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Medicine Nov 2018Autophagy is a mechanism which relies on lysosomes for clearance and recycling of abnormal proteins or organelles. Many studies have demonstrated that the deregulation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Autophagy is a mechanism which relies on lysosomes for clearance and recycling of abnormal proteins or organelles. Many studies have demonstrated that the deregulation of autophagy is associated with the development of various diseases including cancer. The use of autophagy inhibitors is an emerging trend in cancer treatment. However, the value of autophagy inhibitors remains under debate. Thus, a meta-analysis was performed, aiming to evaluate the clinical value of autophagy-inhibitor-based therapy.
METHODS
We searched for clinical studies that evaluated autophagy-inhibitor-based therapy in cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR), 6-month progression-free survival (PFS) rate, and 1-year overall survival (OS) rate.
RESULTS
Seven clinical trials were identified (n = 293). Treatments included 2 combinations of hydroxychloroquine and gemcitabine, 1 combination of hydroxychloroquine and doxorubicin, 1 combination of chloroquine and radiation, 2 combinations of chloroquine, temozolomide, and radiation, and 1 hydroxychloroquine monotherapy. Autophagy-inhibitor-based therapy showed higher ORR (RR: 1.33, 95% confidence interval [CI]: 0.95-1.86, P = .009), PFS (RR: 1.72, 95% CI: 1.05-2.82, P = .000), OS (RR: 1.39, 95% CI: 1.11-1.75, P = .000) values than the therapy without inhibiting autophagy.
CONCLUSION
This meta-analysis showed that autophagy-inhibitor-based therapy has better treatment response compared to chemotherapy or radiation therapy without inhibiting autophagy, which may provide a new strategy for the treatment of cancers.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Chloroquine; Clinical Trials as Topic; Dacarbazine; Deoxycytidine; Doxorubicin; Humans; Hydroxychloroquine; Neoplasms; Risk; Temozolomide; Treatment Outcome; Gemcitabine
PubMed: 30431566
DOI: 10.1097/MD.0000000000012912 -
International Journal of Molecular... Jun 2017Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the... (Review)
Review
Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.
Topics: Animals; Antimalarials; Antineoplastic Agents; Autophagy; Clinical Trials as Topic; Humans; Hydroxychloroquine; Neoplasms
PubMed: 28621712
DOI: 10.3390/ijms18061279 -
Molecules (Basel, Switzerland) Dec 2020Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and...
Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.
Topics: Alzheimer Disease; Animals; Autophagy; Catechin; Cellular Senescence; Dietary Supplements; Flavonols; Humans; Inflammation; Spermidine
PubMed: 33353228
DOI: 10.3390/molecules25246018 -
European Review For Medical and... Feb 2021Autophagy is a main metabolic process in which eukaryotic cells use lysosomes to eliminate abnormal proteins and damaged organelles to maintain cell homeostasis. Studies...
Autophagy is a main metabolic process in which eukaryotic cells use lysosomes to eliminate abnormal proteins and damaged organelles to maintain cell homeostasis. Studies have revealed that neurodegenerative diseases, tumor, hepatic diseases, etc. are related to abnormal autophagy processes in recent years. Recent studies have shown that TFEB is a major transcription regulator of autophagy-lysosomal pathway (ALP) transcriptional regulation, which positively regulates the expression of autophagy and lysosomal biogenesis-related genes, thereby promoting autophagosome formation, autophagosome-lysosome fusion, and degradation of autophagy substrates. It has also been found that TFEB promotes clearance of intracellular substrates through lysosomal exocytosis. Therefore, the study of biological functions and related regulatory mechanisms of TFEB will provide important clues and theoretical basis for further explaining its physiological pathogenesis and the treatment of related diseases.
Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Humans; Lysosomes; Neoplasms; Neurodegenerative Diseases
PubMed: 33629334
DOI: 10.26355/eurrev_202102_24875 -
Life Sciences Nov 2022We conducted a meta-analysis to investigate whether diabetes induced by a high-fat diet (HFD) has the potential to alter the process of autophagy in the murine liver. (Meta-Analysis)
Meta-Analysis Review
AIMS
We conducted a meta-analysis to investigate whether diabetes induced by a high-fat diet (HFD) has the potential to alter the process of autophagy in the murine liver.
METHODS
A systematic literature search was performed with electronic databases (PubMed, EMBASE, Web of Science). Study design, population, intervention, outcome, and risk of bias were analyzed. Given the availability of studies, a quantitative meta-analysis including 23 studies was performed.
KEY FINDINGS
The search found 5754 articles, with 48 matching the eligibility criteria, comprising of 1033 animals. The meta-analysis showed that diabetic murines fed with HFD presented an absence of p62 degradation (SMD 4.63, 95 % CI 2.02 to 7.24, p = 0.0005; I = 77 %), higher expression of p-mTOR/mTOR (SMD 5.20, 95 % CI 1.00 to 9.39, p = 0.01; I = 78 %), and a decreased p-AMPK/AMPK ratio (SMD -2.02, 95 % CI -3.96 to -0.09, p = 0.04; I = 85 %) when compared to nondiabetic murines. When associated with streptozotocin, the animals presented decreased ATG-7 and LC3-II. The meta-regression results showed a decrease in autophagy responses due to increased glycemic levels, fat content, and long-term exposure to HFD, and advanced animal age. The common and species-specific protein responses were also consistent with the inhibition of autophagy.
SIGNIFICANCE
The normal process of autophagy mechanisms in the liver is less competent after HFD consumption. The destabilization of (auto)phagolysosomes contributes to the perpetuation of diabetes, metabolic dysfunction-associated fatty liver disease, and cell death.
Topics: Mice; Animals; Diet, High-Fat; AMP-Activated Protein Kinases; Streptozocin; Liver; Autophagy; TOR Serine-Threonine Kinases; Diabetes Mellitus; Mice, Inbred C57BL
PubMed: 36179817
DOI: 10.1016/j.lfs.2022.121012 -
Frontiers in Physiology 2022Autophagy is a highly conserved process that is indispensable for cell survival, embryonic development, and tissue homeostasis. Activation of autophagy protects cells...
Autophagy is a highly conserved process that is indispensable for cell survival, embryonic development, and tissue homeostasis. Activation of autophagy protects cells against oxidative stress and is a major adaptive response to injury. When autophagy is dysregulated by factors such as smoking, environmental insults and aging, it can lead to enhanced formation of aggressors and production of reactive oxygen species (ROS), resulting in oxidative stress and oxidative damage to cells. ROS activates autophagy, which in turn promotes cell adaptation and reduces oxidative damage by degrading and circulating damaged macromolecules and dysfunctional cell organelles. The cellular response triggered by oxidative stress includes changes in signaling pathways that ultimately regulate autophagy. Chronic obstructive pulmonary disease (COPD) is the most common lung disease among the elderly worldwide, with a high mortality rate. As an induced response to oxidative stress, autophagy plays an important role in the pathogenesis of COPD. This review discusses the regulation of oxidative stress and autophagy in COPD, and aims to provide new avenues for future research on target-specific treatments for COPD.
PubMed: 36225291
DOI: 10.3389/fphys.2022.1004275 -
Journal of Integrative Neuroscience Jan 2022According to the recent findings, autophagy modulation is being a potential therapeutic target in the management of ischemic stroke in a pre-clinical setting. However,... (Meta-Analysis)
Meta-Analysis
According to the recent findings, autophagy modulation is being a potential therapeutic target in the management of ischemic stroke in a pre-clinical setting. However, the pros and cons of autophagic response strongly depend on the activation time of autophagy after injury. In this systematic review, we aimed to explore the impacts of pharmacological modulation of autophagy on infarct size in experimental ischemic stroke models. Based on our preliminary search, 3551 publications were identified. Of twenty-nine publications that met the inclusion criteria, twenty studies reported infarct volume reduction by percentage (%) with no evidence of any publication bias while nine studies reported by mm3, which had publication bias (39.25 units, standardized mean differences (SMD) = 41.92, 95% confidence interval (CI): 30.33 to 53.51). Based on a meta-analysis, the point estimate (pooled mean difference) for improvement of infarct volume during autophagy modulation according to the mm3 and percentage were 35.64 (mean differences (MD) = 35.64, 95% CI: 26.43 to 44.85, z-value = 7.58, -value < 0.001) and 14.38 (MD = 14.38, 95% CI = 10.50 to 18.26, z-value = 7.26, < 0.001) units, respectively. Despite the undeniable role of autophagy in ischemic stroke, the dichotomous effects of autophagy regarding infarct volume reduction should be taken into account. Based on our findings, the studies included in this meta-analysis mostly reported a negative relation between autophagy induction and stroke volume development due to over-activity of autophagy upon the severe ischemic stroke; therefore, further pre-clinical studies are also recommended to establish adjusted autophagy with considering a time-dependent effect as a promising therapeutic target.
Topics: Animals; Autophagy; Cerebral Infarction; Disease Models, Animal; Humans; Ischemic Stroke
PubMed: 35164447
DOI: 10.31083/j.jin2101011 -
Experimental Diabetes Research 2012Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a... (Review)
Review
Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. Autophagy is a major catabolic pathway involved in degrading and recycling macromolecules and damaged organelles to maintain intracellular homeostasis. The study of autophagy in mammalian systems is advancing rapidly and has revealed that it is involved in the pathogenesis of various metabolic or age-related diseases. The functional role of autophagy in the kidneys is also currently under intense investigation although, until recently, evidence showing the involvement of autophagy in the pathogenesis of diabetic nephropathy has been limited. We provide a systematic review of autophagy and discuss the therapeutic potential of autophagy in diabetic nephropathy to help future investigations in this field.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Diabetic Nephropathies; Endoplasmic Reticulum; Homeostasis; Humans; Hypoxia; Kidney; Mice; Microscopy, Electron; Nephrons; Oxidative Stress; Prevalence; Reactive Oxygen Species; Sirtuin 1; TOR Serine-Threonine Kinases
PubMed: 22028701
DOI: 10.1155/2012/628978 -
International Journal of Molecular... Jan 2024The social burden of dementia is remarkable since it affects some 57.4 million people all over the world. Impairment of autophagy in age-related diseases, such as... (Review)
Review
The social burden of dementia is remarkable since it affects some 57.4 million people all over the world. Impairment of autophagy in age-related diseases, such as dementia, deserves deep investigation for the detection of novel disease-modifying approaches. Several drugs belonging to different classes were suggested to be effective in managing Alzheimer's disease (AD) by means of autophagy induction. Useful autophagy inducers in AD should be endowed with a direct, measurable effect on autophagy, have a safe tolerability profile, and have the capability to cross the blood-brain barrier, at least with poor penetration. According to the PRISMA 2020 recommendations, we propose here a systematic review to appraise the measurable effectiveness of autophagy inducers in the improvement of cognitive decline and neuropsychiatric symptoms in clinical trials and retrospective studies. The systematic search retrieved 3067 records, 10 of which met the eligibility criteria. The outcomes most influenced by the treatment were cognition and executive functioning, pointing at a role for metformin, resveratrol, masitinib and TPI-287, with an overall tolerable safety profile. Differences in sample power, intervention, patients enrolled, assessment, and measure of outcomes prevents generalization of results. Moreover, the domain of behavioral symptoms was found to be less investigated, thus prompting new prospective studies with homogeneous design. PROSPERO registration: CRD42023393456.
Topics: Humans; Alzheimer Disease; Cognition; Cognitive Dysfunction; Prospective Studies; Retrospective Studies; Autophagy; Neurodegenerative Diseases
PubMed: 38279266
DOI: 10.3390/ijms25021264 -
Journal of Clinical Medicine May 2024: Although osteoarthritis (OA) development is epidemiologically multifactorial, a primary underlying mechanism is still under debate. Understanding the pathophysiology... (Review)
Review
: Although osteoarthritis (OA) development is epidemiologically multifactorial, a primary underlying mechanism is still under debate. Understanding the pathophysiology of OA remains challenging. Recently, experts have focused on autophagy as a contributor to OA development. : To better understand the pathogenesis of OA, we survey the literature on the role of autophagy and the molecular mechanisms of OA development. To identify relevant studies, we used controlled vocabulary and free text keywords to search the MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and SCOPUS database. Thirty-one studies were included for data extraction and systematic review. Among these studies, twenty-five studies investigated the effects of autophagy in aging and OA chondrocytes, six studies examined the effects of autophagy in normal human chondrocytes, and only one study investigated the effects of mechanical stress-induced autophagy on the development of OA in normal chondrocytes. : The studies suggest that autophagy activation prevents OA by exerting cell-protective effects in normal human chondrocytes. However, in aging and osteoarthritis (OA) chondrocytes, the role of autophagy is intricate, as certain studies indicate that stimulating autophagy in these cells can have a cytotoxic effect, while others propose that it may have a protective (cytoprotective) effect against damage or degeneration. : Mechanical stress-induced autophagy is also thought to be involved in the development of OA, but further research is required to identify the precise mechanism. Thus, autophagy contributions should be interpreted with caution in aging and the types of OA cartilage.
PubMed: 38792546
DOI: 10.3390/jcm13103005