- |||||||||| gefitinib / Generic mfg.
Journal, PARP Biomarker: PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1). (Pubmed Central) - Apr 8, 2022
In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. Abbreviations: 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII.
- |||||||||| Journal: TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy. (Pubmed Central) - Apr 8, 2022
Specifically, we observed dysregulated SNARE complexes upon TNF treatment; e.g., reduced levels of full-length STX17. In summary, we identified RIPK3 as an AMPK-activating kinase and thus a direct link between autophagy- and necroptosis-regulating kinases.Abbreviations ACACA/ACC: acetyl-CoA carboxylase alpha; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; GFP: green fluorescent protein; EBSS: Earle's balanced salt solution; Hs: Homo sapiens; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain like pseudokinase; Mm: Mus musculus; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PLA: proximity ligation assay; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKAA2: protein kinase AMP-activated catalytic subunit alpha 2; PRKAB2: protein kinase AMP-activated non-catalytic subunit beta 2; PRKAG1: protein kinase AMP-activated non-catalytic subunit gamma 1; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; STX7: syntaxin 7; STX17: syntaxin 17; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WT: wild-type.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Combination of autophagy and NFE2L2/NRF2 activation as a treatment approach for neuropathic pain. (Pubmed Central) - Apr 8, 2022
We also demonstrated that simultaneous activation of autophagy and the NFE2L2 pathway further relieved pain, compared to activating autophagy alone. Our study provides an underlying mechanism by which autophagy participates in the regulation of neuropathic pain, and a combination of autophagy and NFE2L2 activation may be a new treatment approach for neuropathic pain.Abbreviation: 3-MA: 3-methyladenine; 8-OHdG: 8-hydroxydeoxy-guanosine; ACTB: actin, beta; AMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; ATG: autophagy-related; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CCL7: chemokine (C-C motif) ligand 7; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; GABA: gamma-aminobutyrate; GCLC: glutamate-cysteine ligase, catalytic subunit; GFAP: glial fibrillary acidic protein; GSH: glutathione; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch-like ECH-associated protein 1; MAP1LC3/LC3-II: microtubule-associated protein 1 light chain 3 beta (phosphatidylethanolamine-conjugated form); MAPK: mitogen-activated protein kinase; MAPK1/ERK: mitogen-activated protein kinase 1; MMP2: matrix metallopeptidase 2; MAPK8/JNK: mitogen-activated protein kinase 8; MAPK14/p38: mitogen-activated protein kinase 14; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; ROS: reactive oxygen species; SLC12A5: solute carrier family 12, member 5; SNL: spinal nerve ligation; TLR4: toll-like receptor 4; TRAF6: TNF receptor-associated factor; TRP: transient receptor potential.
- |||||||||| deferiprone / Generic mfg.
Journal: Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells. (Pubmed Central) - Apr 8, 2022
Most importantly, pulmonary ZnONPs exposure caused vascular inflammation and ferritinophagy in mice, and ferrostatin-1 supplementation significantly reversed the vascular injury induced by pulmonary ZnONPs exposure. Overall, our study indicates that ferroptosis is a novel mechanism for ZnONPs-induced endothelial cytotoxicity, and that NCOA4-mediated ferritinophagy is required for ZnONPs-induced ferroptotic cell death.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: HBx induces hepatocellular carcinogenesis through ARRB1-mediated autophagy to drive the G/S cycle. (Pubmed Central) - Apr 8, 2022
The absence of autophagy abolished the phosphorylation of CDK2 and the activity of the CDK2-CCNE1 complex. Our results demonstrate that ARRB1 plays a critical role in HBV-related HCC via modulating autophagy and the CDKN1B-CDK2-CCNE1-E2F1 axis and indicate that ARRB1 may be a potential therapeutic target for HCC.
- |||||||||| Journal: CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. (Pubmed Central) - Apr 8, 2022
In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system.
- |||||||||| sirolimus / Generic mfg.
Journal: V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis. (Pubmed Central) - Apr 8, 2022
Remarkably, downregulation of subunits of V-ATPase, of Pdk1, or of the Tor (Target of rapamycin) complex 1 (TORC1) component raptor prevents overgrowth and normalize ref(2)P levels...Consistent with evidence in flies, neurospheres from patients with high V-ATPase subunit expression show inhibition of autophagy. Altogether, our data suggest that autophagy is repressed during glial tumorigenesis and that V-ATPase and MTORC1 components acting at lysosomes could represent therapeutic targets against GBM.
- |||||||||| chloroquine phosphate / Generic mfg.
Preclinical, Journal: Deletion of Ulk1 inhibits neointima formation by enhancing KAT2A/GCN5-mediated acetylation of TUBA/α-tubulin in vivo. (Pubmed Central) - Apr 8, 2022
Finally, local transfection of Kat2a siRNA decreased TUBA acetylation and prevented the attenuation of vascular injury-induced neointima formation in ulk1 KO mice. These findings suggest that Ulk1 deletion inhibits neointima formation by reducing autophagic degradation of KAT2A and increasing TUBA acetylation in VSMCs.Abbreviations: ACTA2/α-SMA: actin, alpha 2, smooth muscle, aorta; ACTB: actin beta; ATAT1: alpha tubulin acetyltransferase 1; ATG: autophagy related; BECN1: beclin 1; BP: blood pressure; CAL: carotid artery ligation; CQ: chloroquine diphosphate; EC: endothelial cells; EEL: external elastic layer; FBS: fetal bovine serum; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HASMCs: human aortic smooth muscle cells; HAT1: histone acetyltransferase 1; HDAC: histone deacetylase; IEL: inner elastic layer; IP: immunoprecipitation; KAT2A/GCN5: K(lysine) acetyltransferase 2A; KAT8/hMOF: lysine acetyltransferase 8; MAP1LC3: microtubule associated protein 1 light chain 3; MYH11: myosin heavy chain 11; PBS: phosphate-buffered saline; PDGF: platelet derived growth factor; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; RAC3: Rac family small GTPase 3; SIRT2: sirtuin 2; SPP1/OPN: secreted phosphoprotein 1; SQSTM1/p62: sequestosome 1; TAGLN/SM22: transgelin; TUBA: tubulin alpha; ULK1: unc-51 like autophagy activating kinase; VSMC: vascular smooth muscle cell; VVG: Verhoeff Van Gieson; WT: wild type.
- |||||||||| aspirin / Generic mfg., sirolimus / Generic mfg.
Journal: FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway. (Pubmed Central) - Apr 8, 2022
In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.
- |||||||||| sirolimus / Generic mfg.
Journal: Bombyx mori cypovirus (BmCPV) induces PINK1-Parkin mediated mitophagy via interaction of VP4 with host Tom40. (Pubmed Central) - Apr 8, 2022
Autophagy inducer rapamycin (Rap) and autophagy inhibitor 3-methyladenine (3-MA) were used to monitor the effects of mitophagy on BmCPV proliferation...These results suggested that VP4 induced PINK1-Parkin-mediated mitophagy interacting with Tom40. These findings deepen our understanding of the interaction between BmCPV and silkworm and also provide a molecular target for screening anti-BmCPV drugs.
- |||||||||| Journal: Impairment of ULK1 sulfhydration-mediated lipophagy by SREBF1/SREBP-1c in hepatic steatosis. (Pubmed Central) - Apr 8, 2022
Interestingly, the sulfhydration of ULK1 increases its intrinsic kinase activity to modulate autophagy at both initiation and progression stages of autophagic catabolic flux. This study reveals that SREBF1/SREBP-1c contributes to hepatic lipid accumulation through its combined effect of increased lipid synthesis coupled with decreased lipid degradation mediated by autophagic dysregulation.
- |||||||||| Journal: METTL3-mA-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease. (Pubmed Central) - Apr 8, 2022
Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked LDs clearance. Together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via autophagy pathway and provided a novel insight into mA mRNA methylation in NAFLD.
- |||||||||| Journal: Endothelial cell autophagy keeps neutrophil trafficking under control. (Pubmed Central) - Apr 8, 2022
Genetic ablation of EC autophagy leads to excessive neutrophil tissue infiltration in multiple inflammatory models and supports enhanced neutrophil transendothelial migration (TEM), while pharmacological induction of autophagy inhibits neutrophil migration. Mechanistically, autophagy machinery regulates the architecture of EC contacts and controls the reorganization and degradation of adhesion molecules, constituting a physiological brake on leukocyte trafficking.
- |||||||||| Journal, IO biomarker: Toll-like receptor 4 mutation protects the kidney from Ang-II-induced hypertensive injury. (Pubmed Central) - Apr 8, 2022
TLR4M mice remained protected against all these insults in hypertension. Together, these results suggest that Ang-II-induced TLR4 activation suppresses autophagy, induces apoptosis and kidney injury through in part by activating NF-kB signaling, and TLR4 mutation protects the kidney from Ang-II-induced hypertensive injury.
- |||||||||| temozolomide / Generic mfg.
Journal: Biochanin A Sensitizes Glioblastoma to Temozolomide by Inhibiting Autophagy. (Pubmed Central) - Apr 8, 2022
Moreover, by performing a molecular docking analysis, we demonstrated that BCA interacts with AMPK residues and impairs autophagy by regulating the AMPK/ULK1 pathway. These results suggest that BCA is a potential therapeutic agent that sensitizes GBM to TMZ and provide new insight into its therapeutic potential in chemoresistant GBM.
- |||||||||| Journal: Biomimetic lipidic nanovectors for effective asparaginase supramolecule delivery. (Pubmed Central) - Apr 8, 2022
Fluorescent probes and computational simulations were used to reveal possible interactions between serum albumin/trypsin and Aase/nanovector membrane components which were partly responsible for enhanced bioavailability and bioactivity of AS-XLNs compared to Aase. AS-XLNs significantly increased cytotoxicity against pulmonary tumor cells, due to synergistic effects of Aase and nanovector membrane components (killing tumor cells through apoptosis induced by asparagine depletion and autophagy inhibition or via targets such as vascular endothelial growth factor A, alpha-amylase, p-selectin or androgen receptor).
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Neuroprotective effects of curcumin via autophagy induction in 6-hydroxydopamine Parkinson's models. (Pubmed Central) - Apr 8, 2022
Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.
- |||||||||| Livalo (pitavastatin) / Kowa, Eli Lilly
Journal: Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux. (Pubmed Central) - Apr 8, 2022
Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.
- |||||||||| sirolimus / Generic mfg.
Journal, PARP Biomarker: An Insight into the Role of Apoptosis and Autophagy in Nitric Oxide-Induced Articular Chondrocyte Cell Death. (Pubmed Central) - Apr 7, 2022
These results demonstrate that in chondrocyte cultures with cells induced into an osteoarthritis state, NO inhibits autophagy and induces chondrocyte apoptosis mainly, but not completely through the caspase-independent pathway. Our data suggest that autophagy is a protective mechanism in the pathogenesis of osteoarthritis and could be proposed as a therapeutic target for degenerative joint diseases.
- |||||||||| Sutent (sunitinib) / Pfizer
Trial completion date, Trial primary completion date, Metastases: Sunitinib Malate and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors That Have Not Responded to Chemotherapy (clinicaltrials.gov) - Apr 7, 2022
P1, N=40, Active, not recruiting,
In guinea pigs with OA, the level of autophagy in tibial plateau chondrocytes decreased, and chondrocytes were unable to degrade intracellular glycogen into glucose, leading to less energy for chondrocytes and increased apoptosis. Trial completion date: Sep 2021 --> Jun 2022 | Trial primary completion date: Sep 2021 --> Jun 2022
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: TBC domain family 7-like enhances the tolerance of Penaeus vannamei to ammonia nitrogen by the up-regulation of autophagy. (Pubmed Central) - Apr 7, 2022
Functionally, overexpression of PvTBC1D7 in vitro restored the inhibition to autophagy caused by chloroquine (CLQ) and increased the autophagy level, while the silencing of PvTBC1D7 could inhibit the autophagy...And the reduction of PvTBC1D7 remarkably exacerbated the damage of hepatopancreas, increased the accumulation of ROS, and reduced the survival proportion of shrimp under ammonia nitrogen stress. Altogether, these results indicated that PvTBC1D7 might positively regulate the autophagy by stabilizing the negative regulation of mTOR by TSC complex, reduce the oxidative stress damage and improve shrimp ammonia nitrogen tolerance.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Shikonin, a promising therapeutic drug for osteoarthritis that acts via autophagy activation. (Pubmed Central) - Apr 7, 2022
Moreover, shikonin's promotion of anabolism in chondrocytes through autophagy activation corresponded with the results from the examination using chloroquine, an autophagy inhibitor...Results were analysed using the Osteoarthritis Research Society International (OARSI) score, and suggested that mice cartilage degeneration was alleviated after shikonin treatment. Altogether, we identified that shikonin might be a novel promising drug for OA treatment.
- |||||||||| Roferon A (recombinant interferon alfa-2a) / Roche
Journal: Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication. (Pubmed Central) - Apr 7, 2022
Despite of ISGs induction, HBV replication and gene expression in HepG2.2.15 cells, a cell model with continuous HBV replication, were slightly increased at high doses of IFNα-2a. In conclusion, our study indicates that IFNα-2a treatment may interfere with multiple intracellular signaling pathways, facilitate autophagy initiation, and block autophagic degradation, thereby resulting in slightly enhanced HBV replication.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Cyclic mechanical strain with high-tensile triggers autophagy in growth plate chondrocytes. (Pubmed Central) - Apr 7, 2022
We found the interaction between the Rho family small GTPase, Rac1, and autophagy-associated protein, LC3. Cyclic mechanical strain with high-tensile triggers autophagy in GPCs, which can be suppressed by 3MA and CQ, and cytoskeletal F-actin microfilaments organization plays a key role in chondrocytes' response to mechanical loading.
- |||||||||| temuterkib (LY3214996) / Eli Lilly
Trial completion date, Trial primary completion date, Combination therapy, Metastases: LY3214996 +/- HCQ in Pancreatic Cancer (clinicaltrials.gov) - Apr 7, 2022
P2, N=52, Recruiting,
In conclusion, our findings suggest that AST may induce autophagy by regulating IGF-1/Akt/mTOR and IGF-1/Akt/FoxO3a signaling, thereby delaying age-related neurodegeneration and cognitive decline in SAMP10 mice. Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Mar 2022 --> Mar 2023
- |||||||||| esomeprazole / Generic mfg.
Journal: Esomeprazole inhibits hypoxia/endothelial dysfunction-induced autophagy in preeclampsia. (Pubmed Central) - Apr 6, 2022
In conclusion, this study demonstrates that the excessive autophagy induced by the SIRT1/AMPKα-mTOR pathway plays a significant role in the pathogenesis of PE. However, esomeprazole treatment inhibits AMPKα but activates mTOR, resulting in the inhibition of autophagy in the placenta and, therefore, mitigates PE symptoms.
- |||||||||| Journal: Autophagy protects against high uric acid-induced hepatic insulin resistance. (Pubmed Central) - Apr 6, 2022
Antioxidant N-acetyl-L-cysteine reversed elevated reactive oxygen species levels induced by HUA in HepG2 cells, and AMPKα level was also inhibited, which suggests that AMPKα activation may be derived from reactive oxygen species. Collectively, these findings demonstrate that HUA increased hepatic autophagy, and autophagy activation plays a protective role in hepatic IR, which may suggest a potential therapeutic target for hepatic IR derived from HUA.
- |||||||||| hydroxychloroquine / Generic mfg.
Journal: Nanoprodrug ratiometrically integrating autophagy inhibitor and genotoxic agent for treatment of triple-negative breast cancer. (Pubmed Central) - Apr 6, 2022
Here, we find that the autophagy inhibitor hydroxychloroquine (HCQ) and the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) exhibit synergistic effects when the molar ratio reaches 5:1...More importantly, Combo NP elicits superior therapeutic benefit in metastatic TNBC models, compared to free drug combination as well as single drug nanoparticles. Taken together, our engineered nanosystem highlights a nanoprodrug-based chemosensitizing approach for improving the therapeutic response to TNBC, addressing the major challenges of the current combination therapy.
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