. In conclusion, α-solanine can impair the functions of human trophoblast cells via activation of cell apoptosis and autophagy.
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Pei, ChongZhe, Xiaoyan Wang, Yanjun Lin, Lu Fang, and Shu Meng. "Inhibition of Galectin-3 Alleviates Cigarette Smoke Extract-Induced Autophagy and Dysfunction in Endothelial Progenitor Cells." Oxidative Medicine and Cellular Longevity 2019 (October 13, 2019): 1–13. http://dx.doi.org/10.1155/2019/7252943.
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Endothelial progenitor cells (EPCs) have the potential to repair damaged blood vessels and promote angiogenesis. Smoking, an important risk factor for cardiovascular diseases, is associated with impaired functions of EPCs. However, the underlying mechanisms remain unclear. The aim of the study was to investigate the effects of cigarette smoke extract (CSE) on autophagy and dysfunction of EPCs and the involvement of galectin-3 in its effects. EPCs were treated with 8% CSE for 24 h (without affecting cell viability). EPC functions were assessed by tube formation and migration capacity and intracellular ROS and eNOS expression. Autophagy was assessed by autophagic protein expression by Western blotting and immunofluorescence microscopy and autophagosome accumulation by transmission electron microscopy. Galectin-3 expression was measured by real-time PCR, Western blotting, and immunofluorescence microscopy, while phospho-AMPK and phospho-mTOR were measured by Western blotting. EPCs were transfected by shRNA-Gal-3 or shRNA-NC before treatment with CSE to examine the effects of galectin-3 on CSE-induced autophagy and dysfunction of EPCs. CSE-treated EPCs showed decreased tube formation and migration ability and eNOS expression but increased oxidative stress. CSE also induced autophagy which was characterized by a decrease in p62 protein, an increase in LC3B-II/I ratio, and accumulation of autophagosomes. CSE upregulated galectin-3 expression on EPCs. Inhibition of galectin-3 abrogated CSE-induced autophagy and dysfunction of EPCs. CSE activated phospho-AMPK and inhibited phospho-mTOR, and inhibition of galectin-3 abolished CSE’s effect on activating phospho-AMPK and inhibiting phospho-mTOR. In conclusion, our results suggest that galectin-3 mediates CSE-induced EPC autophagy and dysfunction, likely via the AMPK/mTOR signaling pathway.
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Narasimhan, Prakash Babu, Sameha Tariq, Leor Akabas, David W. Dorward, Thomas B. Nutman, and Roshanak Tolouei Semnani. "Brugia malayi Microfilariae Induce Autophagy through an Interferon-γ Dependent Mechanism in Human Monocytes." American Journal of Tropical Medicine and Hygiene 106, no. 4 (April 6, 2022): 1254–62. http://dx.doi.org/10.4269/ajtmh.21-1134.
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ABSTRACT. Monocyte dysfunction in helminth infection is one of the mechanisms proposed to explain the diminished parasite antigen-specific T cell responses seen with patent filarial infection. In fact, monocytes from filariae-infected individuals demonstrate internalized filarial antigens and, as a consequence, express inhibitory surface molecules and have diminished cytokine production. To investigate the mechanisms underlying monocyte dysfunction in filarial infections, purified human monocytes were exposed to live microfilariae (mf) of Brugia malayi, and the mRNA and protein expression of important inhibitory and/or autophagy-related molecules were assessed. Our data indicate that mf-induced autophagy in human monocytes shown by the formation of autophagic vesicles, by the upregulation in the mRNA expression of autophagy-related genes BCN1, LC3B, ATG5, ATG7 (P < 0.05), and by increase in the levels of LC3B protein. Furthermore, this mf-induced autophagy increased the levels of monocyte CD206 expression. In addition, mf significantly induced the frequency of interferon (IFN)-γ+ human monocytes and at the same time induced the mRNA expression of indoleamine 2,3-dioxygenase (IDO) through an IFN-γ-dependent mechanism; significantly enhanced tryptophan degradation (an indicator of IDO activity; P < 0.005). Interestingly, this autophagy induction by mf in monocytes was IFN-γ-dependent but IDO-independent as was reversed by anti-IFN-γ but not by an IDO inhibitor. Our data collectively suggest that mf of Brugia malayi regulate the function of monocytes by induction of IDO and IFN-γ, induce autophagy through an IFN-γ-dependent mechanism, and increase M2 phenotype through induction of autophagy; all acting in concert to drive monocyte dysfunction.
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Han, Chaoqun, Zhen Ding, Huiying Shi, Wei Qian, Xiaohua Hou, and Rong Lin. "The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells." Cellular Physiology and Biochemistry 38, no. 6 (2016): 2464–78. http://dx.doi.org/10.1159/000445597.
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Background/Aims: Dysfunction of autophagy has been associated with loss of intestinal homeostasis. Lipopolysaccharide (LPS) from Gram-negative bacteria is known to be a major initiator of intestinal epithelial cell (IEC) autophagy. Although probiotics have been recognized to be involved in many therapeutic properties and participate in host defense responses, the molecular mechanisms by which probiotics exert these positive effects remain unknown. This study assessed the effect of probiotics on LPS-induced physical barrier dysfunction and the underlying mechanism of probiotic action in IECs with a focus on autophagy. Methods: A LPS-induced autophagic model was established in rat IEC18 cells wherein cells were treated with culture medium supernatants of Bifidobacteria following LPS intervention at indicated times. Autophagosomes in IEC18 cells were visualized by confocal microscopy after transfection with a tandem GFP-mCherry-LC3 construct and also by transmission electron microscopy. Autophagy-associated protein levels were analyzed by western blot and transepithelial electrical resistance (TEER) was measured using an epithelial voltohmmeter. Results: Probiotic treatment could effectively inhibit LPS-induced autophagy, as evidenced by the decreased ratio of microtubule-associated light chain 3 (LC3)-II/LC3-I, fewer autophagic vacuoles, and reduced punctate distribution of GFP-mCherry-LC3. In addition, probiotics prevented chloroquine (CQ) inhibition of autophagic flux and autophagolysosomal fusion as indicated by a failure to recruit LAMP1 and cathepsin D to lysosomes. Interestingly, ATG16L1 knockdown did not inhibit the effect of probiotics on LPS-induced autophagy. Furthermore, the diminished barrier function could be prevented by probiotics. Conclusions: We provide evidence that autophagy mediation by probiotics may be involved in enteroprotection against LPS-induced intestinal epithelial toxicity, and could serve as a novel mechanism through which probiotics promote and maintain gut homeostasis.
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Guo, Qinyue, Qindong Shi, Huixia Li, Jiali Liu, Shufang Wu, Hongzhi Sun, and Bo Zhou. "Glycolipid Metabolism Disorder in the Liver of Obese Mice Is Improved by TUDCA via the Restoration of Defective Hepatic Autophagy." International Journal of Endocrinology 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/687938.
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Objective.Tauroursodeoxycholic acid (TUDCA) has been considered an important regulator of energy metabolism in obesity. However, the mechanism underlying how TUDCA is involved in insulin resistance is not fully understood. We tested the effects of TUDCA on autophagic dysfunction in obese mice.Material and Methods.500 mg/kg of TUDCA was injected into obese mice, and metabolic parameters, autophagy markers, and insulin signaling molecular were assessed by Western blotting and real-time PCR.Results.The TUDCA injections in the obese mice resulted in a reduced body weight gain, lower blood glucose, and improved insulin sensitivity compared with obese mice that were injected with vehicle. Meanwhile, TUDCA treatment not only reversed autophagic dysfunction and endoplasmic reticulum stress, but also improved the impaired insulin signaling in the liver of obese mice. Additionally, the same results obtained with TUDCA were evident in obese mice treated with the adenoviral Atg7.Conclusions.We found that TUDCA reversed abnormal autophagy, reduced ER stress, and restored insulin sensitivity in the liver of obese mice and that glycolipid metabolism disorder was also improved via the restoration of defective hepatic autophagy.
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Vicencio, Emiliano, Sebastián Beltrán, Luis Labrador, Patricio Manque, Melissa Nassif, and Ute Woehlbier. "Implications of Selective Autophagy Dysfunction for ALS Pathology." Cells 9, no. 2 (February 7, 2020): 381. http://dx.doi.org/10.3390/cells9020381.
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Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.
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Christ, Maximilian, Heike Huesmann, Heike Nagel, Andreas Kern, and Christian Behl. "Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo." Cells 8, no. 3 (March 2, 2019): 211. http://dx.doi.org/10.3390/cells8030211.
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Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.
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Han, Wen, Hao Wang, Longxiang Su, Yun Long, Na Cui, and Dawei Liu. "Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats." Mediators of Inflammation 2018 (June 28, 2018): 1–9. http://dx.doi.org/10.1155/2018/4798209.
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Background. Sepsis-induced myocardial dysfunction is a severe clinical problem. Recent studies have indicated that autophagy and myocardial energy depletion play a major role in myocardial dysfunction during sepsis, a mechanistic target of rapamycin (mTOR) as a master sensor of energy status and autophagy mediator; however, there are little data describing its role during sepsis in the heart. Methods. Cecal ligation and puncture (CLP) or sham operation (SHAM) was performed in rats. After treatment, pathological changes were determined by H&E staining, cardiac functions by echocardiography, the distribution of microtubule-associated protein light chain 3 (LC-3) type II and hypoxia-inducible factor 1α (HIF-1a) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, the mTOR signaling pathway and LC3II, p62, and HIF-1a expression were measured by western blotting. Results. Rapamycin alleviated the pathological damage of myocardial tissue, attenuated cardiac dysfunction (left ventricular ejection fraction (LVEF), p<0.05; fractional shortening (FS), p<0.05), and reduced HIF-1a expression (p<0.05). Expectedly, rapamycin decreased the activity of the mTOR pathway in both sham-operated rats (p<0.0001) and CLP rats (p<0.01). Interestingly, we also found inhibition of the mTOR pathway in CLP rats compared with sham-operated rats; phosphorylation of both mTOR (p<0.001) and pS6K1 (p<0.01) was significantly suppressed following CLP challenge. Furthermore, autophagic processes were elevated by CLP; the ratio of LC3II/LC3I (p<0.05) was increased while p62 expression (p<0.001) was decreased significantly; there were also more autophagic vacuoles in CLP rats; and rapamycin could further elevate the autophagic processes compared with CLP rats (LC3II/LC3I, p<0.05; P62, p<0.05). Conclusion. Inhibition of the mTOR pathway has cardioprotective effects on myocardial dysfunction during sepsis induced by CLP, which is partly mediated through autophagy.
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Tomala, Klaudia, and Bożena Gabryel. "Lysosomal dysfunction in neurodegenerative diseases." Postępy Higieny i Medycyny Doświadczalnej 71, no. 1 (May 4, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.3814.
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Recent data advocate for the implication of lysosomes in the development of programmed cell death. Lysosomal dysfunction decreased the efficiency of autophagosome/lysosome fusion that leads to vacuolation of cells. Autophagic vacuoles containing damaged organelles and altered proteins are hallmarks in most neurodegenerative disorders. These aggregates consequently disrupt cellular homeostasis causing neuronal cell death due apoptosis or necrosis. Moreover calpain mediated or mutation inducted lysosomal rupture result in release of lysosomal cathepsins into the cytoplasm and inducing neuronal cell death. In this review we emphasize the pathophysiological mechanism connecting disrupting autophagy – lysosomal pathway and lysosomal dysfunction in neuronal cell death called lysosomal cell death.
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He, Wei, Aiqing Zhang, Lei Qi, Chen Na, Rui Jiang, Zhining Fan, and Jianping Chen. "FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells." Cellular Physiology and Biochemistry 45, no. 4 (2018): 1506–14. http://dx.doi.org/10.1159/000487576.
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Background/Aims: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells. Methods: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells. Results: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells. Conclusions: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.
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He, Xiu, Shi Chen, Chao Li, Jiaqi Ban, Yungeng Wei, Yangyang He, Fangwei Liu, Ying Chen, and Jie Chen. "Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages." Cells 9, no. 1 (January 4, 2020): 122. http://dx.doi.org/10.3390/cells9010122.
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Silicosis is an occupational lung disease characterized by persistent inflammation and irreversible fibrosis. Crystalline silica (CS) particles are mainly phagocytized by alveolar macrophages (AMs), which trigger apoptosis, inflammation, and pulmonary fibrosis. Previously, we found that autophagy-lysosomal system dysfunction in AMs was involved in CS-induced inflammation and fibrosis. Induction of autophagy and lysosomal biogenesis by transcription factor EB (TFEB) nuclear translocation can rescue fibrotic diseases. However, the role of TFEB in silicosis is unknown. In this study, we found that CS induced TFEB nuclear localization and increased TFEB expression in macrophages both in vivo and in vitro. However, TFEB overexpression or treatment with the TFEB activator trehalose (Tre) alleviated lysosomal dysfunction and enhanced autophagic flux. It also reduced apoptosis, inflammatory cytokine levels, and fibrosis. Both pharmacologically inhibition of autophagy and TFEB knockdown in macrophages significantly abolished the antiapoptotic and anti-inflammatory effects elicited by either TFEB overexpression or Tre treatment. In conclusion, these results uncover a protective role of TFEB-mediated autophagy in silicosis. Our study suggests that restoration of autophagy-lysosomal function by Tre-induced TFEB activation may be a novel strategy for the treatment of silicosis.
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Yuan, Hua, Cynthia N. Perry, Chengqun Huang, Eri Iwai-Kanai, Raquel S. Carreira, Christopher C. Glembotski, and Roberta A. Gottlieb. "LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 2 (February 2009): H470—H479. http://dx.doi.org/10.1152/ajpheart.01051.2008.
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Bacterial endotoxin lipopolysaccharide (LPS) is responsible for the multiorgan dysfunction that characterizes septic shock and is causal in the myocardial depression that is a common feature of endotoxemia in patients. In this setting the myocardial dysfunction appears to be due, in part, to the production of proinflammatory cytokines. A line of evidence also indicates that LPS stimulates autophagy in cardiomyocytes. However, the signal transduction pathway leading to autophagy and its role in the heart are incompletely characterized. In this work, we wished to determine the effect of LPS on autophagy and the physiological significance of the autophagic response. Autophagy was monitored morphologically and biochemically in HL-1 cardiomyocytes, neonatal rat cardiomyocytes, and transgenic mouse hearts after the administration of bacterial LPS or TNF-α. We observed that autophagy was increased after exposure to LPS or TNF-α, which is induced by LPS. The inhibition of TNF-α production by AG126 significantly reduced the accumulation of autophagosomes both in cell culture and in vivo. The inhibition of p38 MAPK or nitric oxide synthase by pharmacological inhibitors also reduced autophagy. Nitric oxide or H2O2induced autophagy in cardiomyocytes, whereas N-acetyl-cysteine, a potent antioxidant, suppressed autophagy. LPS resulted in increased reactive oxygen species (ROS) production and decreased total glutathione. To test the hypothesis that autophagy might serve as a damage control mechanism to limit further ROS production, we induced autophagy with rapamycin before LPS exposure. The activation of autophagy by rapamycin suppressed LPS-mediated ROS production and protected cells against LPS toxicity. These findings support the notion that autophagy is a cytoprotective response to LPS-induced cardiomyocyte injury; additional studies are needed to determine the therapeutic implications.
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Muñoz, Patricia, Sandro Huenchuguala, Irmgard Paris, and Juan Segura-Aguilar. "Dopamine Oxidation and Autophagy." Parkinson's Disease 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/920953.
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The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction,α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxicα-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation ofα-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts withα- andβ-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.
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Barbaro, John M., Ana Maria Cuervo, and Joan W. Berman. "HIV Increases the Inhibitory Impact of Morphine and Antiretrovirals on Autophagy in Primary Human Macrophages: Contributions to Neuropathogenesis." Cells 10, no. 9 (August 24, 2021): 2183. http://dx.doi.org/10.3390/cells10092183.
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HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15–40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.