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  • ||||||||||  Journal:  Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke. (Pubmed Central) -  Oct 29, 2021   
    E2 supplementation significantly inhibited autophagy only in male neurons, and was beneficial for cell survival only in female neurons. This study shows that autophagy in the ischemic brain differs between the sexes, and that autophagy regulators have different effects in a sex-dependent manner in neurons.
  • ||||||||||  chloroquine phosphate / Generic mfg.
    Journal:  Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model. (Pubmed Central) -  Oct 29, 2021   
    Notably, LGMDD2 mutation increase TNPO3 at the transcript and protein level in the Drosophila model Upregulated muscle autophagy observed in LGMDD2 patients was also confirmed in the fly model, in which the anti-autophagic drug chloroquine was able to rescue histologic and functional phenotypes. Overall, we provide a proof of concept of autophagy as a target to treat disease phenotypes and propose a neurogenic component to explain mutant TNPO3 pathogenicity in diseased muscles.
  • ||||||||||  sirolimus / Generic mfg.
    Preclinical, Journal:  Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL-33 signaling in a mouse model of skin wound healing. (Pubmed Central) -  Oct 29, 2021   
    We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP)...To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied...Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.
  • ||||||||||  SP600125 / BMS
    Journal:  EM-2 inhibited autophagy and promoted G/M phase arrest and apoptosis by activating the JNK pathway in hepatocellular carcinoma cells. (Pubmed Central) -  Oct 28, 2021   
    Meanwhile, EM-2 induced apoptosis in a dose-dependent manner and G/M phase arrest in Huh-7 cells, which could be partially reversed when treated with SP600125, a JNK inhibitor...In conclusion, our findings revealed that EM-2 not only promoted G/M phase arrest and activated ER stress but also induced apoptosis by activating the JNK pathway and blocked autophagic flux by inhibiting autolysosome maturation in Huh-7 hepatocellular carcinoma cells. Therefore, EM-2 is a potential therapeutic drug with promising antitumor effects against hepatocellular carcinoma and fewer side effects.
  • ||||||||||  Preclinical, Journal:  Hepcidin inhibits autophagy in intracerebral hemorrhage models in vitro and in vivo. (Pubmed Central) -  Oct 28, 2021   
    We also showed that ad-hepcidin inhibited ICH-induced increase in LC3-II/LC3-I conversion ratio and reversed ICH-induced reduction in p62 content in the brain cortex of rats in vivo. Based on these findings plus previous data on the effects of ad-hepcidin and/or hepcidin peptide on iron contents in ICH models, we suggested that hepcidin-induced inhibition of autophagy might be mediated via reducing iron in hemin-treated neurons in vitro and ICH-rat brain in vivo.
  • ||||||||||  sirolimus / Generic mfg.
    Journal, IO biomarker:  Mycobacterium tuberculosis RipA Dampens TLR4-Mediated Host Protective Response Using a Multi-Pronged Approach Involving Autophagy, Apoptosis, Metabolic Repurposing, and Immune Modulation. (Pubmed Central) -  Oct 28, 2021   
    The use of pharmacological agents, rapamycin and bafilomycin A1, reveals that RipA activates PI3K-AKT-mTORC1 signaling cascade that ultimately culminates in the inhibition of autophagy initiating kinase ULK1 (Unc-51 like autophagy activating kinase)...Furthermore, RipA also inhibited caspase-dependent programed cell death in macrophages, thus hindering an efficient innate antibacterial response. Collectively, our results highlight the role of an endopeptidase to create a permissive replication niche in host cells by inducing the repression of autophagy and apoptosis, along with metabolic reprogramming, and pointing to the role of RipA in disease pathogenesis.
  • ||||||||||  chloroquine phosphate / Generic mfg.
    Journal:  Photoresponsive PAMAM-Assembled Nanocarrier Loaded with Autophagy Inhibitor for Synergistic Cancer Therapy. (Pubmed Central) -  Oct 28, 2021   
    Herein, the authors design a photoresponsive PAMAM-assembled nanoparticle loaded with the autophagy inhibitor (chloroquine, CQ), which exhibits light responsiveness for precisely controlling drug release and superior dark biosafety...Meanwhile, the released CQ can inhibit pro-survival autophagy induced by PAMAM to achieve an excellent synergistic anticancer efficacy in vitro and in vivo. The authors' study provided a vision of utilizing PAMAM as self-carried anticancer therapeutics in combination with an autophagy inhibitor and proposing a cancer therapy with high antitumor efficacy and low side effects to normal tissues.
  • ||||||||||  Journal:  Altered metabolic state impedes limb regeneration in salamanders. (Pubmed Central) -  Oct 28, 2021   
    Hence, tissue autophagy and the regenerative response were tightly coupled only when animals were under stress. Our results demonstrate that under adverse conditions, salamanders can exploit alternative strategies to secure blastema formation for limb regeneration.
  • ||||||||||  Journal:  Autophagy blockade synergistically enhances nanosonosensitizer-enabled sonodynamic cancer nanotherapeutics. (Pubmed Central) -  Oct 27, 2021   
    It has been systematically demonstrated that nanosonosensitizers-augmented SDT induced cytoprotective pro-survival autophagy through activation of MAPK signaling pathway and inhibition of AMPK signaling pathway, and this could be efficaciously inhibited by 3-MA in early-phase autophagy, which significantly decreased the cell resistance to intracellular oxidative stress and complied a remarkable synergistic effect on SDT medicated cancer-cell apoptosis both in vitro at cellular level and in vivo on tumor-bearing animal model. Therefore, our results provide a proof-of-concept combinatorial tumor therapeutics based on nanosonosensitizers for the treatment of ROS-resistant cancer by autophagy inhibition-augmented SDT.
  • ||||||||||  tamoxifen / Generic mfg., docetaxel / Generic mfg.
    Low tumor TLR9 expression results in resistance to growth inhibitory and autophagy responses to common breast cancer treatments (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_1084;    
    Decreased expression of tumor TLR9 is associated with 1) poor prognosis among basal and luminal B subtype patient samples, and in 2) decreased growth inhibitory and 3) decreased autophagy responses to common breast cancer chemotherapies and tamoxifen. Our results suggest that treatment responses, and thereby survival of patients with low-TLR9 tumors, may be improved by enhancing TLR9-associated autophagy.
  • ||||||||||  Ibrance (palbociclib) / Pfizer
    Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer (Hall 1) -  Oct 26, 2021 - Abstract #SABCS2021SABCS_527;    
    Additionally, analysis of three database sets demonstrated that higher breast cancer expression of BRD4, a primary target of ARV-825, correlated with lower recurrence-free survival compared to patients with cancers expressing lower levels of BRD4. These studies indicate that administration of BET inhibitors, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients by prolonging progression-free survival.
  • ||||||||||  chloroquine phosphate / Generic mfg.
    Journal:  Small molecule-mediated induction of endoplasmic reticulum stress in cancer cells. (Pubmed Central) -  Oct 25, 2021   
    We identified a fluorescent small molecule that localized into the endoplasmic reticulum (ER) of HeLa cells, induced ER stress followed by triggering autophagy which was subsequently inhibited by chloroquine (autophagy inhibitor) to initiate apoptosis. This small molecule showed remarkable cancer cell killing efficacy in different cancer cells as mono and combination therapy with chloroquine, thus opening a new direction to illuminate ER-biology towards the development of novel anticancer therapeutics.
  • ||||||||||  paclitaxel / Generic mfg.
    Journal, Cancer stem cells:  Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer. (Pubmed Central) -  Oct 25, 2021   
    Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.
  • ||||||||||  chloroquine phosphate / Generic mfg.
    Journal:  Posidonia oceanica (L.) Delile Extract Reduces Lipid Accumulation through Autophagy Activation in HepG2 Cells. (Pubmed Central) -  Oct 25, 2021   
    Chloroquine (CQ), an autophagy inhibitor, was used to study the relationship between POE-induced autophagy and intracellular lipid accumulation...By blocking autophagy with CQ, the effect of POE on intracellular lipid accumulation was clearly reversed, suggesting that the POE phytocomplex may reduce lipid accumulation in HepG2 cells by activating the autophagic process. This work indicates that P. oceanica may be considered as a promising molecule supplier to discover new natural approaches for the management of NAFLD.
  • ||||||||||  methamphetamine / Generic mfg.
    Preclinical, Journal:  Inhibition of Autophagy In Vivo Extends Methamphetamine Toxicity to Mesencephalic Cell Bodies. (Pubmed Central) -  Oct 25, 2021   
    When METH (5 mg/Kg × 4, 2 h apart) was administered to C57Bl/6 mice following ASN or GLN, a frank loss of cell bodies takes place within SNpc and a loss of both axons and cell bodies of VTA neurons is documented. These data indicate that, ongoing autophagy protects DA neurons and determines the refractoriness of cell bodies to METH-induced toxicity.
  • ||||||||||  Journal:  Epigenetic silencing of miR-342-3p in B cell lymphoma and its impact on autophagy. (Pubmed Central) -  Oct 22, 2021   
    Intronic miR-342-3p is co-regulated with its host gene EVL by tumor-specific promoter DNA methylation in B cell lymphoma. The tumor suppressor function of miR-342-3p was mediated via inhibition of pro-survival autophagy by targeting MAP1LC3B and downregulation of DNMT1 with demethylation and re-expression of tumor suppressor genes.
  • ||||||||||  Journal:  Regulation of autophagosome biogenesis by OFD1-mediated selective autophagy. (Pubmed Central) -  Oct 22, 2021   
    We also show that patients with Oral-Facial-Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self-regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.
  • ||||||||||  dorsomorphin (Compound C) / EMD Serono
    Journal, PARP Biomarker:  Saikosaponin-d increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation. (Pubmed Central) -  Oct 22, 2021   
    Transmission electron microscopy and confocal microscopy results also showed that the number of autophagosomes was significantly higher in the radiation and SSd co-treatment group than in the radiotherapy or SSd alone group; however, the effect of SSd on autophagy in hepatoma cells was decreased after adding MHY1485, siRNA-P53 or AMPK inhibitor (Compound C). Western blot analysis showed that after the addition of SSd, the phosphorylation of mTOR was significantly decreased by radiation, the expression of the autophagy-related proteins LC3-II and Beclin-1 was increased, p62 was decreased, and the expression of cleaved caspase-3 and cleaved PARP was enhanced; this effect of SSd was partially reversed after the addition of MHY1485, siRNA-P53 or Compound C. SSd increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation and providing a possible potential approach for radiosensitization therapy of liver cancer.
  • ||||||||||  SP600125 / BMS
    Journal:  Cadmium Impairs Autophagy Leading to Apoptosis by Ca-Dependent Activation of JNK Signaling Pathway in Neuronal Cells. (Pubmed Central) -  Oct 22, 2021   
    This is supported by the findings that pharmacological inhibition of JNK with SP600125 or expression of dominant negative c-Jun markedly attenuated Cd-induced expansion of autophagosomes and abnormal expression of Atg proteins, as well as apoptosis in PC12 cells and/or primary neurons...Taken together, the results indicate that Cd impairs autophagy leading to apoptosis by Ca-dependent activation of JNK signaling pathway in neuronal cells. Our findings highlight that manipulation of intracellular Ca level and/or JNK activity to ameliorate autophagy may be a promising intervention against Cd-induced neurotoxicity and neurodegeneration.
  • ||||||||||  Torin1 / InvivoGen
    Journal:  The atypical small GTPase GEM/Kir is a negative regulator of the NADPH oxidase and NETs production through macroautophagy. (Pubmed Central) -  Oct 22, 2021   
    Prevention of new autophagosome formation by treatment with SAR405 increased ROS production while induction of autophagy by Torin-1 decreased ROS production in Gem KO neutrophils, and also in wild-type neutrophils, suggesting that macroautophagy contributes to the termination of NADPH oxidase activity...In vivo analysis in a model of Salmonella Typhimurium infection indicates that Gem-deficiency provides a genetic advantage manifested as a moderate increased in survival to infections. Altogether, the data suggest that Gem-deficiency leads to the enhancement of the neutrophil innate immune response by increasing NADPH oxidase assembly and NETs production and that macroautophagy differentially regulates ROS and NETs in neutrophils.