- |||||||||| Journal: Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation. (Pubmed Central) - Sep 8, 2021
When mTOR was inhibited directly via the macrolide rapamycin, peroxisome degradation was still partially suppressed by Ras2, while inactivation of Ras2 resulted in an enhanced degradation of peroxisomes, suggesting a role of Ras2 in the inhibition of peroxisome degradation in glucose-grown cells. In contrast, the inhibition of mTOR by shifting cells from oleate-medium, which lacks glucose, to pexophagy-medium, which contains glucose and is limited in nitrogen, required Ras2-activity for efficient pexophagy, strongly suggesting that the role of Ras2 in glucose sensing-associated signaling is more important in this context than its co-function in mTOR-related autophagy-inhibition.
- |||||||||| Journal: Research Techniques Made Simple: Analysis of Autophagy in the Skin. (Pubmed Central) - Sep 8, 2021
However, the complex regulation of individual autophagy proteins and their involvement in multiple pathways means that several proteins must be analyzed together, preferably over a time course to accurately interpret changes in autophagic activity. Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective.
- |||||||||| Journal: S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells. (Pubmed Central) - Sep 8, 2021
Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective. Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Huaier polysaccharides suppress triple-negative breast cancer metastasis and epithelial-mesenchymal transition by inducing autophagic degradation of Snail. (Pubmed Central) - Sep 7, 2021
Our findings indicate that upregulated SOCC and IP3R channels and subsequent elevated cytoplasmic calcium signaling in hepatocyte fatty lesions inhibits hepatocyte autophagy through (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways, causes lipid accumulation and degeneration in hepatocytes, and promotes NAFLD occurrence and development. This study demonstrated that PS-T could inhibit EMT in breast cancer cells by inducing autophagy to degrade Snail protein, thus improving the prognosis of TNBC, offering potential treatment alternatives for TNBC patients.
- |||||||||| Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Journal, IO biomarker: Novel insights into the pathogenesis and treatment of NRAS mutant melanoma. (Pubmed Central) - Sep 7, 2021
For patients with NRAS advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy...The diverse strategies taken exploit combined MAP kinase signaling blockade with inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.
- |||||||||| niclosamide / Generic mfg.
FDA event, Journal: A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity. (Pubmed Central) - Sep 5, 2021
Vandetanib (IC = 1.6 μM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening.IMPORTANCE No antiviral therapeutics are currently available for dengue virus infections...It also leverages mechanistic work with query compounds used in biomedical research to provide strong hypotheses for the antiviral mechanisms of the safer hit compounds. This workflow to identify compounds with known safety profiles can be expanded to any biological activity for which a small-molecule query compound has been identified, potentially expediting the translation of basic research to clinical interventions.
- |||||||||| Journal: Autophagy activation and photoreceptor survival in retinal detachment. (Pubmed Central) - Sep 5, 2021
These proteins represent numerous biological processes, including phototransduction, cell-cell signaling, metabolism and inflammation. Our findings suggest that competent autophagy machinery is necessary for PR homeostasis and improving PR survival during periods of nutrient deprivation.
- |||||||||| diazepam / Generic mfg.
Journal: Microbial ACBP/DBI-like genes are rare in the human gut microbiome and show no links with obesity. (Pubmed Central) - Sep 5, 2021
In the present study, we found that microbial ACBP/DBI sequences were rarely present in the gut microbiome across multiple metagenomic datasets. Microbes that carried ACBP/DBI in the human gut microbiome included Saccharomyces cerevisiae, Lautropia mirabilis and Comamonas kerstersii, but these microorganisms were not associated with body-mass index, further indicating an unconvincing role for microbial ACBP/DBI in human metabolism.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Autophagy drives fibroblast senescence through MTORC2 regulation. (Pubmed Central) - Sep 4, 2021
Inhibition of senescence by shRNA to TP53/p53 and shRNA CDKN2A/p16 increased myofibroblast differentiation, suggesting a negative feedback loop of senescence on autophagy-induced myofibroblast differentiation. Collectively, our results identify ROS as central inducers of MTORC2 activation during chronic autophagy, which in turn fuels senescence activation and myofibroblast differentiation in distinct cellular subpopulations.Abbreviations: 3-MA: 3-methyladenine; ACTA2: actin, alpha 2, smooth muscle, aorta; AKT1: AKT serine/threonine kinase 1; p-AKT1: AKT1 Ser473 phosphorylation; t-AKT1: total AKT serine/threonine kinase 1; ATG4A: autophagy related 4A cysteine peptidase; ATG7: autophagy gene 7; C12FDG: 5-dodecanoylaminofluorescein Di-β-D-Galactopyranoside; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; Ctl: control; DAPI: 4',6-diamidino-2-phenylindole, dilactate; ECM: extracellular matrix; GSH: L-glutathione reduced; HO: hydrogen peroxide; HLF: adult human lung fibroblasts; Ho: Hoechst 33342 (2'-[4-ethoxyphenyl]-5-[4-methyl-1-piperazinyl]-2.5'-bi-1H-benzimidazole); HSC: hepatic stellate cells; LY: LY294002; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTORC1/2: mechanistic target of rapamycin kinase complex 1/2; N: normal growth medium; NAC: N-acetyl-L-cysteine; PBS: phosphate-buffered saline; PDGFA: platelet derived growth factor subunit A; PRKCA/PKCα: protein kinase C alpha; PtdIns3K: class III phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; R: rapamycin; RICTOR: RPTOR independent companion of MTOR complex 2; ROS: reactive oxygen species; RPTOR: regulatory associated protein of MTOR complex 1; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SGK1: serum/glucocorticoid regulated kinase 1; shRNA: short hairpin RNA; siCtl: control siRNA; siRNA: small interfering RNA; SQSTM1: sequestosome 1; SS: serum-free (serum starvation) medium; TP53: tumor protein p53; TUBA: tubulin alpha; V: vehicle.
- |||||||||| Preclinical, Journal: Transgenic expression of GFP-LC3 perturbs autophagy in exocrine pancreas and acute pancreatitis responses in mice. (Pubmed Central) - Sep 4, 2021
GFP-LC3 expression affected key pancreatitis responses; most dramatically, it worsened increases in serum AMY (amylase), a diagnostic marker of acute pancreatitis, in several mouse models. The results emphasize physiological importance of autophagy for acinar cell function, demonstrate organ-specific effects of GFP-LC3 expression, and indicate that application of GFP-LC3 mice in disease models should be done with caution.Abbreviations: AP: acute pancreatitis; Arg-AP: L-arginine-induced acute pancreatitis; ATG: autophagy-related (protein); AVs: autophagic vacuoles; CCK: cholecystokinin-8; CDE: choline-deficient, D,L-ethionine supplemented diet; CER: caerulein (ortholog of CCK); CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ER: endoplasmic reticulum; LAMP: lysosomal-associated membrane protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; TEM: transmission electron microscopy; TFEB: transcription factor EB; ZG: zymogen granule(s).
- |||||||||| selisistat (SEN-196) / AOP Orphan Pharma
Preclinical, Journal: Melatonin protects against chronic stress-induced oxidative meiotic defects in mice MII oocytes by regulating SIRT1. (Pubmed Central) - Sep 4, 2021
Consistently, melatonin treatment during in vitro maturation also attenuated the meiotic defects induced by HO by regulating autophagy and SIRT1, which could be abolished by SIRT1 inhibitor, Ex527 and autophagy inhibitor Bafilomycin A1 (Baf A1). These data indicate that melatonin can mitigate chronic stress-induced oxidative meiotic defects in mice MII oocytes by regulating SIRT1 and autophagy, providing new understanding for stress-related meiotic errors in MII oocytes and suggesting melatonin and SIRT1 could be new targets for optimizing culture system of oocytes as well as fertility management.
- |||||||||| sirolimus / Generic mfg.
Journal: Rapamycin Promotes Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells in a Stage-Dependent Manner. (Pubmed Central) - Sep 4, 2021
Furthermore, using autophagy inhibitor NH4Cl and GSK-3β inhibitor CHIR-99021, we found rapamycin-induced autophagy promoted cardiomyocyte differentiation at middle stage by negatively regulating the Wnt/β-catenin signaling pathway. These results suggest that rapamycin regulates EB-based cardiomyocyte differentiation in a stage-dependent manner, and the negative regulation of Wnt/β-catenin signaling pathway by autophagy was involved in the pro-differentiation effect of rapamycin at middle stage.
- |||||||||| Journal: LncRNA SNHG3 promotes autophagy-induced neuronal cell apoptosis by acting as a ceRNA for miR-485 to up-regulate ATG7 expression. (Pubmed Central) - Sep 4, 2021
After the OGD treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6 h, 1 mM 3-MA was added and reoxygenated for 24 h, the overexpression of LncRNA SNHG3 raised the ratio of LC3-II/LC3-I and Beclin-1 expression and boosted the apoptosis of N2a cells, while these effects were reversed after the transfection of miR-485 mimic. In general, our data expounded that the interference with LncRNA SNHG3 improved brain I/R injury by up-regulating miR-485 and down-regulating ATG7 to restrain autophagy and neuronal cell apoptosis.
- |||||||||| Journal: Contrast effects of autophagy in the treatment of bladder cancer. (Pubmed Central) - Sep 4, 2021
Therefore, targeting the autophagy pathways may be a potential therapeutic strategy for addressing cancer progression or therapy resistance in the near future. This review will provide a novel insight to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion.
- |||||||||| Review, Journal: Pro-survival Autophagy: An Emerging Candidate of Tumor Progression through Maintaining Hallmarks of Cancer. (Pubmed Central) - Sep 3, 2021
In this review, we discuss the detailed mechanisms of autophagy, the role of pro-survival autophagy that positively drives several classical as well as emerging hallmarks of cancer for tumorigenic progression, and also we address various autophagy inhibitors that could be harnessed against pro-survival autophagy for effective cancer therapeutics. Finally, we highlight some outstanding problems that need to be deciphered extensively in the future to unravel the role of autophagy in tumor progression.
- |||||||||| Review, Journal: Autophagy as a Mechanism for Anti-Angiogenic Therapy Resistance. (Pubmed Central) - Sep 3, 2021
In this review, we discuss the role of angiogenesis in malignancy, mechanisms of resistance to anti-angiogenic therapy in general, the role of autophagy in driving malignancy, and the current literature in autophagy-mediated anti-angiogenic therapy resistance. Finally, we provide future insight into the current challenges of using autophagy inhibitors in the clinic and provides tips for future studies to focus on to effectively target autophagy in overcoming resistance to anti-angiogenic therapy.
- |||||||||| Journal: Autophagy in Cancer: Recent advances and future directions. (Pubmed Central) - Sep 3, 2021
Here, we discuss the updates on the modulation of autophagy via dynamic interactions with different organelles and the exploitation of selective autophagy for exploring therapeutic strategies. We further discuss the role of autophagy inhibitors in cancer preclinical and clinical trials, novel autophagy inhibitors, and challenges likely to be faced by clinicians while inducting autophagy modulators in clinical practice.
- |||||||||| Journal: Mechanisms and Molecular Targets of Artemisinin in Cancer Treatment. (Pubmed Central) - Sep 3, 2021
Therefore, the review is to concentrate on mechanisms and molecular targets of artemisinin as anti-tumor agents. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as potent anticancer agents.
- |||||||||| Journal: Combined effects of hyperthermia and chemotherapy on the regulate autophagy of oral squamous cell carcinoma cells under a hypoxic microenvironment. (Pubmed Central) - Sep 2, 2021
It is founded that hyperthermia and hypoxia cause autophagy in starvation conditions; further, in hypoxia and innutrition tumor microenvironment, hyperthermia combines YC-1 and 3-MA could inhibit HIF-1α/BNIP3/Beclin1 signal pathway and decrease the secretion of HMGB1; moreover, the cell apoptosis rate increases with an inhibited of cell migration capacity. Thus, the present study demonstrated that combined use of YC-1 and 3-MA might increase the death of tumor cells in physiological and hyperthermic conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro, which offers new insight into the therapy of OSCC and its application in treating others study carcinomas.
- |||||||||| Journal: Coibamide A kills cancer cells through inhibiting autophagy. (Pubmed Central) - Sep 2, 2021
In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.
- |||||||||| imatinib / Generic mfg.
Preclinical, Journal: Autophagy Does Not Contribute to TKI Response in a Imatinib-resistant Chronic Myeloid Leukemia Cell Line (Pubmed Central) - Sep 2, 2021
We showed that in the presence of imatinib autophagy was triggered via LC3I/II transformation, p62 protein expression and acidic vacuoles accumulation in tyrosine kinase inhibitor-sensitive K562 cells; whereas in the cell line K562-IR which is imatinib-resistant and Bcr-Abl independent, autophagy is not triggered. With ongoing research and trails to combine tyrosine kinase inhibitors with autophagy inhibitors, our results suggest a model of resistance in which treatment with a TKI inhibitor does not increase autophagy, basically because its presence does not cause cellular stress due to Bcr-Abl signaling not being required for survival.
- |||||||||| Journal: S100A8 promotes chemoresistance via augmenting autophagy in B‑cell lymphoma cells. (Pubmed Central) - Sep 1, 2021
Interference of S100A8 significantly downregulated Bcl‑2/adenovirus E1B 19‑kDa protein‑interacting protein 3 located in the mitochondria and endoplasmic reticulum to further inhibit autophagy. In addition, S100A8 interference markedly inhibited the formation of the BECN1‑PI3KC3 complex and promoted B‑cell lymphoma 2 expression, which collectively inhibited autophagy.
- |||||||||| temozolomide / Generic mfg.
Journal: Knockdown lncRNA CRNDE enhances temozolomide chemosensitivity by regulating autophagy in glioblastoma. (Pubmed Central) - Aug 31, 2021
Our study have showed important implications that 17β-estradiol could promote efficacy of the development of porcine oocytes, enhance the autophagy, reduce ROS levels and apoptosis activity in vitro maturation. Overall, the study provided that lncRNA CRNDE is a reliable clinical predictor of outcome and prognosis and a potential biomarker for predicting TMZ treatment response in GBM by modulating the autophagy through PI3K/Akt/mTOR pathway and ABCG2 expression which may be a novel therapeutic target for regulating TMZ sensitivity to GBM.
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