The Pharmacology of Lysosome

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 6034

Special Issue Editors

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Interests: autophagy; molecular pharmacology; drug screening; lysosome biology
School of Basic Medical Sciences, Guangzhou Medical University, Guang Yi Da Dao, Xinzao Road, Panyu Disdrict, Guangzhou 511436, China
Interests: autophagy; mitophagy; lysosome; membrane trafficking; pharmacology
International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Guangzhou 510006, China
Interests: autophagy; lysosomal biogenesis; mitochondrial dynamics; ER homeostasis; cell death

Special Issue Information

Dear Colleagues,

Autophagy is a well-known lysosome-dependent pathway for protein degradation. Chemicals targeting autophagy–lysosome processes represent an efficient therapy strategy for various diseases. Lysosomes are major organelles that contain high levels of hydrolytic enzymes needed to integrate and digest materials compartmentalized by endocytosis, phagocytosis, or autophagy which serve as a cellular recycling center. The disturbance of lysosome function leads to defective vesicle trafficking, impaired autophagy, and various diseases (such as neurodegeneration, lysosomal storage disorders, and cancer) by interrupting ionic exchange and accumulating toxic materials (such as amyloid beta inside lysosomes). Thus, autophagy- and lysosome-modulating drugs may ameliorate such cell abnormalities.

Treatment with pharmacological agents targeting lysosome and autophagy pathway is becoming a promising strategy for cancer and neurodegenerative disorders therapy. A demonstration of how these drugs regulate autophagy–lysosome pathways, such as autophagosome–lysosome fusion, lysosomal degradation function, lysophagy, lysosome biogenesis, and lysosomal cell death, is urgently needed. In this Special Issue, any studies on the pharmacology of lysosomes regulated by drugs for disease therapy are welcome.

Dr. Min Li
Dr. Du Feng
Dr. Shaogui Wang
Guest Editors

Manuscript Submission Information

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Keywords

  • autophagy
  • cell death
  • lysosome dysfunction
  • drug–lysosome interaction
  • lysosome enzyme
  • lysosomal membrane
  • pharmacology
  • lysophagy
  • drug discovery

Published Papers (3 papers)

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Research

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16 pages, 7173 KiB  
Article
ATL I, Acts as a SIRT6 Activator to Alleviate Hepatic Steatosis in Mice via Suppression of NLRP3 Inflammasome Formation
by Danli Kong, Zhenhua Mai, Yongze Chen, Ling Luo, Hao Liu, Le Zhao, Ruixian Huang, Shuang Wang, Rong Chen, Hao Zhou, Hao Chen, Jingjing Zhang, Haibing Yu and Yuanlin Ding
Pharmaceuticals 2022, 15(12), 1526; https://doi.org/10.3390/ph15121526 - 08 Dec 2022
Cited by 1 | Viewed by 1486
Abstract
Accumulating evidence has highlighted that sirtuin-6 (SIRT6) plays an important role in hepatic gluconeogenesis and lipogenesis. We aim to investigate the underlying mechanisms and pharmacological interventions of SIRT6 on hepatic steatosis treatment. Herein, our results showed that atractylenolide I (ATL I) activated the [...] Read more.
Accumulating evidence has highlighted that sirtuin-6 (SIRT6) plays an important role in hepatic gluconeogenesis and lipogenesis. We aim to investigate the underlying mechanisms and pharmacological interventions of SIRT6 on hepatic steatosis treatment. Herein, our results showed that atractylenolide I (ATL I) activated the deacetylase activity of SIRT6 to promote peroxisome proliferator-activated receptor alpha (PPARα) transcription and translation, while suppressing nuclear factor NF-kappa-B (NFκB)-induced NACHT, LRR, and PYD domains containing protein 3 (NLRP3) inflammasome formation. Together, these decreased the infiltration of F4/80 and CD11B positive macrophages, accompanied by decreased mRNA expression and serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL6), and interleukin-1 beta (IL1β). Additionally, these changes decreased sterol regulatory element-binding protein-1c (SREBP-1c) expression, while restoring carnitine O-palmitoyltransferase 1a (Cpt1a) expression, to decrease the size of adipocytes and adipose deposition, which, in turn, reversed high-fat diet (HFD)-induced liver weight and body weight accumulation in C57 mice. SIRT6 knockout or hepatic SIRT6 knockout in C57 mice largely abolished the effect of ATL I on ameliorating hepatic steatosis. Taken together, our results suggest that ATL I acts as a promising compound that activates SIRT6/PPARα signaling and attenuates the NLRP3 inflammasome to ameliorate hepatic inflammation and steatosis. Full article
(This article belongs to the Special Issue The Pharmacology of Lysosome)
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23 pages, 8744 KiB  
Article
Toosendanin Induces Hepatocyte Damage by Inhibiting Autophagic Flux via TFEB-Mediated Lysosomal Dysfunction
by Li Luo, Yonghong Liang, Yuanyuan Fu, Zhiyuan Liang, Jinfen Zheng, Jie Lan, Feihai Shen and Zhiying Huang
Pharmaceuticals 2022, 15(12), 1509; https://doi.org/10.3390/ph15121509 - 03 Dec 2022
Cited by 4 | Viewed by 1363
Abstract
Toosendanin (TSN) is a triterpenoid from the fruit or bark of Melia toosendan Sieb et Zucc, which has clear antitumor and insecticidal activities, but it possesses limiting hepatotoxicity in clinical application. Autophagy is a degradation and recycling mechanism to maintain cellular homeostasis, and [...] Read more.
Toosendanin (TSN) is a triterpenoid from the fruit or bark of Melia toosendan Sieb et Zucc, which has clear antitumor and insecticidal activities, but it possesses limiting hepatotoxicity in clinical application. Autophagy is a degradation and recycling mechanism to maintain cellular homeostasis, and it also plays an essential role in TSN-induced hepatotoxicity. Nevertheless, the specific mechanism of TSN on autophagy-related hepatotoxicity is still unknown. The hepatotoxicity of TSN in vivo and in vitro was explored in this study. It was found that TSN induced the upregulation of the autophagy-marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) and P62, the accumulation of autolysosomes, and the inhibition of autophagic flux. The middle and late stages of autophagy were mainly studied. The data showed that TSN did not affect the fusion of autophagosomes and lysosomes but significantly inhibited the acidity, the degradation capacity of lysosomes, and the expression of hydrolase cathepsin B (CTSB). The activation of autophagy could alleviate TSN-induced hepatocyte damage. TSN inhibited the expression of transcription factor EB (TFEB), which is a key transcription factor for many genes of autophagy and lysosomes, such as CTSB, and overexpression of TFEB alleviated the autophagic flux blockade caused by TSN. In summary, TSN caused hepatotoxicity by inhibiting TFEB-lysosome-mediated autophagic flux and activating autophagy by rapamycin (Rapa), which could effectively alleviate TSN-induced hepatotoxicity, indicating that targeting autophagy is a new strategy to intervene in the hepatotoxicity of TSN. Full article
(This article belongs to the Special Issue The Pharmacology of Lysosome)
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Review

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21 pages, 1686 KiB  
Review
Advances in Drug Discovery Targeting Lysosomal Membrane Proteins
by Hongna Wang, Yidong Zhu, Huiyan Liu, Tianxiang Liang and Yongjie Wei
Pharmaceuticals 2023, 16(4), 601; https://doi.org/10.3390/ph16040601 - 17 Apr 2023
Cited by 2 | Viewed by 2357
Abstract
Lysosomes are essential organelles of eukaryotic cells and are responsible for various cellular functions, including endocytic degradation, extracellular secretion, and signal transduction. There are dozens of proteins localized to the lysosomal membrane that control the transport of ions and substances across the membrane [...] Read more.
Lysosomes are essential organelles of eukaryotic cells and are responsible for various cellular functions, including endocytic degradation, extracellular secretion, and signal transduction. There are dozens of proteins localized to the lysosomal membrane that control the transport of ions and substances across the membrane and are integral to lysosomal function. Mutations or aberrant expression of these proteins trigger a variety of disorders, making them attractive targets for drug development for lysosomal disorder-related diseases. However, breakthroughs in R&D still await a deeper understanding of the underlying mechanisms and processes of how abnormalities in these membrane proteins induce related diseases. In this article, we summarize the current progress, challenges, and prospects for developing therapeutics targeting lysosomal membrane proteins for the treatment of lysosomal-associated diseases. Full article
(This article belongs to the Special Issue The Pharmacology of Lysosome)
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