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  • ||||||||||  Mozobil (plerixafor) / Sanofi
    Perturbing Proteostasis to Deplete Plasma Cells (Hynes Room 310) -  May 20, 2022 - Abstract #ATC2022ATC_1408;    
    P1/2
    * Two allosensitized patients (cPRA >20%) enrolled in our trial combining plerixafor and bortezomib to deplete BMPCs (clinicaltrials.gov, NCT02522572) had BM aspirates collected prior to (D-10) and after treatment (D8 or D9)...Autophagic flux was assessed using imaging cytometry to quantitate LC3+ punctae in mouse BMPCs cultured with carfilzomib (CFZ) vs vehicle and the lysosomal inhibitor, Lys05, vs vehicle... Data from in vitro murine studies and in vivo human studies demonstrate that BMPCs upregulate autophagy in response to proteasome inhibition and suggest that inhibiting both pathways can enhance BMPC depletion.
  • ||||||||||  Journal:  PCNA negatively regulates MITA through the autophagy pathway in miiuy croaker (Miichthys miiuy). (Pubmed Central) -  May 18, 2022   
    PCNA inhibits interferon production by targeting MITA and avoids excessive immune response. In summary, our results indicate that PCNA is involved in the immune response by degrading MITA through the autophagy pathway, which will provide new ideas for further studies on the regulatory mechanism of immune signaling pathways in lower vertebrates.
  • ||||||||||  Lonsurf (trifluridine/tipiracil) / Servier, Otsuka
    Journal:  Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy. (Pubmed Central) -  May 18, 2022   
    Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer...Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway...In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.
  • ||||||||||  cisplatin / Generic mfg.
    Journal:  Knockout of farnesoid X receptor gene aggravates cisplatin-induced kidney injury. (Pubmed Central) -  May 18, 2022   
    These results provide a new therapeutic strategy targeting autophagy which is induced in tumor cells by D‑allose administration, and may be used to improve therapies for lung cancer. Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.
  • ||||||||||  givinostat (ITF2357) / Italfarmaco
    Journal:  Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination. (Pubmed Central) -  May 17, 2022   
    Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.
  • ||||||||||  MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute
    Journal:  OTX2's Dual Mode of Degradation is Regulated by O-GlcNAcylation. (Pubmed Central) -  May 14, 2022   
    Using a combination of proteasome inhibition (MG-132 mediated) and O-GlcNAc increase (Thiamet-G, TG), we demonstrated that endogenous OTX2 was indeed degraded by the proteasome...We showed that the macroautophagy inhibitor Chloroquine (CQ) prevented OTX2 degradation, and the addition of TG did not further stabilize the protein...Like many homeobox proteins, OTX2 level needs to be tightly regulated for proper patterning and development, and its deregulation amongst other proteins is a major driver of Medulloblastoma. Therefore, we foresee that O-GlcNAcylated OTX2 may play a major role in Medulloblastoma pathogenesis.
  • ||||||||||  Journal:  An in-Depth Analysis of the PAK1 Autophagy Signaling Pathway in H9C2 Cardiomyoblasts. (Pubmed Central) -  May 14, 2022   
    Collectively, these results suggest that the ability of PAK1 knockdown to inhibit autophagy and mitophagy is mediated by reduced expression levels of several important regulators of autophagy and/or mitophagy pathways. Future research is warranted to determine whether restoring the expression levels of these target genes can overcome the inhibition of autophagy and mitophagy by PAK1 deficiency.
  • ||||||||||  azacitidine / Generic mfg.
    PROTEOGENOMIC CHARACTERIZATION OF 5-AZACYTIDINE EFFECTS ON ACUTE MYELOID LEUKEMIA IMMUNOPEPTIDOME () -  May 13, 2022 - Abstract #EHA2022EHA_720;    
    Conclusion Altogether our results show that AZA promotes the presentation of CTA-derived rather than ERE-derived MAPs and that autophagy induction could enable the survival of AML cells to AZA-induced proteotoxic stress. Our findings suggest that autophagy inhibitors could synergize with AZA in AML therapy.
  • ||||||||||  Jakafi (ruxolitinib) / Novartis, Incyte, CHZ868 - Novartis, Memorial Sloan / Kettering Cancer Center
    IN VITRO AND IN VIVO EFFICACY OF A NOVEL KINASE INHIBITOR TARGETING JAK2 GENE REARRANGEMENTS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA () -  May 13, 2022 - Abstract #EHA2022EHA_592;    
    In combination with dexamethasone, a further decrease of viability was observed...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased after ruxolitinib and chloroquine (autophagy inhibitor) combination(+20% vs ruxolitinib alone, p<0.01)...Conclusion CHZ868 is a promising drugfor the treatment of JAK2 fusionsBCP-ALL. Further studies will include combination with standard chemotherapy drugs, by reducing the intensity and toxicity of chemotherapy.
  • ||||||||||  Mozobil (plerixafor) / Sanofi
    Journal:  CXCR4 inhibition attenuates calcium oxalate crystal deposition-induced renal fibrosis. (Pubmed Central) -  May 12, 2022   
    Renal injury and fibrosis were significantly suppressed by inhibiting CXCR4 with AMD3100 or siRNA in hyperoxaluric mice and oxalate-stimulated HK-2 cells; EMT, reactive oxygen species (ROS) levels, and autophagy were also suppressed...Our results suggest that CXCR4 inhibition attenuates CaOx crystal deposition-induced renal fibrosis by suppressing autophagy and EMT through the NF-κB pathway. Therefore, CXCR4 is a potential target for preventing renal fibrosis in patients with nephrolithiasis.
  • ||||||||||  Journal:  SIRT1 alleviates IL-1β induced nucleus pulposus cells pyroptosis via mitophagy in intervertebral disc degeneration. (Pubmed Central) -  May 12, 2022   
    In vivo, SIRT1 agonist (SRT1720) treatment decreased the expression of NLRP3, p20, and IL-1β, increased the expression of PINK1 and LC3, delayed IVDD process in the rat model. Taken together, our results indicate that SIRT1 alleviates IL-1β induced NLRP3 inflammasome activation via mitophagy in NPCs, SIRT1 may be a potential therapeutic target to alleviate NLRP3- activated pyroptosis in the inflammatory stress related IVDD.
  • ||||||||||  Journal:  Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation. (Pubmed Central) -  May 12, 2022   
    Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.
  • ||||||||||  chloroquine phosphate / Generic mfg., sirolimus / Generic mfg.
    Journal:  Enhanced autophagy promotes radiosensitivity by mediating Sirt1 downregulation in RM-1 prostate cancer cells. (Pubmed Central) -  May 12, 2022   
    Notably, overexpression of Sirt1 by plasmid significantly alleviated radiation-induced apoptosis, but silenced Sirt1 by siRNA further induced apoptosis, indicating the radioprotective effect of Sirt1 on RM-1 cells. In summary, our findings suggested that autophagy-mediated Sirt1 downregulation might be a promising therapeutic target for PC.
  • ||||||||||  dorsomorphin (Compound C) / EMD Serono
    Journal:  Mogrol suppresses lung cancer cell growth by activating AMPK-dependent autophagic death and inducing p53-dependent cell cycle arrest and apoptosis. (Pubmed Central) -  May 12, 2022   
    Further studies revealed that mogrol stirred excessive autophagy and autophagic flux, and finally, autophagic cell death, in lung cancer cells, which could be attenuated by autophagy inhibitors, 3-MA and chloroquine...In addition, mogrol induced a significant increase in p53 activity in lung cancer cells, accompanied with cell cycle arrest and apoptosis, which could be weakened by p53 silence. Our results indicated that mogrol effectively suppressed lung cancer cells in vivo and in vitro by inducing the excessive autophagy and autophagic cell death via activating AMPK signaling pathway, as well as cell cycle arrest and apoptosis via activating p53 pathway.
  • ||||||||||  Real-Time In Vivo Analysis of Beta-Cell Autophagy in Autoimmune Diabetes (Poster Hall (Halls D-E); Board No. 1443) -  May 11, 2022 - Abstract #ADA2022ADA_974;    
    However, in contrast, in pre-diabetic NOD mice, islet autophagic flux did not respond effectively to chloroquine treatment. Collectively, these data support the conclusion that autophagy defects precede hyperglycemia and suggest a potential role for these defects in beta cell demise during T1D pathogenesis.
  • ||||||||||  chloroquine phosphate / Generic mfg.
    Journal:  HIF-1α/FOXO1 axis regulated autophagy is protective for β cell survival under hypoxia in human islets. (Pubmed Central) -  May 10, 2022   
    CoCl2 treatment caused the increase of β cell apoptosis, yet inhibiting autophagy by Chloroquine or by FOXO1 knockdown further aggravated apoptosis, suggesting that FOXO1-regulated autophagy is protective for β cell survival under hypoxia...Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits β cell survival under hypoxia and autophagy dysregulation may account for β cell mass loss in T2DM. BRIEF SUMMARY: Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits β cell survival under hypoxia and autophagy dysregulation may account for β cell mass loss in T2DM.
  • ||||||||||  irinotecan / Generic mfg.
    Journal:  Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy. (Pubmed Central) -  May 8, 2022   
    We further investigated the effects of TSN on the in vitro and in vivo TNBC models, in combination with chemotherapeutic drug irinotecan (or its active metabolite 7-ethyl-10-hydroxycamptothecin), a topoisomerase I inhibitor showing therapeutic potential for TNBC. The data showed that TSN blocked 7-ethyl-10-hydroxycamptothecin (SN-38)/irinotecan-induced protective autophagy, and significantly induced apoptosis in TNBC cells and tumor xenograft models when compared to SN-38/irinotecan alone group.
  • ||||||||||  Journal:  Autophagy and cancer metabolism-The two-way interplay. (Pubmed Central) -  May 7, 2022   
    Thus, inhibition of autophagy or autophagy-mediated metabolic reprogramming may be a promising strategy for anticancer therapy. Better understanding the metabolic rewiring mechanisms of autophagy for its pro-tumor effects will provide insights into patient treatment.
  • ||||||||||  ebselen (SPI-1005) / Sound Pharma
    Preclinical, Journal:  Ebselen ameliorates renal ischemia-reperfusion injury via enhancing autophagy in rats. (Pubmed Central) -  May 7, 2022   
    The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.
  • ||||||||||  Journal, IO biomarker:  Exosomes From Human Umbilical Cord Mesenchymal Stem Cells Treat Corneal Injury via Autophagy Activation. (Pubmed Central) -  May 7, 2022   
    In contrast, clinical indications, apoptosis, and inflammation were aggravated after the application of the autophagy inhibitor. HucMSC-Exos combined with an autophagy activator significantly enhanced HCECs functions and alleviated corneal defects, apoptosis, and inflammation by activating the autophagy signaling pathway, AMPK-mTOR-ULK1, providing a new biological therapy for corneal wound healing and ocular surface regeneration.
  • ||||||||||  Journal:  Proteotoxic stress disrupts epithelial integrity by inducing MTOR sequestration and autophagy overactivation. (Pubmed Central) -  May 7, 2022   
    Improving proteostasis capacity by reducing DAF-2 insulin/IGF1 signaling markedly relieves the aggregation of LET-363/MTOR and alleviates autophagy overactivation, which in turn reverses derailed endosomal trafficking and rescues epithelial morphogenesis defects in C53A5.6/RIKE-1-deficient animals. Hence, our studies reveal that C53A5.6/RIKE-1-mediated proteostasis is critical for maintaining the basal level of autophagy and epithelial integrity.Abbreviations: ACT-5: actin 5; ACTB: actin beta; ALs: autolysosomes; APs: autophagosomes; AJM-1: apical junction molecule; ATG: autophagy related; C. elegans: Caenorhabditis elegans; CPL-1: cathepsin L family; DAF: abnormal dauer formation; DLG-1: Drosophila discs large homolog; ERM-1: ezrin/radixin/moesin; EPG: ectopic P granule; GFP: freen fluorescent protein; HLH-30: helix loop helix; HSP: heat shock protein; LAAT-1: lysosome associated amino acid transporter; LET: lethal; LGG-1: LC3, GABARAP and GATE-16 family; LMP-1: LAMP (lysosome-associated membrane protein) homolog; MTOR: mechanistic target of rapamycin kinase; NUC-1: abnormal nuclease; PEPT-1/OPT-2: Peptide transporter family; PGP-1: P-glycoprotein related; RAB: RAB family; RIKE-1: RING and Kelch repeat-containing protein; SLCF-1: solute carrier family; SQST-1: sequestosome related; SPTL-1: serine palmitoyl transferase family.