bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–03–26
53 papers selected by
Viktor Korolchuk, Newcastle University
  1. SB2301-mediated perturbation of membrane composition in lipid droplets induces lipophagy and lipid droplets ubiquitination.
  2. Umbelliferone protects against cerebral ischemic injury through selective autophagy of mitochondria.
  3. The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice.
  4. Non-essential amino acid availability influences proteostasis and breast cancer cell survival during proteotoxic stress.
  5. A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
  6. Crosstalk between cGAS-STING pathway and autophagy in cancer immunity.
  7. Monitoring autophagic flux in vivo revealed its physiological response and significance of heterogeneity in pancreatic beta cells.
  8. Regulatory effect of orexin system on various diseases through mTOR signaling pathway.
  9. Activation of ROS-PERK-TFEB by Filbertone Ameliorates Neurodegenerative Diseases via Enhancing the Autophagy-Lysosomal Pathway.
  10. Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation.
  11. Autophagy-Mediated Phosphate Homeostasis in Arabidopsis Involves Modulation of Phosphate Transporters.
  12. MicroRNA-17-3p protects against excessive posthypoxic autophagy in H9C2 cardiomyocytes via PTEN-Akt-mTOR signaling pathway.
  13. Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
  14. Autophagy orchestrates resistance in hepatocellular carcinoma cells.
  15. Rift Valley Fever Virus Nucleoprotein Triggers Autophagy to Dampen Antiviral Innate Immune Responses.
  16. Cross-Talk and Multiple Control of Target of Rapamycin (TOR) in Sclerotinia sclerotiorum.
  17. Coronavirus subverts ER-phagy by hijacking FAM134B and ATL3 into p62 condensates to facilitate viral replication.
  18. Structure-based design and characterization of Parkin-activating mutations.
  19. Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease.
  20. WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism.
  21. Two-photon excited red-green "discoloration" bioprobes for monitoring lipid droplets and lipid droplet-lysosomal autophagy.
  22. Hormonal regulation of metabolism-recent lessons learned from insulin and estrogen.
  23. Topoisomerase I poisons-induced autophagy: Cytoprotective, Cytotoxic or Non-protective.
  24. Septins and K63 chains form separate bacterial microdomains during autophagy of entrapped Shigella.
  25. TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy.
  26. Chinese herbal medicine and its active compounds in attenuating renal injury via regulating autophagy in diabetic kidney disease.
  27. Rapamycin encourages the maintenance of mitochondrial dynamic balance and mitophagy activity for improving developmental competence of blastocysts in porcine embryos in vitro.
  28. Harnessing the Noncanonical Keap1-Nrf2 Pathway for Human Cytomegalovirus Control.
  29. A novel optinEuRin stress connection in glaucoma.
  30. Arsenite-induced cytotoxicity is regulated by poly-ADP ribose polymerase 1 activation and parthanatos in p53-deficient H1299 cells: The roles of autophagy and p53.
  31. Mitochondrial Membrane Potential Independent Near-Infrared Mitochondrial Viscosity Probes for Real-Time Tracking Mitophagy.
  32. A novel gene REPTOR2 activates the autophagic degradation of wing disc in pea aphid.
  33. The sequestosome 1 protein: therapeutic vulnerabilities in ovarian cancer.
  34. Irisin Ameliorates PM2.5-Induced Acute Lung Injury by Regulation of Autophagy Through AMPK/mTOR Pathway.
  35. ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages.
  36. BMP9 promotes autophagy and inhibits migration and invasion in breast cancer cells through the c-Myc/SNHG3/mTOR signaling axis.
  37. Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
  38. MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model.
  39. Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade.
  40. Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson's disease.
  41. Astragaloside trigger autophagy: Implication a potential therapeutic strategy for pulmonary fibrosis.
  42. A proinsulin-dependent interaction between ENPL-1 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.
  43. PROTAC-Mediated Selective Degradation of Cytosolic Soluble Epoxide Hydrolase Enhances ER Stress Reduction.
  44. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  45. Circadian gene CLOCK accelerates atherosclerosis by promoting endothelial autophagy.
  46. AKR7A3 modulates the metastasis of pancreatic ductal adenocarcinoma through regulating PHGDH-suppressed autophagy.
  47. Curbing Rhes Actions: Mechanism-Based Molecular Target for Huntington's Disease and Tauopathies.
  48. Small molecule '4ab' induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions.
  49. Inhibition of autophagy in macrophage promotes IL-1β-mediated hepatocellular carcinoma progression via inflammasome accumulation and self-recruitment.
  50. EGCG identified as an autophagy inducer for rosacea therapy.
  51. Autophagy inhibition and ferroptosis activation during atherosclerosis: Hypoxia-inducible factor 1α inhibitor PX-478 alleviates atherosclerosis by inducing autophagy and suppressing ferroptosis in macrophages.
  52. Targeting autophagy process in center nervous trauma.
  53. Crosstalk Between Autophagy and Inflammation in Chronic Cerebral Ischaemia.
  1. Commun Biol. 2023 Mar 21. 6(1): 300
    SB2301-mediated perturbation of membrane composition in lipid droplets induces lipophagy and lipid droplets ubiquitination.
    Jinjoo Jung, Jongbeom Park, Mingi Kim, Jaeyoung Ha, Hana Cho, Seung Bum Park.
      Lipid droplets (LDs) are involved in various biological events in cells along with their primary role as a storage center for neutral lipids. Excessive accumulation of LDs is highly correlated with various diseases, including metabolic diseases. Therefore, a basic understanding of the molecular mechanism of LD degradation would be beneficial in both academic and industrial research. Lipophagy, a selective autophagy mechanism/LD degradation process, has gained increased attention in the research community. Herein, we sought to elucidate a novel lipophagy mechanism by utilizing the LD-degrading small molecule, SB2301, which activates ubiquitin-mediated lipophagy. Using a label-free target identification method, we revealed that ethanolamine-phosphate cytidylyltransferase 2 (PCYT2) is a potential target protein of SB2301. We also demonstrated that although SB2301 does not modulate PCYT2 function, it induces the cellular translocation of PCYT2 to the LD surface and spatially increases the phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio of the LD membrane, causing LD coalescence, leading to the activation of lipophagy process to maintain energy homeostasis.
    DOI:  https://doi.org/10.1038/s42003-023-04682-9
  2. Neurochem Int. 2023 Mar 16. pii: S0197-0186(23)00048-7. [Epub ahead of print] 105520
    Umbelliferone protects against cerebral ischemic injury through selective autophagy of mitochondria.
    Zhuchen Zhou, Yan Zhang, Feng Han, Zhong Chen, Yanrong Zheng.
      Effective therapeutic treatments for ischemic stroke are limited. Previous studies suggest selective activation of mitophagy alleviates cerebral ischemic injury while excessive autophagy is detrimental. However, few compounds are available to selectively activate mitophagy without affecting autophagy flux. Here, we found that acute administration of Umbelliferone (UMB) upon reperfusion exerted neuroprotective effects against ischemic injury in mice subjected to transient middle cerebral artery occlusion (tMCAO) and suppressed oxygen-glucose deprivation reperfusion (OGD-R)-induced apoptosis in SH-SY5Y cells. Interestingly, UMB promoted the translocation of mitophagy adaptor SQSTM1 to mitochondria and further reduced the mitochondrial content as well as the expression of SQSTM1 in SHSY5Y cells after OGD-R. Importantly, both the mitochondrial loss and reduction of SQSTM1 expression after UMB incubation can be reversed by autophagy inhibitor chloroquine and wortmannin, proving the mitophagy activation by UMB. Nevertheless, UMB failed to further affect neither LC3 lipidation nor the number of autophagosomes after cerebral ischemia in vivo and in vitro. Furthermore, UMB facilitated OGD-R-induced mitophagy in a Parkin-dependent manner. Inhibition of autophagy/mitophagy either pharmaceutically or genetically abolished the neuroprotective effects of UMB. Taken all, these results suggest that UMB protects against cerebral ischemic injury, both in vivo and in vitro, via promoting mitophagy without increasing the autophagic flux. UMB might serve as a potential leading compound for selectively activating mitophagy and the treatment of ischemic stroke.
    Keywords:  Autophagy; Ischemic stroke; Mitophagy; Parkin; Umbelliferone
    DOI:  https://doi.org/10.1016/j.neuint.2023.105520
  3. Biol Res. 2023 Mar 25. 56(1): 14
    The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice.
    Carlos Sepúlveda, Juan Manuel Rodríguez, Matías Monsalves-Álvarez, Camila Donoso-Barraza, Francisco Pino-de la Fuente, Isabelle Matías, Thierry Leste-Lasserre, Philippe Zizzari, Eugenia Morselli, Daniela Cota, Miguel Llanos, Rodrigo Troncoso.
      The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.
    Keywords:  Autophagy; Endocannabinoid receptor; High-fat diet; Skeletal muscle
    DOI:  https://doi.org/10.1186/s40659-023-00426-5
  4. Mol Cancer Res. 2023 Mar 24. pii: MCR-22-0843. [Epub ahead of print]
    Non-essential amino acid availability influences proteostasis and breast cancer cell survival during proteotoxic stress.
    Sara Sannino, Allison M Manuel, Chaowei Shang, Stacy G Wendell, Peter Wipf, Jeffrey L Brodsky.
      Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition. Implications: These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0843
  5. Hum Mol Genet. 2023 Mar 20. pii: ddad040. [Epub ahead of print]
    A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddad040
  6. Front Immunol. 2023 ;14 1139595
    Crosstalk between cGAS-STING pathway and autophagy in cancer immunity.
    Qijun Lu, Yukun Chen, Jianwen Li, Feng Zhu, Zhan Zheng.
      The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is critical in cancer immunity. Autophagy is a highly conserved process that is responsible for the degradation of cytoplasmic material and is involved in both innate and adaptive immunity. Recently, cGAS-STING and autophagy have been shown to be interconnected, which may influence the progression of cancer. Although cGAS-STING and autophagy have been shown to be interrelated in innate immunity, little has been reported about cancer immunity. As cancer immunity is key to treating tumors, it is essential to summarize the relationship and interactions between the two. Based on this, we systematically sorted out the recent findings of cGAS-STING and autophagy in cancer immunity and explored the interactions between cGAS-STING and autophagy, although these interactions have not been extensively studied. Lastly, we provide an outlook on how cGAS-STING and autophagy can be combined, with the hope that our research can help people better understand their potential roles in cancer immunity and bring light to the treatment of cancer.
    Keywords:  antitumor; autophagy; cGAS-STING; cancer; immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1139595
  7. Cell Chem Biol. 2023 Mar 16. pii: S2451-9456(23)00060-0. [Epub ahead of print]
    Monitoring autophagic flux in vivo revealed its physiological response and significance of heterogeneity in pancreatic beta cells.
    Shuhei Aoyama, Yuya Nishida, Hirotsugu Uzawa, Miwa Himuro, Akiko Kanai, Kyosei Ueki, Minami Ito, Hitoshi Iida, Isei Tanida, Takeshi Miyatsuka, Yoshio Fujitani, Masaki Matsumoto, Hirotaka Watada.
      Autophagy plays an essential role in preserving cellular homeostasis in pancreatic beta cells. However, the extent of autophagic flux in pancreatic islets induced in various physiological settings remains unclear. In this study, we generate transgenic mice expressing pHluorin-LC3-mCherry reporter for monitoring systemic autophagic flux by measuring the pHluorin/mCherry ratio, validating them in the starvation and insulin-deficient model. Our findings reveal that autophagic flux in pancreatic islets enhances after starvation, and suppression of the flux after short-term refeeding needs more prolonged re-starvation in islets than in the other insulin-targeted organs. Furthermore, heterogeneity of autophagic flux in pancreatic beta cells manifests under insulin resistance, and intracellular calcium influx by glucose stimulation increases more in high- than low-autophagic flux beta cells, with differential gene expression, including lipoprotein lipase. Our pHluorin-LC3-mCherry mice enable us to reveal biological insight into heterogeneity in autophagic flux in pancreatic beta cells.
    Keywords:  autophagy; diabetes mellitus; heterogeneity; insulin resistance; insulin secretion; pHluorin; pancreatic beta cells
    DOI:  https://doi.org/10.1016/j.chembiol.2023.03.001
  8. Trends Endocrinol Metab. 2023 Mar 16. pii: S1043-2760(23)00051-6. [Epub ahead of print]
    Regulatory effect of orexin system on various diseases through mTOR signaling pathway.
    Ying Song, Beibei Wang, Wenjun Wang, Qiwen Shi.
      Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.
    Keywords:  cerebral ischemia–reperfusion injury; mammalian target of rapamycin; orexin; orexinergic receptor
    DOI:  https://doi.org/10.1016/j.tem.2023.02.008
  9. J Nutr Biochem. 2023 Mar 21. pii: S0955-2863(23)00058-X. [Epub ahead of print] 109325
    Activation of ROS-PERK-TFEB by Filbertone Ameliorates Neurodegenerative Diseases via Enhancing the Autophagy-Lysosomal Pathway.
    Jeongmin Park, Jeong Heon Gong, Yubing Chen, Thu-Hang Thi Nghiem, Sonam Chandrawanshi, Eunyeong Hwang, Chae Ha Yang, Byung-Sam Kim, Jeong Woo Park, Stefan W Ryter, Byungyong Ahn, Yeonsoo Joe, Hun Taeg Chung, Rina Yu.
      The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B (NF-κB). Here, we report that filbertone activates PERK through mitochondrial ROS (mtROS) production, resulting in the increased nuclear translocation of transcription factor-EB (TFEB) in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway (ALP), which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet (HFD). Filbertone treatment also reduced HFD-induced α-synuclein accumulation through upregulation of the ALP pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the MPTP-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease.
    Keywords:  Filbertone; Parkinson's disease; Reactive oxygen species; TFEB; α-Synuclein
    DOI:  https://doi.org/10.1016/j.jnutbio.2023.109325
  10. Biomol Ther (Seoul). 2023 Mar 21.
    Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation.
    Mihwa Hwang, Dong Wha Jun, Bo Ram Song, Hanna Shim, Chang-Hun Lee, Sunshin Kim.
      Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.
    Keywords:  ATM; Autolysosome; Autophagy; Cancer therapy; Combination therapy
    DOI:  https://doi.org/10.4062/biomolther.2023.003
  11. Plant Cell Physiol. 2023 Mar 03. pii: pcad015. [Epub ahead of print]
    Autophagy-Mediated Phosphate Homeostasis in Arabidopsis Involves Modulation of Phosphate Transporters.
    Chang-Yi Chiu, Hui-Fang Lung, Wen-Chun Chou, Li-Yen Lin, Hong-Xuan Chow, Yu-Hao Kuo, Pei-Shan Chien, Tzyy-Jen Chiou, Tzu-Yin Liu.
      Autophagy in plants is regulated by diverse signaling cascades in response to environmental changes. Fine-tuning of its activity is critical for the maintenance of cellular homeostasis under basal and stressed conditions. In this study, we compared the Arabidopsis autophagy-related (ATG) system transcriptionally under inorganic phosphate (Pi) deficiency versus nitrogen deficiency and showed that most ATG genes are only moderately upregulated by Pi starvation, with relatively stronger induction of AtATG8f and AtATG8h among the AtATG8 family. We found that Pi shortage increased the formation of GFP-ATG8f-labeled autophagic structures and the autophagic flux in the differential zone of the Arabidopsis root. However, the proteolytic cleavage of GFP-ATG8f and the vacuolar degradation of endogenous ATG8 proteins indicated that Pi limitation does not drastically alter the autophagic flux in the whole roots, implying a cell type-dependent regulation of autophagic activities. At the organismal level, the Arabidopsis atg mutants exhibited decreased shoot Pi concentrations and smaller meristem sizes under Pi sufficiency. Under Pi limitation, these mutants showed enhanced Pi uptake and impaired root cell division and expansion. Despite a reduced steady-state level of several PHOSPHATE TRANSPORTER 1s (PHT1s) in the atg root, cycloheximide treatment analysis suggested that the protein stability of PHT1;1/2/3 is comparable in the Pi-replete wild type and atg5-1. By contrast, the degradation of PHT1;1/2/3 is enhanced in the Pi-deplete atg5-1. Our findings reveal that both basal autophagy and Pi starvation-induced autophagy are required for the maintenance of Pi homeostasis and may modulate the expression of PHT1s through different mechanisms.
    Keywords:   Arabidopsis thaliana ; Phosphate homeostasis; Phosphate transporter; Plant autophagy
    DOI:  https://doi.org/10.1093/pcp/pcad015
  12. Cell Biol Int. 2023 Mar 19.
    MicroRNA-17-3p protects against excessive posthypoxic autophagy in H9C2 cardiomyocytes via PTEN-Akt-mTOR signaling pathway.
    Yi He, Dengwen Zhang, Qingqing Zhang, Yin Cai, Chongfeng Huang, Zhengyuan Xia, Sheng Wang.
      The activity of phosphatase and tensin homolog (PTEN) can be inhibited by miR-17-3p, which results in attenuating myocardial ischemia/reperfusion injury (IRI), however, the mechanism behind this phenomenon is still elusive. Suppression of PTEN leads to augmented protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling strength and constrained autophagy activation, which might be the one mechanism for the ameliorated myocardial IRI. Thus, we tested the hypothesis that miR-17-3p attenuated hypoxia/reoxygenation (H/R)-mediated damage in cardiomyocytes by downregulating excessive autophagy via the PTEN-Akt-mTOR axis. The expression of miR-17-3p was remarkably increased after H/R treatment (6-h hypoxia followed by 6-h reoxygenation; H6/R6), which was concomitant with the increase of the release of lactic acid dehydrogenase (cell injury marker) and the enhancement LC3II/I ratio (autophagy markers) in H9C2 cardiomyocytes. Ectoexpression of miR-17-3p agomir led to remarkable augmentation of miR-17-3p expression and evidently attenuated H/R-mediated cell damage and excessive autophagy. Furthermore, an increase in miR-17-3p expression elicited constrained phosphorylation of PTEN (Ser380 ) while enhanced the phosphorylation of Akt (Thr308 , Ser473 ) and mTOR (Ser536 ) after H/R stimulation. In addition, pretreatment with LY-294002 (an Akt selective inhibitor) and rapamycin (an mTOR selective inhibitor) significantly abrogated the protective function of miR-17-3p on H/R-mediated cell damage and autophagy in H9C2 cardiomyocytes. Taken together, these observations indicated that the enhancement of the PTEN/Akt/mTOR axis and the consequent suppression of autophagy overactivation might represent an underlying mechanism by which miR-17-3p attenuated H/R-mediated damage in H9C2 cells.
    Keywords:  autophagy; cardiomyocytes; hypoxia/reoxygenation; microRNA; rat
    DOI:  https://doi.org/10.1002/cbin.11999
  13. Cell Stem Cell. 2023 Mar 16. pii: S1934-5909(23)00071-1. [Epub ahead of print]
    Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
    Bernadette A Chua, Connor J Lennan, Mary Jean Sunshine, Daniela Dreifke, Ashu Chawla, Eric J Bennett, Robert A J Signer.
      Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.
    Keywords:  Bag3; aggrephagy; aggresome; aging; autophagy; hematopoietic stem cell; proteasome; protein degradation; proteostasis; stem cell
    DOI:  https://doi.org/10.1016/j.stem.2023.02.010
  14. Biomed Pharmacother. 2023 Mar 22. pii: S0753-3322(23)00275-5. [Epub ahead of print]161 114487
    Autophagy orchestrates resistance in hepatocellular carcinoma cells.
    Homeyra Seydi, Kosar Nouri, Niloufar Rezaei, Atena Tamimi, Moustapha Hassan, Hamed Mirzaei, Massoud Vosough.
      Treatment resistance is one of the major barriers for therapeutic strategies in hepatocellular carcinoma (HCC). Many studies have indicated that chemotherapy and radiotherapy induce autophagy machinery (cell protective autophagy) in HCC cells. In addition, many experiments report a remarkable crosstalk between treatment resistance and autophagy pathways. Thus, autophagy could be one of the key factors enabling tumor cells to hinder induced cell death after medical interventions. Therefore, extensive research on the molecular pathways involved in resistance induction and autophagy have been conducted to achieve the desired therapeutic response. The key molecular pathways related to the therapy resistance are TGF-β, MAPK, NRF2, NF-κB, and non-coding RNAs. In addition, EMT, drug transports, apoptosis evasion, DNA repair, cancer stem cells, and hypoxia could have considerable impact on the hepatoma cell's response to therapies. These mechanisms protect tumor cells against various treatments and many studies have shown that each of them is connected to the molecular pathways of autophagy induction in HCC. Hence, autophagy inhibition may be an effective strategy to improve therapeutic outcome in HCC patients. In this review, we further highlight how autophagy leads to poor response during treatment through a complex molecular network and how it enhances resistance in primary liver cancer. We propose that combinational regimens of approved HCC therapeutic protocols plus autophagy inhibitors may overcome drug resistance in HCC therapy.
    Keywords:  Autophagy inducer pathway; Autophagy pathway; Hepatocellular carcinoma; Resistance signaling pathway; Treatment resistance
    DOI:  https://doi.org/10.1016/j.biopha.2023.114487
  15. J Virol. 2023 Mar 20. e0181422
    Rift Valley Fever Virus Nucleoprotein Triggers Autophagy to Dampen Antiviral Innate Immune Responses.
    Xiangtao Zhu, Zihan Guan, Yujie Fang, Yulan Zhang, Zhenqiong Guan, Shufen Li, Ke Peng.
      Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes severe and potentially fatal hemorrhagic fever in humans. Autophagy is a self-degradative process that can restrict viral replication at multiple infection steps. In this study, we evaluated the effects of RVFV-triggered autophagy on viral replication and immune responses. Our results showed that RVFV infection triggered autophagosome formation and induced complete autophagy. Impairing autophagy flux by depleting autophagy-related gene 5 (ATG5), ATG7, or sequestosome 1 (SQSTM1) or treatment with autophagy inhibitors markedly reduced viral RNA synthesis and progeny virus production. Mechanistically, our findings demonstrated that the RVFV nucleoprotein (NP) C-terminal domain interacts with the autophagy receptor SQSTM1 and promotes the SQSTM1-microtubule-associated protein 1 light chain 3 B (LC3B) interaction and autophagy. Deletion of the NP C-terminal domain impaired the interaction between NP and SQSTM1 and its ability to trigger autophagy. Notably, RVFV-triggered autophagy promoted viral infection in macrophages but not in other tested cell types, including Huh7 hepatocytes and human umbilical vein endothelial cells, suggesting cell type specificity of this mechanism. It was further revealed that RVFV NP-triggered autophagy dampens antiviral innate immune responses in infected macrophages to promote viral replication. These results provide novel insights into the mechanisms of RVFV-triggered autophagy and indicate the potential of targeting the autophagy pathway to develop antivirals against RVFV. IMPORTANCE We showed that RVFV infection induced the complete autophagy process. Depletion of the core autophagy genes ATG5, ATG7, or SQSTM1 or pharmacologic inhibition of autophagy in macrophages strongly suppressed RVFV replication. We further revealed that the RVFV NP C-terminal domain interacted with SQSTM1 and enhanced the SQSTM1/LC3B interaction to promote autophagy. RVFV NP-triggered autophagy strongly inhibited virus-induced expression of interferon-stimulated genes in infected macrophages but not in other tested cell types. Our study provides novel insights into the mechanisms of RVFV-triggered autophagy and highlights the potential of targeting autophagy flux to develop antivirals against this virus.
    Keywords:  Rift Valley fever virus; autophagy; innate immune responses; nucleoprotein; sequestosome 1; viral replication
    DOI:  https://doi.org/10.1128/jvi.01814-22
  16. Microbiol Spectr. 2023 Mar 21. e0001323
    Cross-Talk and Multiple Control of Target of Rapamycin (TOR) in Sclerotinia sclerotiorum.
    Wenli Jiao, Weichen Ding, Jeffrey A Rollins, Jinliang Liu, Yanhua Zhang, Xianghui Zhang, Hongyu Pan.
      Sclerotinia sclerotiorum is a necrotrophic phytopathogenic fungus that cross-talks with its hosts for control of cell-death pathways for colonization. Target of rapamycin (TOR) is a central regulator that controls cell growth, intracellular metabolism, and stress responses in a variety of eukaryotes, but little is known about TOR signaling in S. sclerotiorum. In this study, we identified a conserved TOR signaling pathway and characterized SsTOR as a critical component of this pathway. Hyphal growth of S. sclerotiorum was retarded by silencing SsTOR, moreover, sclerotia and compound appressoria formation were severely disrupted. Notably, pathogenicity assays of strains shows that the virulence of the SsTOR-silenced strains were dramatically decreased. SsTOR was determined to participate in cell wall integrity (CWI) by regulating the phosphorylation level of SsSmk3, a core MAP kinase in the CWI pathway. Importantly, the inactivation of SsTOR induced autophagy in S. sclerotiorum potentially through SsAtg1 and SsAtg13. Taken together, our results suggest that SsTOR is a global regulator controlling cell growth, stress responses, cell wall integrity, autophagy, and virulence of S. sclerotiorum. IMPORTANCE TOR is a conserved protein kinase that regulates cell growth and metabolism in response to growth factors and nutrient abundance. Here, we used gene silencing to characterize SsTOR, which is a critical component of TOR signaling pathway. SsTOR-silenced strains have limited mycelium growth, and the virulence of the SsTOR-silenced strains was decreased. Phosphorylation analysis indicated that SsTOR influenced CWI by regulating the phosphorylation level of SsSmk3. Autophagy is essential to preserve cellular homeostasis in response to cellular and environmental stresses. Inactivation of SsTOR induced autophagy in S. sclerotiorum potentially through SsAtg1 and SsAtg13. These findings further indicated that SsTOR is a global regulator of the growth, development, and pathogenicity of S. sclerotiorum in multiple ways.
    Keywords:  MAPK; Sclerotinia sclerotiorum; TOR; autophagy; mitogen-activated protein kinases; pathogenicity
    DOI:  https://doi.org/10.1128/spectrum.00013-23
  17. Cell Rep. 2023 Mar 10. pii: S2211-1247(23)00297-8. [Epub ahead of print]42(4): 112286
    Coronavirus subverts ER-phagy by hijacking FAM134B and ATL3 into p62 condensates to facilitate viral replication.
    Xuan Tan, Kun Cai, Jiajia Li, Zhen Yuan, Ruifeng Chen, Hurong Xiao, Chuanrui Xu, Bing Hu, Yali Qin, Binbin Ding.
      ER-phagy is a form of autophagy that is mediated by ER-phagy receptors and selectively degrades endoplasmic reticulum (ER). Coronaviruses have been shown to use the ER as a membrane source to establish their double-membrane vesicles (DMVs). However, whether viruses modulate ER-phagy to drive viral DMV formation and its underlying molecular mechanisms remains largely unknown. Here, we demonstrate that coronavirus subverts ER-phagy by hijacking the ER-phagy receptors FAM134B and ATL3 into p62 condensates, resulting in increased viral replication. Mechanistically, we show that viral protein ORF8 binds to and undergoes condensation with p62. FAM134B and ATL3 interact with homodimer of ORF8 and are aggregated into ORF8/p62 liquid droplets, leading to ER-phagy inhibition. ORF8/p62 condensates disrupt ER-phagy to facilitate viral DMV formation and activate ER stress. Together, our data highlight how coronavirus modulates ER-phagy to drive viral replication by hijacking ER-phagy receptors.
    Keywords:  CP: Microbiology; ER stress; ER-phagy; ORF8; SARS-CoV-2; double membrane vesicles; p62 condendation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112286
  18. Life Sci Alliance. 2023 Jun;pii: e202201419. [Epub ahead of print]6(6):
    Structure-based design and characterization of Parkin-activating mutations.
    Michael U Stevens, Nathalie Croteau, Mohamed A Eldeeb, Odetta Antico, Zhi Wei Zeng, Rachel Toth, Thomas M Durcan, Wolfdieter Springer, Edward A Fon, Miratul Mk Muqit, Jean-François Trempe.
      Autosomal recessive mutations in the Parkin gene cause Parkinson's disease. Parkin encodes an ubiquitin E3 ligase that functions together with the kinase PINK1 in a mitochondrial quality control pathway. Parkin exists in an inactive conformation mediated by autoinhibitory domain interfaces. Thus, Parkin has become a target for the development of therapeutics that activate its ligase activity. Yet, the extent to which different regions of Parkin can be targeted for activation remained unknown. Here, we have used a rational structure-based approach to design new activating mutations in both human and rat Parkin across interdomain interfaces. Out of 31 mutations tested, we identified 11 activating mutations that all cluster near the RING0:RING2 or REP:RING1 interfaces. The activity of these mutants correlates with reduced thermal stability. Furthermore, three mutations V393D, A401D, and W403A rescue a Parkin S65A mutant, defective in mitophagy, in cell-based studies. Overall our data extend previous analysis of Parkin activation mutants and suggests that small molecules that would mimic RING0:RING2 or REP:RING1 destabilisation offer therapeutic potential for Parkinson's disease patients harbouring select Parkin mutations.
    DOI:  https://doi.org/10.26508/lsa.202201419
  19. Chem Biol Interact. 2023 Mar 21. pii: S0009-2797(23)00129-1. [Epub ahead of print] 110462
    Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease.
    Ran Duan, Chun-Gu Hong, Meng-Lu Chen, Xin Wang, Zhi-Lin Pang, Hui Xie, Zheng-Zhao Liu.
      Alzheimer's disease (AD) is a common degenerative disease among the elderly population. In addition to cognitive impairment, AD is often accompanied by behavioral manifestations. However, little attention has been paid to changes in bone metabolism and related mechanisms in patients with AD. We found that AD mice (APPswe/PS1dE9) had reduced bone density, weakened bone strength, and amyloid beta (Aβ) deposition in the bone tissue. It was further found that targeting autophagy receptors Optineurin (OPTN) and Sequestosome 1 (SQSTM1) increased bone density and bone strength in AD mice, promoted the clearance of Aβ in the bone tissue, and maintained bone homeostasis. Our study suggests that abnormal Aβ deposition may be the co-pathogenesis of AD and osteoporosis (OP). Targeting OPTN and SQSTM1 has a dual-functional effect of alleviating both AD and OP through selective autophagy that specifically targets Aβ for clearance. Therapeutic strategies targeting autophagy may help guide the treatment of patients with AD complicated with OP.
    Keywords:  Alzheimer's disease; Autophagy; OPTN; Osteoporosis; SQSTM1
    DOI:  https://doi.org/10.1016/j.cbi.2023.110462
  20. Free Radic Biol Med. 2023 Mar 18. pii: S0891-5849(23)00118-1. [Epub ahead of print]
    WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism.
    Qiuhong Xiong, Huimin Sun, Wenxiu Xing, Xin Li, Guangxin Chen, Zhonghua Zhao, Changxin Wu, Ping Li.
      Ferritin is the main iron storage protein that plays a pivotal role in the regulation of iron homeostasis. Mutations in the autophagy protein WD repeat domain 45 (WDR45) that lead to iron overload is associated with the human β-propeller protein-associated neurodegeneration (BPAN). Previous studies have demonstrated that ferritin was decreased in WDR45 deficient cells, but the mechanism remains unclear. In this study, we have demonstrated that the ferritin heavy chain (FTH) could be degraded via chaperone-mediated autophagy (CMA) in ER stress/p38-dependent pathway. In HeLa cells, inducing the ER stress activated CMA, therefore facilitated the degradation of FTH, and increased the content of Fe2+. However, the increased CMA activity and Fe2+ as well as the decreased FTH by ER stress inducer were restored by pre-treatment with p38 inhibitor. Overexpression of a mutant WDR45 activated CMA thus promoted the degradation of FTH. Furthermore, inhibition of ER stress/p38 pathway resulted in reduced activity of CMA, which consequently elevated the protein level of FTH but reduced the Fe2+ level. Our results revealed that WDR45 mutation dysregulates iron homeostasis by activating CMA, and promotes FTH degradation through ER stress/p38 signaling pathway.
    Keywords:  BPAN; Chaperone-mediated autophagy; ER stress; FTH; Iron homeostasis; WDR45; p38
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.012
  21. J Mater Chem B. 2023 Mar 22.
    Two-photon excited red-green "discoloration" bioprobes for monitoring lipid droplets and lipid droplet-lysosomal autophagy.
    Ming-Xuan Liu, Li Xu, Peng-Fei Zhu, Xin Li, Miao Shan, Wei Jin, Jing Chen, Yong Ling, Xiao-Ling Zhang.
      Lipid droplets (LDs) and their autophagy by lysosomes are closely related to a variety of physiological and pathological conditions. Therefore, identifying and tracking LDs and the dynamic process of autophagy can provide useful information for the diagnostics and treatment of related diseases. However, few organic small molecule-based fluorescent probes can specifically recognize LDs and dynamically track their autophagy process. Herein, we synthesized a "discoloration" fluorescent bioprobe DPABP-BI with distinguishable features including red fluorescence emission (630 nm), large Stokes shift (145 nm), two-photon excitation and outstanding photostability and biocompatibility. In particular, LDs could be specifically identified via the red fluorescence emission of DPABP-BI (colocalization constant of 0.98), while autophagolysosomes could be visualized via the green fluorescence emission of its acid-hydrolyzed product (colocalization constant of 0.90) to track the autophagy dynamic process. In addition, DPABP-BI enabled the specific recognition of fatty substances in zebrafish larvae. In this study, a two-photon excited red light small molecule probe was constructed to identify LDs and track their autophagy dynamic process by changing the fluorescence emission wavelength.
    DOI:  https://doi.org/10.1039/d2tb02621j
  22. Clin Sci (Lond). 2023 Mar 31. 137(6): 415-434
    Hormonal regulation of metabolism-recent lessons learned from insulin and estrogen.
    Zhipeng Tao, Zhiyong Cheng.
      Hormonal signaling plays key roles in tissue and metabolic homeostasis. Accumulated evidence has revealed a great deal of insulin and estrogen signaling pathways and their interplays in the regulation of mitochondrial, cellular remodeling, and macronutrient metabolism. Insulin signaling regulates nutrient and mitochondrial metabolism by targeting the IRS-PI3K-Akt-FoxOs signaling cascade and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERβ, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and β3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders.
    Keywords:  Insulin; autophagy; estrogen; metabolic disease; metabolism; mitochondria
    DOI:  https://doi.org/10.1042/CS20210519
  23. Autophagy Rep. 2023 ;2(1): 1-16
    Topoisomerase I poisons-induced autophagy: Cytoprotective, Cytotoxic or Non-protective.
    Ahmed M Elshazly, Polina A Wright, Jingwen Xu, David A Gewirtz.
      Topoisomerase I inhibitors represent a widely used class of antineoplastic agents that promote both single-stranded and double-stranded breaks in the DNA of tumor cells, leading to tumor cell death. Topotecan and irinotecan are the clinically relevant derivatives of the parent drug, camptothecin. As is the case with many if not most anticancer agents, irinotecan and topotecan promote autophagy. However, whether the autophagy is cytotoxic, cytoprotective, or non-protective is not clearly defined, and may depend largely upon the genetic background of the tumor cell being investigated. This review explores the available literature regarding the nature of the autophagy induced by these clinically utilized topoisomerase I inhibitors in preclinical tumor models with the goal of determining whether the targeting of autophagy might have potential as a therapeutic strategy to enhance the antitumor response and/or overcome drug resistance.
    Keywords:  Autophagy; Cytoprotective; Cytotoxic; Irinotecan; Non-protective; Topotecan
    DOI:  https://doi.org/10.1080/27694127.2022.2155904
  24. J Cell Sci. 2023 Mar 20. pii: jcs.261139. [Epub ahead of print]
    Septins and K63 chains form separate bacterial microdomains during autophagy of entrapped Shigella.
    Damián Lobato-Márquez, José Javier Conesa, Ana Teresa López-Jiménez, Michael E Divine, Jonathan N Pruneda, Serge Mostowy.
      During host cell invasion, Shigella escapes to the cytosol and polymerizes actin for cell-to-cell spread. To restrict cell-to-cell spread, host cells employ cell-autonomous immune responses including antibacterial autophagy and septin cage entrapment. How septins interact with autophagy to target Shigella to destruction is poorly understood. Here, we employed a correlative light and cryo-soft X-ray tomography (cryo-SXT) pipeline to study Shigella septin cage entrapment in its near native state. Quantitative cryo-SXT showed that Shigella fragments mitochondria and enabled visualization of X-ray dense structures (∼30 nm resolution) surrounding Shigella entrapped in septin cages. Using Airyscan confocal microscopy, we observed Lysine 63 (K63)-linked ubiquitin chains decorating septin caged entrapped Shigella. Remarkably, septins and K63 chains form separate bacterial microdomains, indicating they are recruited separately during antibacterial autophagy. Cryo-SXT and live cell imaging revealed an interaction between septins and LC3B-positive membranes during autophagy of Shigella. Together, these findings demonstrate how septin caged Shigella are targeted to autophagy and provide fundamental insights into autophagy-cytoskeleton interactions.
    Keywords:   Shigella ; Autophagy; Cryo-SXT; Cytoskeleton; Septins; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.261139
  25. J Biol Chem. 2023 Mar 17. pii: S0021-9258(23)00263-6. [Epub ahead of print] 104621
    TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy.
    Tanjing Song, Suli Lv, Xianyun Ma, Xuefeng Zhao, Li Fan, Qingli Zou, Neng Li, Yingying Yan, Wen Zhang, Lidong Sun.
      Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss-of-function of TRIM28, a multi-function protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28-TFE3-KDM6A signal axis which plays a critical role in kidney cancer cell autophagy and proliferation.
    Keywords:  KDM6A; TFE3; TRIM28; autophagy; histone methylation; kidney cancer; ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2023.104621
  26. Front Endocrinol (Lausanne). 2023 ;14 1142805
    Chinese herbal medicine and its active compounds in attenuating renal injury via regulating autophagy in diabetic kidney disease.
    Peng Liu, Wenhui Zhu, Yang Wang, Guijie Ma, Hailing Zhao, Ping Li.
      Diabetic kidney disease (DKD) is the main cause of end-stage renal disease worldwide, and there is a lack of effective treatment strategies. Autophagy is a highly conserved lysosomal degradation process that maintains homeostasis and energy balance by removing protein aggregates and damaged organelles. Increasing evidence suggests that dysregulated autophagy may contribute to glomerular and tubulointerstitial lesions in the kidney under diabetic conditions. Emerging studies have shown that Chinese herbal medicine and its active compounds may ameliorate diabetic kidney injury by regulating autophagy. In this review, we summarize that dysregulation or insufficiency of autophagy in renal cells, including podocytes, glomerular mesangial cells, and proximal tubular epithelial cells, is a key mechanism for the development of DKD, and focus on the protective effects of Chinese herbal medicine and its active compounds. Moreover, we systematically reviewed the mechanism of autophagy in DKD regulated by Chinese herb compound preparations, single herb and active compounds, so as to provide new drug candidates for clinical treatment of DKD. Finally, we also reviewed the candidate targets of Chinese herbal medicine regulating autophagy for DKD. Therefore, further research on Chinese herbal medicine with autophagy regulation and their targets is of great significance for the realization of new targeted therapies for DKD.
    Keywords:  Chinese medicine; active compounds; autophagy; diabetic kidney disease (DKD); herbal extracts
    DOI:  https://doi.org/10.3389/fendo.2023.1142805
  27. Mol Reprod Dev. 2023 Mar 21.
    Rapamycin encourages the maintenance of mitochondrial dynamic balance and mitophagy activity for improving developmental competence of blastocysts in porcine embryos in vitro.
    Hyo-Jin Park, Gyeong-Deok Heo, Seul-Gi Yang, Deog-Bon Koo.
      Rapamycin induces autophagosome formation and activity during oocyte maturation, improved fertilization ability of matured oocytes, and early embryonic developmental competence. However, potential changes in mitochondrial fission and mitophagy via regulation of autophagy in early porcine embryonic development have not been previously studied. Here, we investigated embryonic developmental ability and quality of porcine embryos 2 days after in vitro fertilization and following treatment with 1 and 10 nM rapamycin. As a results, 1 nM rapamycin exposure significantly improved (p < 0.05) blastocyst developmental competence compared to that in nontreated embryos (nontreated: 26.2 ± 5.7% vs. 1 nM rapamycin: 35.3 ± 5.1%). We observed autophagic (LC3B) and mitochondrial fission protein expression (dynamin-related protein-1 [DRP1] and pDRP1-Ser616) at the cleavage stage of 1 and 10 nM rapamycin-treated porcine embryos, using Western blot and immunofluorescence analyses. Interestingly, 1 nM rapamycin treatment significantly improved autophagy formation, mitochondrial activation, and mitochondrial fission protein levels (p < 0.05; p-DRP1 [Ser616]) at the cleavage stage of porcine embryos. Additionally, mitophagy was significantly increased in blastocysts treated with 1 nM rapamycin. In conclusion, our results suggest that rapamycin promotes blastocyst development ability in porcine embryos through mitochondrial fission, activation, and mitophagy in in vitro culture.
    Keywords:  in vitro culture; mitochondrial fission; mitophagy; porcine embryos; rapamycin
    DOI:  https://doi.org/10.1002/mrd.23681
  28. J Virol. 2023 Mar 20. e0016023
    Harnessing the Noncanonical Keap1-Nrf2 Pathway for Human Cytomegalovirus Control.
    Ayan K Ghosh, Yu-Pin Su, Michael Forman, Robert F Keyes, Brian C Smith, Xin Hu, Marc Ferrer, Ravit Arav-Boger.
      Host-derived cellular pathways can provide an unfavorable environment for virus replication. These pathways have been a subject of interest for herpesviruses, including the betaherpesvirus human cytomegalovirus (HCMV). Here, we demonstrate that a compound, ARP101, induces the noncanonical sequestosome 1 (SQSTM1)/p62-Keap1-Nrf2 pathway for HCMV suppression. ARP101 increased the levels of both LC3 II and SQSTM1/p62 and induced phosphorylation of p62 at the C-terminal domain, resulting in its increased affinity for Keap1. ARP101 treatment resulted in Nrf2 stabilization and translocation into the nucleus, binding to specific promoter sites and transcription of antioxidant enzymes under the antioxidant response element (ARE), and HCMV suppression. Knockdown of Nrf2 recovered HCMV replication following ARP101 treatment, indicating the role of the Keap1-Nrf2 axis in HCMV inhibition by ARP101. SQSTM1/p62 phosphorylation was not modulated by the mTOR kinase or casein kinase 1 or 2, indicating ARP101 engages other kinases. Together, the data uncover a novel antiviral strategy for SQSTM1/p62 through the noncanonical Keap1-Nrf2 axis. This pathway could be further exploited, including the identification of the responsible kinases, to define the biological events during HCMV replication. IMPORTANCE Antiviral treatment for human cytomegalovirus (HCMV) is limited and suffers from the selection of drug-resistant viruses. Several cellular pathways have been shown to modulate HCMV replication. The autophagy receptor sequestosome 1 (SQSTM1)/p62 has been reported to interact with several HCMV proteins, particularly with components of HCMV capsid, suggesting it plays a role in viral replication. Here, we report on a new and unexpected role for SQSTM1/p62, in HCMV suppression. Using a small-molecule probe, ARP101, we show SQSTM1/p62 phosphorylation at its C terminus domain initiates the noncanonical Keap1-Nrf2 axis, leading to transcription of genes under the antioxidant response element, resulting in HCMV inhibition in vitro. Our study highlights the dynamic nature of SQSTM1/p62 during HCMV infection and how its phosphorylation activates a new pathway that can be exploited for antiviral intervention.
    Keywords:  ARP101; SQSTM1/p62; antioxidant response element; human cytomegalovirus; noncanonical Keap1-Nrf2 pathway; p62-Keap1-Nrf2
    DOI:  https://doi.org/10.1128/jvi.00160-23
  29. FEBS J. 2023 Mar 23.
    A novel optinEuRin stress connection in glaucoma.
    Elodie Lafont, Tony Avril.
      The endoplasmic reticulum (ER) is the organelle where the production and shaping of most secreted and transmembrane proteins happens. ER function is finely regulated to prevent accumulation of misfolded proteins generating ER stress. ER stress is common in both healthy and pathological situations due to multiple intrinsic and extrinsic factors including acute demand in protein synthesis, hypoxia or impaired protein folding caused by gene mutations. Sayyad et al. found that the M98K mutation of optineurin sensitizes glaucoma retinal ganglion cells to ER stress-induced cell death. This is associated with an autophagy-dependent elevation of ER stress sensor expression.
    Keywords:  ER stress; autophagy; cell death; glaucoma; optineurin
    DOI:  https://doi.org/10.1111/febs.16774
  30. Biochem Biophys Res Commun. 2023 Mar 14. pii: S0006-291X(23)00295-4. [Epub ahead of print]656 78-85
    Arsenite-induced cytotoxicity is regulated by poly-ADP ribose polymerase 1 activation and parthanatos in p53-deficient H1299 cells: The roles of autophagy and p53.
    Keum-Young So, Seon-Hee Oh.
      Arsenic is a double-edged sword metalloid since it is both an environmental carcinogen and a chemopreventive agent. Arsenic cytotoxicity can be dependent or independent of the tumor suppressor p53. However, the effects and the underlying molecular mechanisms of arsenic cytotoxicity in p53-deficient cells are still unclear. Here, we report a distinctive cell death mode via PARP-1 activation by arsenic in p53-deficient H1299 cells. H1299 (p53-/-) cells showed higher sensitivity to sodium arsenite (NaAR) than H460 (p53+/+) cells. H460 cells induced canonical apoptosis through caspase-dependent poly-ADP ribose polymerase 1 (PARP-1) cleavage and induced the expression of phospho-p53 and p21. However, H1299 cells induced poly-ADP-ribose (PAR) polymer accumulation and caspase-independent parthanatos, which was inhibited by 3-aminobenzamide (AB) and nicotinamide (NAM). Fractionation studies revealed the mitochondrial translocation of PAR polymers and nuclear translocation of the apoptosis-inducing factor (AIF). Although the exposure of NaAR to p53-overexpressing H1299 cells increased the PAR polymer levels, it inhibited parthanatos by inducing p21 and phospho-p53 expression. LC3-II and p62 accumulated in a NaAR dose- and exposure time-dependent manner, and this accumulation was further enhanced by autophagy inhibition, indicating that arsenic inhibits autophagic flux. p53 overexpression led to a decrease in the p62 levels, an increase in the LC3-II levels, and reduced parthanatos, indicating that arsenic induces p53-dependent functional autophagy. These results show that the NaAR-induced cytotoxicity in p53-deficient H1299 cells is regulated by PARP-1 activation-mediated parthanatos, which is promoted by autophagy inhibition. This suggests that PARP-1 activation could be used as an effective therapeutic approach for arsenic toxicity in p53-deficient cells.
    Keywords:  Arsenic; Autophagy; Parthanatos; Poly-ADP polymer; Poly-ADP ribose Polymerase 1 activation; p53
    DOI:  https://doi.org/10.1016/j.bbrc.2023.03.018
  31. Anal Chem. 2023 Mar 20.
    Mitochondrial Membrane Potential Independent Near-Infrared Mitochondrial Viscosity Probes for Real-Time Tracking Mitophagy.
    Jiaxin Hong, Xiaogang Guan, Yao Chen, Xiaodong Tan, Shiya Zhang, Guoqiang Feng.
      Mitophagy is a vital cellular process playing vital roles in regulating cellular metabolism and mitochondrial quality control. Mitochondrial viscosity is a key microenvironmental index, closely associated with mitochondrial status. To monitor mitophagy and mitochondrial viscosity, three molecular rotors (Mito-1, Mito-2, and Mito-3) were developed. All probes contain a cationic quinolinium unit and a C12 chain so that they can tightly bind mitochondria and are not affected by the mitochondrial membrane potential. Optical studies showed that all probes are sensitive to viscosity changes with an off-on fluorescence response, and Mito-3 shows the best fluorescence enhancement. Bioimaging studies showed that all these probes can not only tightly locate and visualize mitochondria with near-infrared fluorescence but also effectively monitor the mitochondrial viscosity changes in cells. Moreover, Mito-3 was successfully applied to visualize the mitophagy process induced by starvation, and mitochondrial viscosity was found to show an increase during mitophagy. We expect Mito-3 to become a useful imaging tool for studying mitochondrial viscosity and mitophagy.
    DOI:  https://doi.org/10.1021/acs.analchem.2c05568
  32. Elife. 2023 03 21. pii: e83023. [Epub ahead of print]12
    A novel gene REPTOR2 activates the autophagic degradation of wing disc in pea aphid.
    Erliang Yuan, Huijuan Guo, Weiyao Chen, Bingru Du, Yingjie Mi, Zhaorui Qi, Yiyang Yuan, Keyan Zhu-Salzman, Feng Ge, Yucheng Sun.
      Wing dimorphism in insects is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between dispersing and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that, while developing normally in winged-destined pea aphids, the wing disc in wingless-destined aphids degenerated 30-hr postbirth and that this degeneration was due to autophagy rather than apoptosis. Activation of autophagy in first instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. REPTOR2, associated with TOR signaling pathway, was identified by RNA-seq as a differentially expressed gene between the two morphs with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event that occurred exclusively in pea aphids on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTOR's canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. Co-suppression of TOR and REPTOR2 showed that dsREPTOR2 could mask the positive effect of dsTOR on autophagy, suggesting that REPTOR2 acted as a key regulator downstream of TOR in the signaling pathway. These results revealed that the TOR signaling pathway suppressed autophagic degradation of the wing disc in pea aphids by negatively regulating the expression of REPTOR2.
    Keywords:  REPTOR2,; TOR; autophagy; developmental biology; developmental plasticity; evolutionary biology; pea aphid; wing disc
    DOI:  https://doi.org/10.7554/eLife.83023
  33. Clin Transl Oncol. 2023 Mar 25.
    The sequestosome 1 protein: therapeutic vulnerabilities in ovarian cancer.
    Maryam Nurzadeh, Seyedeh Mojgan Ghalandarpoor-Attar, Seyedeh Noushin Ghalandarpoor-Attar, Maryam Rabiei.
      Ovarian cancer (OC) is the most deadly tumor that may develop in a woman's reproductive system. It is also one of the most common causes of death among those who have been diagnosed with cancer in women. An adapter protein known as sequestosome 1(SQSTM1) or p62 is primarily responsible for the transportation, degradation, and destruction of a wide variety of proteins. This adapter protein works in conjunction with the autophagy process as well as the ubiquitin proteasome degradation pathway. In addition, the ability of SQSTM1 to interact with multiple binding partners link SQSTM1 to various pathways in the context of antioxidant defense system and inflammation. In this review, we outline the processes underlying the control that SQSTM1 has on these pathways and how their dysregulation contributes to the development of OC. At the final, the therapeutic approaches based on SQSTM1 targeting have been discussed.
    Keywords:  Autophagy; Cell signaling; Ovarian cancer; SQSTM1/p62; Sequestosome 1
    DOI:  https://doi.org/10.1007/s12094-023-03148-y
  34. J Inflamm Res. 2023 ;16 1045-1057
    Irisin Ameliorates PM2.5-Induced Acute Lung Injury by Regulation of Autophagy Through AMPK/mTOR Pathway.
    Jiao Ma, Zhuoxiao Han, Rui Jiao, Guanli Yuan, Cuiqing Ma, Xixin Yan, Aihong Meng.
       Background: PM2.5 exposure is one of the major inducements of various respiratory diseases and related mortality. Meanwhile, irisin, a metabolism and thermogenesis-related hormone, is found to be protective against acute lung injury induced by LPS, which indicates its therapeutic function in lung injury. However, the function and underlying mechanism of irisin in PM2.5-induced acute lung injury (ALI) are still unclear. This study is aimed to discover the potential mechanisms of irisin in PM2.5-induced acute lung injury.
    Methods: Atg5 deficient mice and cells were established to clarify the relationship between irisin and autophagy in PM2.5-induced ALI. We also used Ad-mCherry-GFP-LC3B as a monitor of autophagy flux to claim the effects of irisin on autophagy. Western blotting and qPCR were used to reveal the molecular mechanism.
    Results: As a result, PM2.5 exposure induced lung injury whereas mitigated by irisin. Moreover, PM2.5 hampered autophagy flux, characterized by accumulation of p62, and autophagosomes, as well as blocked autolysosomes. Irisin improved the disturbed autophagy flux, which was abrogated by deficiency of Atg5. Additionally, we demonstrated that irisin activated AMPK and inhibited mTOR, which indicated the enhanced autophagy. Moreover, blockage of AMPK by compound C terminated irisin's induction of autophagy in cultured MH-S cells.
    Conclusion: Our findings reveal that irisin performs protective effects against PM2.5-induced ALI by activating autophagy through AMPK/mTOR signaling pathway.
    Keywords:  PM2.5; acute lung injury; autophagy; irisin
    DOI:  https://doi.org/10.2147/JIR.S390497
  35. Nat Microbiol. 2023 Mar 23.
    ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages.
    Beren Aylan, Elliott M Bernard, Enrica Pellegrino, Laure Botella, Antony Fearns, Natalia Athanasiadi, Claudio Bussi, Pierre Santucci, Maximiliano G Gutierrez.
      Autophagy is a cellular innate-immune defence mechanism against intracellular microorganisms, including Mycobacterium tuberculosis (Mtb). How canonical and non-canonical autophagy function to control Mtb infection in phagosomes and the cytosol remains unresolved. Macrophages are the main host cell in humans for Mtb. Here we studied the contributions of canonical and non-canonical autophagy in the genetically tractable human induced pluripotent stem cell-derived macrophages (iPSDM), using a set of Mtb mutants generated in the same genetic background of the common lab strain H37Rv. We monitored replication of Mtb mutants that are either unable to trigger canonical autophagy (Mtb ΔesxBA) or reportedly unable to block non-canonical autophagy (Mtb ΔcpsA) in iPSDM lacking either ATG7 or ATG14 using single-cell high-content imaging. We report that deletion of ATG7 by CRISPR-Cas9 in iPSDM resulted in increased replication of wild-type Mtb but not of Mtb ΔesxBA or Mtb ΔcpsA. We show that deletion of ATG14 resulted in increased replication of both Mtb wild type and the mutant Mtb ΔesxBA. Using Mtb reporters and quantitative imaging, we identified a role for ATG14 in regulating fusion of phagosomes containing Mtb with lysosomes, thereby enabling intracellular bacteria restriction. We conclude that ATG7 and ATG14 are both required for restricting Mtb replication in human macrophages.
    DOI:  https://doi.org/10.1038/s41564-023-01335-9
  36. Tissue Cell. 2023 Mar 17. pii: S0040-8166(23)00061-7. [Epub ahead of print]82 102073
    BMP9 promotes autophagy and inhibits migration and invasion in breast cancer cells through the c-Myc/SNHG3/mTOR signaling axis.
    Huomei Yu, Yuanxiang Chen, Lei Lang, Deyu Liao, Shiyan Liu, Tao Yu, Kai Hu, Lan Zhou, Yan Zhang.
      We previously reported that BMP9 inhibited breast cancer progression. However, the precise molecular mechanism is still unknown. Based on our RNA-sequencing (RNA-seq) results, BMP9 significantly down-regulated the expression of long non-coding RNA SNHG3. Exogenous BMP9 promoted autophagy and inhibited migration and invasion in MDA-MB-231 cells, which was effectively blunted by SNHG3 overexpression. Interestingly, SNHG3 was negatively connected with autophagy. Knockdown of SNHG3 induced autophagy by increasing the formation of autophagic vacuoles and thus inhibited the migration and invasion of MDA-MB-231 cells. Mechanically, BMP9-SNHG3 activated AMPK, AKT and mTOR signaling pathways to induce autophagy and inhibit migration and invasion. Meanwhile, BMP9 regulated SNHG3 transcription by suppressing c-Myc entry into the nucleus. In conclusion, BMP9 promotes autophagy and inhibits migration and invasion in breast cancer cells through the c-Myc/SNHG3/mTOR signaling axis, which might offer a fresh perspective on BMP9's breast cancer-inhibiting properties.
    Keywords:  Autophagy; BMP9; Breast cancer; Invasion; Long non-coding RNA; Migration
    DOI:  https://doi.org/10.1016/j.tice.2023.102073
  37. bioRxiv. 2023 Mar 12. pii: 2023.03.11.532186. [Epub ahead of print]
    Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) is a network of eIF2 α kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk- deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
    DOI:  https://doi.org/10.1101/2023.03.11.532186
  38. iScience. 2023 Mar 17. 26(3): 106270
    MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model.
    Saba Shahin, Bin Lu, Yueqin Zhou, Hui Xu, Jason Chetsawang, Robert H Baloh, Shaomei Wang.
      Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene (MFN2 R94Q ) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of MFN2 R94Q mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in MFN2 R94Q mice. Finally, transgenic MFN1 augmentation (MFN2 R94Q :MFN1) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy.
    Keywords:  Biological sciences; Molecular neuroscience; Neuroscience; Sensory neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2023.106270
  39. Emerg Microbes Infect. 2023 Mar 23. 2195020
    Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade.
    Alexandra Pm Cloherty, Anusca G Rader, Kharishma S Patel, Jimena Perez-Vargas, Connor Ah Thompson, Siobhan Ennis, Masahiro Niikura, Manon E Wildenberg, Vanesa Muncan, Renée Rce Schreurs, François Jean, Carla Ms Ribeiro.
      SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory clearance. Despite global vaccination and existing antiviral treatments, variants of concern are still emerging and circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies and demonstrate an increased preference for entry via the endocytic entry route. Alternative to direct-acting antivirals, host-directed therapies interfere with host mechanisms hijacked by viruses, and enhance cell-mediated resistance with a reduced likelihood of drug resistance development. Here, we demonstrate that the autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents SARS-CoV-2 acquisition by human intestinal epithelial cells via an autophagy-mediated BNIP3 mechanism. Strikingly, berbamine dihydrochloride exhibited pan-antiviral activity against Omicron subvariants BA.2 and BA.5 at nanomolar potency, providing a proof of concept for the potential for targeting autophagy machinery to thwart infection of current circulating SARS-CoV-2 subvariants. Furthermore, we show that autophagy-blocking therapies limited virus-induced damage to intestinal barrier function, affirming the therapeutic relevance of autophagy manipulation to avert the intestinal permeability associated with acute COVID-19 and post-COVID-19 syndrome. Our findings underscore that SARS-CoV-2 exploits host autophagy machinery for intestinal dissemination and indicate that repurposed autophagy-based antivirals represent a pertinent therapeutic option to boost protection and ameliorate disease pathogenesis against current and future SARS-CoV-2 variants of concern.
    Keywords:  Viral entry routes / Drug repurposing / Extrapulmonary COVID-19 / Host-directed antiviral therapy Autophagy
    DOI:  https://doi.org/10.1080/22221751.2023.2195020
  40. Cell Death Dis. 2023 Mar 22. 14(3): 206
    Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson's disease.
    Rebeka Popovic, Amrita Mukherjee, Nuno Santos Leal, Lydia Morris, Yizhou Yu, Samantha H Y Loh, L Miguel Martins.
      Parkinson's disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
    DOI:  https://doi.org/10.1038/s41419-023-05729-9
  41. Biomed Pharmacother. 2022 Oct;pii: S0753-3322(22)00992-1. [Epub ahead of print]154 113603
    Astragaloside trigger autophagy: Implication a potential therapeutic strategy for pulmonary fibrosis.
    Jing-Ze Yu, Jing Wen, Yi Ying, Wen Yin, Si-Qi Zhang, Wen-Ling Pang, Cui Wang, Yao Bian, Jia-Li Yuan, Jin-Yuan Yan, Zhong-Shan Yang.
      Pulmonary fibrosis is an abnormal wound-healing response to repeated alveolar injury, characterized by continuous inflammation and abnormal collagen deposition. Its treatment is problematic. Astragaloside (AST) is an active component of Astragalus membranaceus with anti-inflammatory and anti-tumor properties. Although the underlying mechanisms are unknown, AST is also used to treat fibrotic diseases. This study aimed to investigate the mechanisms of action of AST in pulmonary fibrosis treatment. We found that AST significantly improved restrictive ventilatory impairment, compliance, total lung capacity, and functional residual capacity. In mice with pulmonary fibrosis, extracellular matrix deposition in the pulmonary parenchyma and intemperate inflammation were reversed. This therapeutic effect can be attributed to autophagy, activating the genes for autophagy flux and autophagic vacuoles. Impaired autophagy increased susceptibility to pulmonary fibrosis by exacerbating collagen deposition in vitro and in vivo. Using a combination of molecular docking and network pharmacology, the Ras/Raf/MEK/ERK signaling pathway was identified as a possible candidate for the pharmacologic target of AST. Functional dephosphorylation of MEK and ERK inhibited the Ras/Raf/MEK/ERK signaling pathway, which converges at the rapamycin switch to initiate autophagy. Inhibitors of Ras and MEK regulated autophagy. These findings suggest that AST might treat pulmonary fibrosis by modulating the Ras/Raf/MEK/ERK signaling pathway mediated by depression.
    Keywords:  Astragaloside; Autophagy; Extracellular matrix; Pulmonary fibrosis; Ras/Raf/MEK/ERK signaling pathway
    DOI:  https://doi.org/10.1016/j.biopha.2022.113603
  42. Development. 2023 03 15. pii: dev201035. [Epub ahead of print]150(6):
    A proinsulin-dependent interaction between ENPL-1 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.
    Agnieszka Podraza-Farhanieh, Dorota Raj, Gautam Kao, Peter Naredi.
      Neuropeptides, including insulin, are important regulators of physiological functions of the organisms. Trafficking through the Golgi is crucial for the regulation of secretion of insulin-like peptides. ASNA-1 (TRC40) and ENPL-1 (GRP94) are conserved insulin secretion regulators in Caenorhabditis elegans (and mammals), and mouse Grp94 mutants display type 2 diabetes. ENPL-1/GRP94 binds proinsulin and regulates proinsulin levels in C. elegans and mammalian cells. Here, we have found that ASNA-1 and ENPL-1 cooperate to regulate insulin secretion in worms via a physical interaction that is independent of the insulin-binding site of ENPL-1. The interaction occurs in DAF-28/insulin-expressing neurons and is sensitive to changes in DAF-28 pro-peptide levels. Consistently, ASNA-1 acted in neurons to promote DAF-28/insulin secretion. The chaperone form of ASNA-1 was likely the interaction partner of ENPL-1. Loss of asna-1 disrupted Golgi trafficking pathways. ASNA-1 localization to the Golgi was affected in enpl-1 mutants and ENPL-1 overexpression partially bypassed the ASNA-1 requirement. Taken together, we find a functional interaction between ENPL-1 and ASNA-1 that is necessary to maintain proper insulin secretion in C. elegans and provides insights into how their loss might cause diabetes in mammals.
    Keywords:  Diabetes; ER chaperone; Insulin signaling
    DOI:  https://doi.org/10.1242/dev.201035
  43. ACS Chem Biol. 2023 Mar 22.
    PROTAC-Mediated Selective Degradation of Cytosolic Soluble Epoxide Hydrolase Enhances ER Stress Reduction.
    Yuxin Wang, Christophe Morisseau, Akihiro Takamura, Debin Wan, Dongyang Li, Simone Sidoli, Jun Yang, Dennis W Wolan, Bruce D Hammock, Seiya Kitamura.
      Soluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTAC small-molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. Remarkably, our sEH PROTAC molecule has higher potency in cellular assays compared to the parent sEH inhibitor as measured by the significantly reduced ER stress. Interestingly, our mechanistic data indicate that our PROTAC directs the degradation of cytosolic sEH via the lysosome, not through the proteasome. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof of concept for the superior cellular potency of sEH degradation over sEH enzymatic inhibition, as well as subcellular compartment-selective modulation of a protein by PROTACs.
    DOI:  https://doi.org/10.1021/acschembio.3c00017
  44. bioRxiv. 2023 Mar 09. pii: 2023.03.08.531792. [Epub ahead of print]
    RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
    Francesco Scavone, Samantha C Gumbin, Paul A DaRosa, Ron R Kopito.
      Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.
    Significance Statement: UFM1 is a ubiquitin-like protein that is selectively conjugated to the large (60S) subunit of ribosomes bound to the endoplasmic reticulum (ER), but the specific biological function of this modification is unclear. Here, we show that UFMylation facilitates proteasome-mediated degradation of arrest polypeptides (APs) which are generated following splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER. We propose that UFMylation weakens the tightly sealed ribosome-translocon junction, thereby allowing the cytosolic ubiquitin-proteasome and ribosome-associated quality control machineries to access ER-APs.
    DOI:  https://doi.org/10.1101/2023.03.08.531792
  45. Biotechnol Genet Eng Rev. 2023 Mar 22. 1-16
    Circadian gene CLOCK accelerates atherosclerosis by promoting endothelial autophagy.
    Chen Wang, Xiaohu Yang, Zhenyu Guo, Guanglang Zhu, Longhua Fan.
      Atherosclerosis (AS) is a chronic inflammatory disease which gives rise to life-threatening complications like ischemic stroke. Rupture of carotid atherosclerotic plaque is the main cause of ischemic stroke. Emerging evidence has demonstrated that disturbed circadian rhythms could accelerate the progression of atherosclerosis by regulating endothelial function. Moreover, our previous study implicated the circadian gene circadian locomotor output cycles kaput (CLOCK) in the pathogenesis of unstable plaques. In this study, we explored the underlying mechanism that CLOCK mediates endothelial cell autophagy involved in the progression of AS. Circadian and autophagy gene expression was analyzed in the GSE41571 dataset and human carotid atherosclerotic plaque samples. Then we used ox-LDL to treat HUVECs, and analyzed CLOCK and autophagy gene in endothelial cells. Besides that, we comprehensively analyzed in vivo experiments to explore the function of CLOCK in autophagy and atherosclerosis using different staining including HE, MT and IF staining. In the dataset and patient samples, CLOCK expression and autophagy were decreased in the unstable plaque group compared with the stable group. Decreased Beclin1, ATG5, LC3, and CLOCK were also observed in HUVECs under oxidative stress condition which also enhances cell proliferation. In vivo, we also found decreasing level of CLOCK, Beclin1, LC3 and ATG5 in ApoE-/- mice compared with WT mice. Silencing of CLOCK in ApoE-/- mice may further aggravate atherosclerosis including decreased cap thickness and collagens. Our findings implicated that downregulation CLOCK would impair endothelial cell autophagy and accelerate atherosclerotic plaque, which provides a novel strategy for treatment of progression in AS.
    Keywords:  Autophagy; CLOCK; atherosclerosis; endothelial cell; plaque stability
    DOI:  https://doi.org/10.1080/02648725.2023.2193061
  46. Cancer Sci. 2023 Mar 23.
    AKR7A3 modulates the metastasis of pancreatic ductal adenocarcinoma through regulating PHGDH-suppressed autophagy.
    Lei Hua, Yang Song, Jie Min, Ronglin Wang, Hong Li, Liaoliao Zhu, Yongdong Guo, Dongxue Gan, Shanshan Li, Peixiang Ma, Cheng Yang, Jing Yang, Jingjie Shi, Junqiang Li, Haichuan Su.
      AKR7A3 is a member of Aldo-Keto Reductase(AKR) protein family whose primary purpose is to reduce aldehydes and ketones to generate primary and secondary alcohols. It has been reported that AKR7A3 is downregulated in pancreatic cancer (PC). However, the mechanism underlying the effects of AKR7A3 in PC remains largely unclarified. Here, we explored the biological function, molecular mechanism and clinical relevance of AKR7A3 in pancreatic ductal adenocarcinoma (PDAC). AKR7A3 expression was downregulated in PDAC compared to adjacent normal tissues, and the lower AKR7A3 expression was related to poor prognosis. In addition, our results demonstrated that AKR7A3 could be a potential diagnostic marker for PDAC, especially in the early stages. Knockdown of AKR7A3 promoted PDAC progression and chemoresistance, while inhibiting the autophagy flux. Mechanistically, AKR7A3 affected the metastatic, autophagy and chemoresistance of PDAC by regulating PHGDH. Overall, the present study suggests that AKR7A3 inhibits PDAC progression by regulating PHGDH-induced autophagy. In addition, AKR7A3 inhibits chemoresistance via regulating PHGDH, and may serve as a new therapeutic target for PDAC.
    Keywords:  Autophagy,AKR7A3,PHGDH; Pancreatic ductal adenocarcinoma; Progression
    DOI:  https://doi.org/10.1111/cas.15798
  47. CNS Neurol Disord Drug Targets. 2023 Mar 20.
    Curbing Rhes Actions: Mechanism-Based Molecular Target for Huntington's Disease and Tauopathies.
    Srinivasa Subramaniam, Siddaraju Boregowda.
      A highly interconnected network of diverse brain regions is necessary for the precise execution of human behaviors, including cognitive, psychiatric, and motor functions. Unfortunately, degeneration of specific brain regions causes several neurodegenerative disorders, but the mechanisms that elicit selective neuronal vulnerability remain unclear. This knowledge gap greatly hinders the development of effective mechanism-based therapies, despite the desperate need for new treatments. Here, we emphasize the importance of the Rhes (Ras homolog-enriched in the striatum) protein as an emerging therapeutic target. Rhes, an atypical small GTPase with a SUMO (small ubiquitin-like modifier) E3-ligase activity, modulates biological processes such as dopaminergic transmission, alters gene expression, and acts as an inhibitor of motor stimuli in the brain striatum. Mutations in the Rhes gene have also been identified in patients with autism and schizophrenia. Moreover, Rhes SUMOylates pathogenic form of mutant huntingtin (mHTT) and tau, enhancing their solubility and cell toxicity in Huntington's disease and tauopathy models. Notably, Rhes uses membrane projections resembling tunneling nanotubes to transport mHTT between cells and Rhes deletion diminishes mHTT spread in the brain. Thus, we predict that effective strategies aimed at diminishing brain Rhes levels will prevent or minimize the abnormalities that occur in HD and tauopathies and potentially in other brain disorders. We review the emerging technologies that enable specific targeting of Rhes in the brain to develop effective disease-modifying therapeutics.
    Keywords:  CNS drugs; SUMO; autophagy; brain disease; dual target; neurodegeneration; neuronal vulnerability; rationale therapy; tunneling nanotubes
    DOI:  https://doi.org/10.2174/1871527322666230320103518
  48. Med Oncol. 2023 Mar 20. 40(4): 121
    Small molecule '4ab' induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions.
    Sameer Ullah Khan, Kaneez Fatima, Umed Singh, Parvinder Paul Singh, Fayaz Malik.
      Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.
    Keywords:  Apoptosis; Autophagy; Endoplasmic reticulum; Metastasis; Paraptosis; Triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s12032-023-01963-5
  49. Biomed Pharmacother. 2023 Mar 18. pii: S0753-3322(23)00348-7. [Epub ahead of print]161 114560
    Inhibition of autophagy in macrophage promotes IL-1β-mediated hepatocellular carcinoma progression via inflammasome accumulation and self-recruitment.
    Zheng Gao, Shan-Ru Feng, Jia-Feng Chen, Xiao-Gang Li, Ying-Hong Shi, Zheng Tang, Wei-Ren Liu, Xin Zhang, Ao Huang, Xuan-Ming Luo, Hai-Ying Zeng, Qiang Gao, Guo-Ming Shi, Ai-Wu Ke, Jian Zhou, Jia Fan, Xiu-Tao Fu, Zhen-Bin Ding.
      Hepatocellular carcinoma (HCC) has a complex and changeable tumor microenvironment. Despite emerging evidence focusing on autophagy process within immune cells, the function and regulatory mechanism of macrophage autophagy in tumor progression remains unclear. Our results of multiplex-immunohistochemistry and RNA-sequencing identified the reduced levels of autophagy in tumor macrophages in the HCC microenvironment, associated with a poor prognosis and increased microvascular metastasis in HCC patients. Specifically, HCC suppressed the macrophage autophagy initiation through the up-regulation of mTOR and ULK1 phosphorylation at Ser757. Knockdown of autophagy-related proteins to further inhibit autophagy significantly boosted the metastatic potential of HCC. Mechanistically, the accumulation of NLRP3 inflammasome mediated by autophagy inhibition promoted the cleavage, maturation, and release of IL-1β, which facilitated the HCC progression, eventually accelerating HCC metastasis via the epithelial-mesenchymal transition. Autophagy inhibition provoked macrophage self-recruitment through the CCL20-CCR6 signaling was also a crucial account of HCC progression. Recruited macrophages mediated the cascade amplification of IL-1β and CCL20 to form a novel pro-metastatic positive feedback loop through promoting HCC metastasis and increased macrophage recruitment, respectively. Notably, targeting IL-1β/IL-1 receptor signaling impaired lung metastasis induced by macrophage autophagy inhibition in a mice HCC lung metastasis model. In summary, this study highlighted that inhibition of tumor macrophage autophagy facilitated HCC progression by increasing IL-1β secretion via NLRP3 inflammasome accumulation and by macrophage self-recruitment through the CCL20 signaling pathway. Interruption of this metastasis-promoting loop by IL-1β blockade may provide a promising therapeutic strategy for HCC patients.
    Keywords:  Cancer therapy; Cytokines; Hepatocellular carcinoma; Macroautophagy; Macrophage; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.biopha.2023.114560
  50. Front Pharmacol. 2023 ;14 1092473
    EGCG identified as an autophagy inducer for rosacea therapy.
    Lei Zhou, Yun Zhong, Yaling Wang, Zhili Deng, Yingxue Huang, Qian Wang, Hongfu Xie, Yiya Zhang, Ji Li.
      Background: Rosacea is a common facial skin inflammatory disease featured by hyperactivation of mTORC1 signaling in the epidermis. Due to unclear pathogenesis, the effective treatment options for rosacea remain limited. Methods: Weighted gene co-expression network analysis (WGCNA) analyzed the relationship between epidermis autophagy and mTOR pathways in rosacea, and further demonstrated it through immunofluorescence and qPCR analysis. A potential therapeutic agent for rosacea was predicted based on the key genes of the WGCNA module. In vivo and in vitro experiments were conducted to verify its therapeutic role. Drug-target prediction (TargetNet, Swiss, and Tcmsp) and molecular docking offered potential pharmacological targets. Results: WGCNA showed that epidermis autophagy was related to the activation of mTOR pathways in rosacea. Next, autophagy was downregulated in the epidermis of rosacea, which was regulated by mTOR. In addition, the in vivo experiment demonstrated that autophagy induction could be an effective treatment strategy for rosacea. Subsequently, based on the key genes of the WGCNA module, epigallocatechin-3-gallate (EGCG) was predicted as a potential therapeutic agent for rosacea. Furthermore, the therapeutic role of EGCG on rosacea was confirmed in vivo and in vitro. Finally, drug-target prediction and molecular docking revealed that AKT1/MAPK1/MMP9 could be the pharmacological targets of EGCG in rosacea. Conclusion: Collectively, our findings revealed the vital role of autophagy in rosacea and identified that EGCG, as a therapeutic agent for rosacea, attenuated rosacea-like inflammation via inducing autophagy in keratinocytes.
    Keywords:  EGCG; autophagy; mTOR; rosacea; skin inflammation
    DOI:  https://doi.org/10.3389/fphar.2023.1092473
  51. Biomed Pharmacother. 2023 Mar 20. pii: S0753-3322(23)00121-X. [Epub ahead of print]161 114333
    Autophagy inhibition and ferroptosis activation during atherosclerosis: Hypoxia-inducible factor 1α inhibitor PX-478 alleviates atherosclerosis by inducing autophagy and suppressing ferroptosis in macrophages.
    Guofu Hu, Zihui Yuan, Jian Wang.
       OBJECTIVE: To elucidate the key regulator responsible for autophagy and ferroptosis, and if specific pharmacological inhibitor of upregulated gene exerted the pro-autophagic and anti-ferroptotic effect on macrophage to alleviate the atherosclerosis.
    METHODS: Autophagy and ferroptosis were evaluated in atherosclerotic lesions and THP-1 macrophages exposed to ox-LDL. Autophagy/ferroptosis-related differentially expressed genes (DEGs) in atherosclerosis were identified by bioinformatic analysis of GSE97210 dataset, and were validated in atherosclerotic cells and tissues. The efficacy and mechanism of pharmacological inhibition of the validated DEGs on alleviating atherosclerosis were explored in vivo and in vitro.
    RESULTS: Atherosclerotic lesions were characterized by autophagy inhibition and ferroptosis activation in macrophages. The crosslink between autophagy and ferroptosis were demonstrated. Ox-LDL induced THP-1 macrophage foam cell formation, autophagy dysfunction, and ferroptosis occurrence. Rapamycin ameliorated and, conversely, erastin deteriorated the effect of ox-LDL on THP-1 macrophages. Eleven autophagy/ferroptosis-related DEGs were identified in atherosclerosis vs. normal. The up-regulated expression of HIF-1α was verified in atherosclerotic lesions and THP-1 macrophages induced by ox-LDL. HIF-1α inhibitor PX-478 restored autophagy function, depressed ferroptosis, and reduced lipid accumulation in ox-LDL induced THP-1 macrophage. Autophagy inhibitor 3-MA obviously abrogated the pro-autophagic, anti-ferroptotic, and anti-atherosclerotic effects of PX-478. PX-478 treatment down-regulated HIF-1α expression and reduced atherosclerotic plaques in the mice model.
    CONCLUSIONS: Autophagy is inhibited, ferroptosis is activated, and crosslink occurs between autophagy and ferroptosis during atherosclerosis. HIF-1α, an upregulated DEG between atherosclerosis and normal, co-regulates autophagy and ferroptosis. HIF-1α inhibitor PX-478 attenuates foam cell formation and lessens atherosclerosis by enhancing autophagy and depressing ferroptosis in macrophages.
    Keywords:  Atherosclerosis; Autophagy; Ferroptosis; HIF-1α; Macrophages; PX-478
    DOI:  https://doi.org/10.1016/j.biopha.2023.114333
  52. Front Neurosci. 2023 ;17 1128087
    Targeting autophagy process in center nervous trauma.
    Shanshan Wei, Bing Leng, Genquan Yan.
      The central nervous system (CNS) is the primary regulator of physiological activity, and when CNS is compromised, its physical functions are affected. Spinal cord injury (SCI) and traumatic brain injury (TBI) are common trauma in CNS that are difficult to recover from, with a higher global disability and mortality rate. Autophagy is familiar to almost all researchers due to its role in regulating the degradation and recycling of cellular defective or incorrect proteins and toxic components, maintaining body balance and regulating cell health and function. Emerging evidence suggests it has a broad and long-lasting impact on pathophysiological process such as oxidative stress, inflammation, apoptosis, and angiogenesis, involving the alteration of autophagy marker expression and function recovery. Changes in autophagy level are considered a potential therapeutic strategy and have shown promising results in preclinical studies for neuroprotection following traumatic brain injury. However, the relationship between upward or downward autophagy and functional recovery following SCI or TBI is debatable. This article reviews the regulation and role of autophagy in repairing CNS trauma and the intervention effects of autophagy-targeted therapeutic agents to find more and better treatment options for SCI and TBI patients.
    Keywords:  autophagy; autophagy flux; central nervous trauma; spinal cord injury (SCI); traumatic brain injury (TBI)
    DOI:  https://doi.org/10.3389/fnins.2023.1128087
  53. Cell Mol Neurobiol. 2023 Mar 23.
    Crosstalk Between Autophagy and Inflammation in Chronic Cerebral Ischaemia.
    Hai-Qian Zhou, Li-Mei Zhang, Xiao Li, Zhi-Hua Huang.
      Chronic cerebral ischaemia (CCI) is a high-incidence cardiovascular and cerebrovascular disease that is very common in clinical practice. Although many pathogenic mechanisms have been explored, there is still great controversy among neuroscientists regarding the pathogenesis of CCI. Therefore, it is important to elucidate the mechanisms of CCI occurrence and progression for the prevention and treatment of ischaemic cerebrovascular disorders. Autophagy and inflammation play vital roles in CCI, but the relationship between these two processes in this disease remains unknown. Here, we review the progression and discuss the functions, actions and pathways of autophagy and inflammation in CCI, including a comprehensive view of the transition from acute disease to CCI through ischaemic repair mechanisms. This review may provide a reference for future research and treatment of CCI. Schematic diagram of the interplay between autophagy and inflammation in CCI. CCI lead to serious, life-threatening complications. This review summarizes two factors in CCI, including autophagy and inflammation, which have been focused for the mechanisms of CCI. In short, the possible points of intersection are shown in the illustration. CCI, Chronic cerebral ischaemia; ER stress, Endoplasmic reticulum stress; ROS, Reactive oxygen species.
    Keywords:  Autophagy; Chronic cerebral ischaemia; Inflammation
    DOI:  https://doi.org/10.1007/s10571-023-01336-6
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