- |||||||||| Journal: AHCYL1 senses SAH to inhibit autophagy through interaction with PIK3C3 in an MTORC1-independent manner. (Pubmed Central) - Apr 27, 2022
More importantly, this observation was further validated in vivo, indicating that SAH functions as a signaling molecule. Our study uncovers a new axis of SAH-AHCYL1-PIK3C3, which senses the intracellular level of SAH to inhibit autophagy in an MTORC1-independent manner.Abbreviations: ADOX: adenosine dialdehyde; AHCY: adenosylhomocysteinase; AHCYL1: adenosylhomocysteinase like 1; cLEU: cycloleucine; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; SAH: S-adenosyl-l-homocysteine; SAM: S-adenosyl-l-methionine.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. (Pubmed Central) - Apr 27, 2022
CCDC88A/GIV and its other effector, GNAI3, decreased autophagic flux by enhancing the insulin-induced AKT-MTOR pathway, thereby inhibiting HBV antigens autophagic degradation. In conclusion, CCDC88A/GIV enhanced HBV replication by increasing endosomal trafficking and reducing autophagic degradation of HBV antigens, suggesting that CCDC88A/GIV-mediated endosomal trafficking plays an important role in HBV replication and progeny secretion.AbbreviationsACTB: actin beta; AO: acridine orange; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G protein subunit alpha i3; HBV: hepatitis B virus; HBV RIs: HBV replication intermediates; HBcAg: HBV core protein; HBsAg: HBV surface antigen; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PHH: primary human hepatocyte; pSM2: a HBV replication-competent plasmid; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA; SEM: standard error of the mean; UPR: unfolded protein response.
- |||||||||| chloroquine phosphate / Generic mfg., temozolomide / Generic mfg.
Journal: Repurposing melanoma chemotherapy to activate inflammasomes in treatment of BRAF/MAPK inhibitor resistant melanoma. (Pubmed Central) - Apr 27, 2022
The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2 or NLRP3 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome targeted therapy.
- |||||||||| Journal: Paraquat Inhibits Autophagy Via Intensifying the Interaction Between HMGB1 and α-Synuclein. (Pubmed Central) - Apr 27, 2022
Moreover, the expression of α-synuclein is modulated by HMGB1 and the interaction between HMGB1 and α-synuclein was intensified by PQ exposure. Taken together, our results revealed that HMGB1-mediated α-synuclein accumulation could competitively perturb the complex formation of HMGB1 and Beclin1, thereby inhibiting the autophagy function in SH-SY5Y cells.
- |||||||||| gentamicin sulfate / Generic mfg.
Journal: MiR-1298-5p level downregulation induced by Helicobacter pylori infection inhibits autophagy and promotes gastric cancer development by targeting MAP2K6. (Pubmed Central) - Apr 26, 2022
Furthermore, the downregulation of miR-1298-5p levels remarkably inhibited autophagy, ultimately increasing the intracellular H. pylori load, which was detected using a gentamicin protection assay...Moreover, MAP2K6/p38 mitogen-activated protein kinase (MAPK) axis was determined to be the downstream pathway of miR-1298-5p. These findings revealed that H. pylori infection was found to inhibit autophagy and promote tumor growth by regulating miR-1298-5p expression and the miR-1298-5p/MAP2K6/p38 MAPK axis might be a new avenue for the clinical management of H. pylori infection and H. pylori-associated GC.
- |||||||||| Journal: Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy. (Pubmed Central) - Apr 26, 2022
To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k, endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late-stage autophagy inhibitors by impairing autophagosome-lysosome fusion.
- |||||||||| LY294002 / Eli Lilly
Journal: Poly(I:C) attenuates myocardial ischemia/reperfusion injury by restoring autophagic function. (Pubmed Central) - Apr 26, 2022
Mechanistically, poly(I:C) activated the PI3K/AKT/mTOR pathway to induce autophagy, which was abolished by LY294002 (PI3K antagonist), rapamycin (autophagy activator and mTOR inhibitor), or 3-methyladenine (autophagy inhibitor), suggesting either inhibition of the PI3K/Akt/mTOR pathway or autophagy activity interrupt the beneficial effect of poly(I:C) preconditioning. In conclusion, poly(I:C) promotes cardiomyocyte survival from ischemia/reperfusion injury by regulating autophagy via the PI3K/Akt/mTOR pathway.
- |||||||||| Journal: Acetylation of SCFD1 regulates SNARE complex formation and autophagosome-lysosome fusion. (Pubmed Central) - Apr 26, 2022
Finally, we demonstrated that SCFD1 acetylation inhibits autophagic flux, specifically by blocking STX17-SNAP29-VAMP8 SNARE complex formation. Thus, our study reveals a mechanism through which phosphorylation and acetylation modifications of SCFD1 mediate SNARE complex formation to regulate autophagosome maturation.ACLY: ATP citrate lyase; CREB: cAMP responsive element binding protein; EBSS: nutrient-deprivation medium; EP300: E1A binding protein p300; KAT5/TIP60: lysine acetyltransferase 5; HOPS: homotypic fusion and protein sorting; MS: mass spectroscopy; SCFD1: sec1 family domain containing 1; SM: Sec1/Munc18; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; UVRAG: UV radiation resistance associated.
- |||||||||| PD98059 / Wayne State University
AUTOPHAGY ENHANCES INTESTINAL TIGHT JUNCTION BARRIER BY INCREASING THE LEVELS AND MEMBRANE LOCALIZATION OF OCCLUDIN, AND PROTECTS AGAINST INFLAMMATION INDUCED BARRIER LOSS, IN-VIVO. (27 - San Diego Convention Center) - Apr 25, 2022 - Abstract #DDW2022DDW_3956;
Results : Autophagy induction using nutrient starvation as well as known autophagy activators SMER28, calcitrol, metformin, and rapamycin increased total occludin levels and reduced large molecule inulin flux in Caco-2 cells...Autophagy also enhanced the phosphorylation of ERK-1/2 and genetic knockout of ERK1/2 in Caco-2 cells or pharmacological inhibition using U0126 or PD 98059 in Caco-2 cells and surgically resected human colonic tissue inhibited starvation and rapamycin-induced enhancement of TJ barrier and membrane localization of occludin...Conclusion : Our data suggest a novel role of autophagy in promoting intestinal TJ barrier via reduction in endocytosis and degradation of occludin while increasing its membrane localization, in a MAPK-dependent manner. Consistent with its role as a cell survival mechanism, autophagy prevents inflammation-associated loss of mouse colonic TJ barrier.
- |||||||||| AP2M1 AND LC3 LIPIDATION GUIDES CLAUDIN-2 INTO AUTOLYSOSOME (27 - San Diego Convention Center) - Apr 25, 2022 - Abstract #DDW2022DDW_3953;
Conclusion : Our study suggests that AP2M1 plays a pivotal role in autophagy-induced CME mediated claudin-2 degradation. Autophagy inhibition compromises intestinal TJ barrier.
- |||||||||| Lorbrena (lorlatinib) / Pfizer
Journal: Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC. (Pubmed Central) - Apr 24, 2022
Meanwhile, we found that the combination of lorlatinib and CQ, an inhibitor of autophagy, inhibited autophagy and promoted apoptosis both in vitro and in vivo, which sensitized cells to lorlatinib through the dephosphorylation of Foxo3a and promoted nuclear translocation, then activation of Foxo3a/Bim axis. Taken together, our results suggest that inhibition of protective autophagy might be a therapeutic target for delaying the occurrence of acquired resistance to lorlatinib in ALK-positive NSCLC patients.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Restoration of Autophagic Flux Improves Endothelial Function in Diabetes Through Lowering Mitochondrial ROS-mediated eNOS Monomerization. (Pubmed Central) - Apr 23, 2022
Inhibition of autophagic flux by chloroquine or bafilomycin A1 were sufficient to induce eNOS monomerization and lower nitric oxide bioavailability by increasing mitochondrial reactive oxygen species (mtROS)...Moreover, calorie restriction also elevated TFEB expression, improved autophagic flux, and restored EDR in the aortas of db/db mice. Taken together, the present study reveals that mtROS-induced eNOS monomerization is closely associated with the impaired TFEB-autophagic flux axis leading to endothelial dysfunction in diabetic mice.
- |||||||||| Journal: GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer. (Pubmed Central) - Apr 23, 2022
In addition, reducing dietary fructose or pharmacological blockade of fructose utilization significantly reduced CRC growth and sensitized CRC cells to chemotherapy in vivo. Taken together, our findings highlight the role of elevated fructose utilization mediated by the GLUT5-KHK axis in governing CRC growth and imply that efforts to refine fructose intake or inhibit fructose-mediated actions may serve as potential therapeutic strategies.
- |||||||||| Journal: Autophagy inhibitors enhance biomolecular delivery efficiency of extracellular vesicles. (Pubmed Central) - Apr 23, 2022
We demonstrated that autophagy inhibitors, used for reducing lysosomal degradation of EVs, enhanced the protein or plasmid DNA delivery efficiency of EVs in recipient cells without influencing the uptake of EVs by recipient cells. Moreover, autophagy inhibitors could also improve gene-editing efficiency of EV-loaded CRISPR/Cas9 system.
- |||||||||| cisplatin / Generic mfg.
Review, Journal: Is Autophagy Always a Barrier to Cisplatin Therapy? (Pubmed Central) - Apr 23, 2022
In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic.
- |||||||||| sirolimus / Generic mfg.
Preclinical, Journal: Activation of Autophagy Ameliorates Age-Related Neurogenesis Decline and Neurodysfunction in Adult Mice. (Pubmed Central) - Apr 22, 2022
Conversely, stimulating autophagy by rapamycin not only revitalized the viability of middle-adult NPCs, but also facilitated the neurogenesis in middle-adult SVZ/SGZ...Taken together, our results reveal that compromised autophagy is involved in the decline of adult neurogenesis, which could be reversed by autophagy activation. It also shed light on the regulation of adult neurogenesis and paves the way for developing a therapeutic strategy for aging and neurodegenerative diseases.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Starvation after infection restricts enterovirus D68 replication. (Pubmed Central) - Apr 22, 2022
SAI had the same effect in multiple cell types, and restricted the replication of several medically relevant picornaviruses. Our results highlight the significance of autophagosomes for picornavirus replication and identify SAI as an attractive broad-spectrum anti-picornavirus strategy.Abbreviations: BAF: bafilomycin A; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CQ: chloroquine; CVB3: coxsackievirus B3; EV-D68: enterovirus D68; hpi: hour post-infection; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; NSP2B: nonstructural protein 2B; PV: poliovirus; RES: resveratrol; RV14: rhinovirus 14; SAI: starvation after infection; SBI: starvation before infection; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.
- |||||||||| chloroquine phosphate / Generic mfg., hydroxychloroquine / Generic mfg.
Journal: Targeting autophagy in disease: established and new strategies. (Pubmed Central) - Apr 21, 2022
Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible.Abbreviations: ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related gene; AUTAC: autophagy-targeting chimera; CNS: central nervous system; CQ: chloroquine; GABARAP: gamma-aminobutyric acid type A receptor-associated protein; HCQ: hydroxychloroquine; LYTAC: lysosome targeting chimera; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NDD: neurodegenerative disease; PDAC: pancreatic ductal adenocarcinoma; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; PROTAC: proteolysis-targeting chimera; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.
- |||||||||| GNS561 / Genoscience Pharma
Clinical, Journal, PARP Biomarker: GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions. (Pubmed Central) - Apr 21, 2022
We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco's modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC: mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NHCl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn: zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone.
- |||||||||| Journal: Desferrioxamine Ameliorates Lipopolysaccharide-Induced Lipocalin-2 Upregulation via Autophagy Activation in Primary Astrocytes. (Pubmed Central) - Apr 21, 2022
The suppressive effects of DFO were consistent with autophagy inducer rapamycin or carfilzomib, blocked by autophagy inhibitor 3-methyladenine rather than chloroquine or bafilomycin A1, meanwhile, while were not dependent on proteasome system and NF-κB pathway...These data suggest that DFO could serve as an autophagy activator, capable of ameliorating the upregulation of LCN2 in astrocytes by acting on the formation of autophagosomes and secretory autophagy. This provides better understandings of DFO-mediated neuroprotection against neuroinflammation and provides new insights that autophagy activation could be beneficial approaches in PD.
- |||||||||| Journal, IO biomarker: Selective autophagy of NLRC5 promotes immune evasion of endometrial cancer. (Pubmed Central) - Apr 21, 2022
Of special note is that autophagy protein MAP1LC3/LC3 interacts with NLRC5 to inhibit the NLRC5-mediated MHC-I antigen presentation pathway in vitro and in vivo, which presents a novel mechanism underlying NLRC5-mediated immune evasion by autophagy in EC. Our results reveal a previously unknown mechanism of autophagy protein LC3 in the regulation of NLRC5-mediated MHC-I antigen presentation in EC, and highlight a potential immunotherapy approach in EC patients by inhibiting LC3 and promoting NLRC5.
- |||||||||| Journal: Microwave radiation induces neuronal autophagy through miR-30a-5p/AMPKα2 signal pathway. (Pubmed Central) - Apr 21, 2022
Importantly, miR-30a overexpression abolished microwave-activated autophagy and inhibited microwave-induced AMPKα2 upregulation and AMPKα (Thr172) phosphorylation. In conclusion, AMPKα2 was a newly identified downstream genes of miR-30a, microwave radiation promoted the occurrence of autophagy in neurons through the miR-30a/AMPKα2 pathway.
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