- |||||||||| Journal: ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress. (Pubmed Central) - Dec 22, 2021
When these residues are introduced into SARS-CoV ORF3a, it acquires the ability to promote lysosomal exocytosis and inhibit autophagy. Our results reveal a mechanism by which SARS-CoV-2 interacts with host factors to promote its extracellular egress.
- |||||||||| selisistat (SEN-196) / AOP Orphan Pharma
Preclinical, Journal: Melatonin ameliorates cerebral ischemia-reperfusion injury in diabetic mice by enhancing autophagy via the SIRT1-BMAL1 pathway. (Pubmed Central) - Dec 22, 2021
Streptozotocin-induced diabetic mice and high-glucose-cultured HT22 cells were exposed to melatonin, with or without administration of the autophagy inhibitor 3-methyladenine (3-MA) and the specifically silent information regulator 1 (SIRT1) inhibitor EX527, and then subjected to CIR or oxygen-glucose deprivation/reperfusion operation...Additionally, our cellular experiments demonstrated that melatonin increased the SIRT1-BMAL1 pathway-related proteins' expression in a dose-dependent manner. In conclusion, these results indicate that melatonin treatment can protect against CIR-induced brain damage in diabetic mice, which may be achieved by the autophagy enhancement mediated by the SIRT1-BMAL1 pathway.
- |||||||||| Preclinical, Journal, PD(L)-1 Biomarker, IO biomarker: Macrophage autophagy protects against hepatocellular carcinogenesis in mice. (Pubmed Central) - Dec 21, 2021
Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.
- |||||||||| Journal: Effect of PRRX1 on autophagy of salivary adenoid cystic carcinoma cells (Pubmed Central) - Dec 21, 2021
By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance. PRRX1 inhibits the autophagy of SACC cells.
- |||||||||| Impairment of autophagy in microglia/macrophage potentiates neuroinflammation after spinal cord injury (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_3618;
Taken together, our data indicate that inhibition of autophagy in microglia/macrophage potentiates pro-inflammatory activation that is associated with poorer functional outcome. These findings highlight the importance of autophagy in resident immune cells of CNS and further elucidates its role in secondary injury after SCI.; Grant Support: NIH Grant R01NS094527
- |||||||||| Involvement of autophagy in levodopa-induced dyskinesia (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_3126;
These findings indicate that, in Parkinson's disease, augmented responsiveness at D1 receptors leads to dysregulated autophagy, and results in the emergence of l-dopa-induced dyskinesia. They further suggest the enhancement of autophagy as a therapeutic strategy against dyskinesia.; Grant Support: Åhlens and Magnus Bergvalls Foundations; Karolinska Institutet/National Institutes of Health PhD program in Neuroscience; NIDA R01 DA07418; Swedish Brain Foundation; NIH NINDS R01 NS095435; Swedish Parkinson Foundation; Simons and JPB Foundations; Hållstens Foundation; Swedish Research Council; Strategic Research Area in Neuroscience at Karolinska Institutet (StratNeuro)
- |||||||||| Interaction between autophagy initiator ULK1 and SARM1 in axonal degeneration (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_3079;
Supporting the hypothesis of autophagy regulating SARM1 in axonal degeneration, we found that axonal accumulation of SARM1 was decreased after SCI in Becn1 +/- autophagy hypomorph mice as compared to WT controls. Further study will be required to directly manipulate ULK1 in vivo to examine the effects on ULK1-SARM1 interaction and axonal degeneration after SCI.; Grant Support: NIH Grant 5R01NS094527-05
- |||||||||| Autophagy Dysregulation Exaccerbates NeuroInflammation Following Experimntal TBI in Mice (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_2759;
Mice with microglia/macrophage-specific knockout of the autophagy gene Beclin1 (Beclin1-flox/LysM-Cre ) showed increased expression of pro-inflammatory gene and protein markers, and in particular, marked exacerbation of innate immune responses, including activation of the NLRP3 inflammasome and the type I IFN pathways and performed worse than LysM-Cre controls on behavioral tasks after CCI. Overall, these findings indicate that impairment of autophagy in microglia/macrophages exacerbates neuroinflammation after TBI and contributes to functional deficits.; Grant Support: R01 NS091218
- |||||||||| “Investigating the mechanisms responsible for turnover of the ER stress sensing protein PERK” (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_2339;
Co-localization studies of PCFP-PERK with lysosomal markers are also planned to determine if PERK is degraded through a lysosomal or ER - Phagy pathway. Data generated from these studies will lead to a better understanding of PERK turnover, which in turn, may lead to new pharmacological targets for treating neurodegenerative disorders associated with PERK.; Grant Support: 1 RF1 Ag058778
- |||||||||| Bictegravir-mediated lysosomal de-acidification inhibits oligodendrocyte maturation and autophagic flux (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_2199;
Furthermore, this work has implications for other disorders characterized by WM injury, including multiple sclerosis, where OPC differentiation is impaired and remyelination is insufficient. Thus, our work suggests therapeutic targeting of lysosomal acidification or Ca 2+ efflux may promote oligodendrocyte differentiation and myelin repair.; Grant Support: NIH Grant AI007632; NIH Grant MH098742; NIH Grant MH118121
- |||||||||| Autophagy regulates local synaptic RNA metabolism (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_1564;
Thus, autophagy may contribute to synaptic plasticity via regulation of local RNA metabolism. This study may contribute to understanding of the underlying pathophysiology of neurological disorders and pathways for novel therapeutics.; Grant Support: NIH Grant 1K08NS114039
- |||||||||| Activity-dependent cytoskeleton associated protein is regulated by the autophagy pathway (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_1557;
In addition, a reporter system generally employed to measure autophagic flux, which was engineered to express ARC, revealed that learning leads to ARC transport along an intracellular compartment that traffics from basic to acidic compartments, suggesting that ARC undergoes autophagic flux. Collectively, these data suggest that the autophagy pathway, which is activated in response to learning, regulates ARC protein degradation.; Grant Support: NIMH grant MH065635
- |||||||||| sirolimus / Generic mfg.
Subcellular segregation of synaptic long-term depression in hippocampus CA1 (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_1513;
This effect was autophagy specific, as rapamycin administration in ATG5 knockout slices had no effect on LTD. Further investigations will revolve on the behavioral relevance of this form of LTD in adult animals, as well as how the existing differences between autophagy and LTD at proximal and distal dendrites affect dendritic spine refinement throughout development.
- |||||||||| ONC212 / Chimerix
Review, Journal: Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma. (Pubmed Central) - Dec 20, 2021
In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.
- |||||||||| temozolomide / Generic mfg.
Journal: Autophagy inhibition reinforces stemness together with exit from dormancy of polydisperse glioblastoma stem cells. (Pubmed Central) - Dec 18, 2021
Temozolomide (TMZ) treatment failed to induce apoptotic death in shBeclin1-transfected cells, contrary to control...The classical stemness fraction (i.e. F3) highlighted data obtained with the overall cellular population, exhibiting enhancement of stemness markers and escape from dormancy. Our results contributed to illustrate CSCs polydispersity and to show how these cells develop capacity to bypass autophagy inhibition, thanks to their acute adaptability and plasticity.
- |||||||||| sirolimus / Generic mfg.
Journal: D4F alleviates the C/EBP homologous protein-mediated apoptosis in glycated high-density lipoprotein-treated macrophages by facilitating autophagy. (Pubmed Central) - Dec 18, 2021
Furthermore, the inhibition effect of D4F on gly-HDL-induced ER stress-CHOP-induced apoptosis of macrophages was restrained after beclin-1 siRNA and 3-methyladenine (3-MA, an inhibitor of autophagy) treatments, while this effect was further reinforced after rapamycin (Rapa, an inducer of autophagy) treatment...However, the opposite results were obtained when 3-MA was administered to these mice. These results support that D4F effectively protects macrophages against gly-HDL-induced ER stress-CHOP-mediated apoptosis by promoting autophagy.
- |||||||||| MLi-2 / Merck (MSD)
LRRK2 IN PARKINSON’S DISEASE: THE ROLE IN LYSOSOMAL AND MITOCHONDRIAL FUNCTION (ONSITE: 114) - Dec 17, 2021 - Abstract #ADPD2022ADPD_223;
Furthermore, we investigate the potential of MLi-2, a LRRK2 kinase inhibitor, and Clioquinol, a zinc ionophore that can restore lysosomal function in LRRK2 related defects...Conclusions This could elucidate how autophagy-lysosomal and mitochondrial deficits are related to PD. Ultimately the outcome of this study could have an impact on PD treatment, focusing on novel drug approaches to correct lysosomal and mitochondrial dysfunction.
- |||||||||| Trial completion date, Trial primary completion date: GROSSAUTOP: Autophagy/Apoptosis Balance During Pregnancy (clinicaltrials.gov) - Dec 17, 2021
P=N/A, N=120, Recruiting,
Moreover, SNCADupl-induced aSyn overload is sufficient to cause PD-related aSyn pathology and neurodegeneration. Trial completion date: Sep 2022 --> Sep 2024 | Trial primary completion date: Sep 2022 --> Dec 2023
- |||||||||| sirolimus / Generic mfg.
Journal: Short-term waterlogging-induced autophagy in root cells of wheat can inhibit programmed cell death. (Pubmed Central) - Dec 17, 2021
The autophagy promoter rapamycin (RAPA) reduced PCD levels, whereas the autophagy inhibitor 3-methyladenine (3-MA) enhanced them...In summary, our results showed that short-term waterlogging induced autophagy which could inhibit PCD. Mechanisms of response to waterlogging stress differed between cortex and stele cells and between two wheat cultivars of contrasting waterlogging tolerance.
- |||||||||| deoxyglucose / Generic mfg.
Journal: Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis. (Pubmed Central) - Dec 17, 2021
Mechanisms of response to waterlogging stress differed between cortex and stele cells and between two wheat cultivars of contrasting waterlogging tolerance. This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.
- |||||||||| deoxyglucose / Generic mfg.
Journal: 3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms. (Pubmed Central) - Dec 17, 2021
We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone...Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.
- |||||||||| Journal: Inhibition of autophagy by a small molecule through covalent modification of LC3. (Pubmed Central) - Dec 17, 2021
DC-LC3in-D5 compromises LC3B lipidation in vitro and in HeLa cells, leading to deficiency in the formation of autophagic structures and autophagic substrate degradation. DC-LC3in-D5 could serve as a powerful tool for autophagy research as well as for therapeutic interventions.
- |||||||||| Review, Journal: Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions. (Pubmed Central) - Dec 16, 2021
Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.
- |||||||||| sirolimus / Generic mfg.
Preclinical, Journal: The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABA receptors in rat glaucoma models. (Pubmed Central) - Dec 16, 2021
To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1)...A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis. (Pubmed Central) - Dec 16, 2021
Overall, these studies show that the well-established pathway of lysosomal fusion to the plasma membrane is the primary route for the disposal of FAs derived from lipophagy. Moreover, the efflux of FAs and their reuptake or subsequent extracellular trafficking to adjacent cells may play an important role in cell-to-cell lipid exchange and signaling.Abbreviations: ACTB: beta actin; ADRA1A: adrenergic receptor alpha, 1a; ALB: albumin; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; BECN1: beclin 1; BHBA: beta-hydroxybutyrate; BSA: bovine serum albumin; CDH1: e-cadherin; CQ: chloroquine; CTSB: cathepsin B; DGAT: diacylglycerol O-acyltransferase; FA: fatty acid; HFD: high-fat diet; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lysosomal acid lipase A; LLME: Leu-Leu methyl ester hydrobromide; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryo fibroblast; PBS: phosphate-buffered saline; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN: perilipin; PNPLA2/ATGL patatin-like phospholipase domain containing 2; RUBCN (rubicon autophagy regulator); SM: sphingomyelin; TAG: triacylglycerol; TMEM192: transmembrane protein 192; VLDL: very low density lipoprotein.
- |||||||||| amitriptyline / Generic mfg., sirolimus / Generic mfg.
Journal: Amitriptyline Protects Against Lidocaine-induced Neurotoxicity in SH-SY5Y Cells via Inhibition of BDNF-mediated Autophagy. (Pubmed Central) - Dec 16, 2021
The overexpression of BDNF or application of exogenous recombinant BDNF significantly suppressed autophagy and protected SH-SY5Y cells from apoptosis induced by Lido, whereas the neuroprotection of AMI was abolished by either knockdown of BDNF or use of a tropomyosin-related kinase B (TrkB) inhibitor ANA-12 in SH-SY5Y cells. Overall, our findings demonstrated that the protective effect of AMI against lidocaine-induced neurotoxicity correlated with inhibition of autophagy activity through upregulation of BDNF expression.
- |||||||||| dexamethasone / Generic mfg.
Preclinical, Journal: Glucocorticoids induce femoral head necrosis in rats through the ROS/JNK/c-Jun pathway. (Pubmed Central) - Dec 16, 2021
Dexamethasone (Dex) was used to induce apoptosis in osteoblasts, and this resulted in a significant increase in levels of p-JNK, p-c-Jun, Bax, caspase-3, caspase-9, cytochrome C, Beclin-1, and LC3, and a decrease in levels of P62 and Bcl-2...Furthermore, 3-MA treatment decreased the effect of Dex on GC-induced ONFH and osteoblast apoptosis in rats and could counteract microstructure destruction due to femoral head necrosis. In summary, our data suggest that GC can induce osteoblast apoptosis and autophagy through the ROS/JNK/c-Jun signaling pathway, which contributes to ONFH.
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