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Article: Lysosomal TRPML1 Channel: Implications in Cardiovascular and Kidney Diseases.

Li, Guangbi / Li, Pin-Lan

Advances in experimental medicine and biology

2022 Volume 1349, Page(s) 275–301

Abstract: Lysosomal ion channels mediate ion flux from lysosomes and regulate membrane potential across the lysosomal membrane, which are essential for lysosome biogenesis, nutrient sensing, lysosome trafficking, lysosome enzyme activity, and cell membrane repair. ...

Abstract	Lysosomal ion channels mediate ion flux from lysosomes and regulate membrane potential across the lysosomal membrane, which are essential for lysosome biogenesis, nutrient sensing, lysosome trafficking, lysosome enzyme activity, and cell membrane repair. As a cation channel, the transient receptor potential mucolipin 1 (TRPML1) channel is mainly expressed on lysosomes and late endosomes. Recently, the normal function of TRPML1 channels has been demonstrated to be important for the maintenance of cardiovascular and renal glomerular homeostasis and thereby involved in the pathogenesis of some cardiovascular and kidney diseases. In arterial myocytes, it has been found that Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP), an intracellular second messenger, can induce Ca
MeSH term(s)	Calcium/metabolism ; Cardiovascular System/metabolism ; Humans ; Kidney Diseases ; Lysosomes/metabolism ; Sarcoplasmic Reticulum/metabolism ; Transient Receptor Potential Channels/genetics
Chemical Substances	Transient Receptor Potential Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-02-09
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-981-16-4254-8_13
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Article ; Online: Lysosome Function in Cardiovascular Diseases.

Bhat, Owais M / Li, Pin-Lan

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2021 Volume 55, Issue 3, Page(s) 277–300

Abstract: The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as ... ...

Abstract	The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.
MeSH term(s)	Animals ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Lysosomes/metabolism ; Lysosomes/pathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Sphingolipids/metabolism
Chemical Substances	Sphingolipids
Language	English
Publishing date	2021-05-19
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000373
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Article ; Online: Cardiovascular pathobiology of inflammasomes: inflammatory machinery and beyond.

Li, Pin-Lan

Antioxidants & redox signaling

2015 Volume 22, Issue 13, Page(s) 1079–1083

Abstract: Significance: In response to infection or cellular stress, inflammasomes are assembled and activated to mediate host defense and to initiate or promote the development of different diseases, in particular, autoinflammatory diseases and chronic ... ...

Abstract	Significance: In response to infection or cellular stress, inflammasomes are assembled and activated to mediate host defense and to initiate or promote the development of different diseases, in particular, autoinflammatory diseases and chronic degenerative diseases. Understanding of inflammasomes and related physiological and pathological relevance to the cardiovascular system will open a new chapter on the pathogenesis of inflammation and related diseases and will help develop novel therapeutic strategies for prevention or treatment of cardiovascular diseases. Recent advances: The inflammasome, in particular the nucleotide oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, has been recently recognized as a fundamental mechanism to mediate or promote the pathogenesis of degenerative diseases. Some important mechanisms responsible for NLRP3 inflammasome activation have been proposed and many molecular targets associated with this inflammasome activation are shown to be the possible candidates of therapeutic targets for treatment of cardiovascular diseases. Critical issues: The concepts that NLRP3 inflammasome activation occurs just in immune cells or phagocytes and that its role is only for the inflammatory progression of cardiovascular diseases are oversimplified. A large body of other cell types are capable of NLRP3 inflammasome activation, and many uncanonical effects of this inflammasome may also be implicated in the development of cardiovascular diseases, which are discussed in a great detail by this Forum. Future directions: More mechanistic and translational studies will rapidly widen the horizon of knowledge on NLRP3 inflammasome activation and regulation, which may help develop novel effective therapeutic strategies to target this inflammasome for treatment or prevention of cardiovascular diseases.
MeSH term(s)	Cardiovascular System/immunology ; Cardiovascular System/metabolism ; Cardiovascular System/pathology ; Carrier Proteins/metabolism ; Humans ; Inflammasomes/immunology ; Inflammasomes/metabolism ; Inflammation/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein
Chemical Substances	Carrier Proteins ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human
Language	English
Publishing date	2015-05-01
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2015.6319
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Zs.A 5488: Show issues

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Article ; Online: Contribution of Hepatic Steatosis-Intensified Extracellular Vesicle Release to Aggravated Inflammatory Endothelial Injury in Liver-Specific Asah1 Gene Knockout Mice.

Yuan, Xinxu / Bhat, Owais M / Zou, Yao / Zhang, Yang / Li, Pin-Lan

The American journal of pathology

2023 Volume 193, Issue 4, Page(s) 493–508

Abstract: To study the mechanism by which nonalcoholic fatty liver disease (NAFLD) contributes to vascular endothelial Nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation and neointima hyperplasia, NAFLD was established in high-fat diet (HFD)-treated ... ...

Abstract	To study the mechanism by which nonalcoholic fatty liver disease (NAFLD) contributes to vascular endothelial Nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation and neointima hyperplasia, NAFLD was established in high-fat diet (HFD)-treated Asah1
MeSH term(s)	Mice ; Animals ; Inflammasomes/metabolism ; Non-alcoholic Fatty Liver Disease/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice, Knockout ; Acid Ceramidase/genetics ; Acid Ceramidase/metabolism ; Endothelial Cells/metabolism ; Neointima/metabolism ; Gene Knockout Techniques ; Hyperplasia ; Liver/metabolism ; Extracellular Vesicles/metabolism ; Ceramides ; Diet, High-Fat/adverse effects ; Mice, Inbred C57BL
Chemical Substances	Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Acid Ceramidase (EC 3.5.1.23) ; Ceramides ; Asah1 protein, mouse (EC 3.5.1.23)
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2022.12.007
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Article ; Online: Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation.

Huang, Dandan / Kidd, Jason M / Zou, Yao / Wu, Xiaoyuan / Li, Ningjun / Gehr, Todd W B / Li, Pin-Lan / Li, Guangbi

American journal of physiology. Renal physiology

2024

Abstract: Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of ... ...

Abstract	Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene attenuates hHcy-induced NLRP3 inflammasome activation and associated exosome release in podocytes and thereby suppresses glomerular inflammatory response and injury.
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00195.2023
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Article ; Online: Bioactive Lipids and Redox Signaling: Molecular Mechanism and Disease Pathogenesis.

Li, Pin-Lan / Gulbins, Erich

Antioxidants & redox signaling

2018 Volume 28, Issue 10, Page(s) 911–915

Abstract: The actions of bioactive lipids and reactive oxygen species (ROS) are usually coupled, and their interplay is a common and important mechanism mediating tissue injury, inflammation, and other pathologies. Understanding the interplay of ROS and lipid ... ...

Abstract	The actions of bioactive lipids and reactive oxygen species (ROS) are usually coupled, and their interplay is a common and important mechanism mediating tissue injury, inflammation, and other pathologies. Understanding the interplay of ROS and lipid mediators will extend horizons for researchers to clarify the pathogenesis of different diseases and help identify therapeutic targets for treatment of these diseases. Some bioactive lipids are converted into oxidized lipids during cell or tissue oxidative stress such as isoprostanes and isoketals, which are even more bioactive than their precursors. Moreover, many enzymes that produce lipid mediators such as prostaglandin H synthases, lipoxygenases, and cytochrome P450 isoforms may catalyze the production of ROS. Bioactive lipids-lysophospholipids, sphingolipids, or deposited lipids in cells-are shown to stimulate redox enzymes to produce ROS. In addition, a lipid-channel-ROS axis in different organelles may be associated with the crosstalk of ROS and bioactive lipids. This Forum focuses on the crosstalk of ROS with sphingolipids, P450 eicosanoids, lysophospholipids, and deposited plasma lipids and related novel signaling pathway in their reciprocal actions, which is expected to provide novel insights into the pathogenesis of different diseases associated with the participation of these lipid mediators. It is imperative to further understand the molecular mechanism mediating the crosstalk of ROS with specific lipid mediators and to develop more effective therapeutic strategies to target the interplay of ROS and lipid mediators for treatment specific to different organ diseases.
Language	English
Publishing date	2018-01-24
Publishing country	United States
Document type	Editorial
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2017.7467
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Article ; Online: Podocyte Lysosome Dysfunction in Chronic Glomerular Diseases.

Li, Guangbi / Kidd, Jason / Li, Pin-Lan

International journal of molecular sciences

2020 Volume 21, Issue 5

Abstract: Podocytes are visceral epithelial cells covering the outer surface of glomerular capillaries in the kidney. Blood is filtered through the slit diaphragm of podocytes to form urine. The functional and structural integrity of podocytes is essential for the ...

Abstract	Podocytes are visceral epithelial cells covering the outer surface of glomerular capillaries in the kidney. Blood is filtered through the slit diaphragm of podocytes to form urine. The functional and structural integrity of podocytes is essential for the normal function of the kidney. As a membrane-bound organelle, lysosomes are responsible for the degradation of molecules via hydrolytic enzymes. In addition to its degradative properties, recent studies have revealed that lysosomes may serve as a platform mediating cellular signaling in different types of cells. In the last decade, increasing evidence has revealed that the normal function of the lysosome is important for the maintenance of podocyte homeostasis. Podocytes have no ability to proliferate under most pathological conditions; therefore, lysosome-dependent autophagic flux is critical for podocyte survival. In addition, new insights into the pathogenic role of lysosome and associated signaling in podocyte injury and chronic kidney disease have recently emerged. Targeting lysosomal functions or signaling pathways are considered potential therapeutic strategies for some chronic glomerular diseases. This review briefly summarizes current evidence demonstrating the regulation of lysosomal function and signaling mechanisms as well as the canonical and noncanonical roles of podocyte lysosome dysfunction in the development of chronic glomerular diseases and associated therapeutic strategies.
MeSH term(s)	Animals ; Autophagy ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Glomerulonephritis/metabolism ; Glomerulonephritis/pathology ; Humans ; Lipid Metabolism ; Lysosomes/metabolism ; Podocytes/metabolism
Language	English
Publishing date	2020-02-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21051559
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Article ; Online: Podocyte Sphingolipid Signaling in Nephrotic Syndrome.

Li, Guangbi / Kidd, Jason / Gehr, Todd W B / Li, Pin-Lan

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2021 Volume 55, Issue S4, Page(s) 13–34

Abstract: Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and peripheral edema. The pathogenesis of NS has evolved through several hypotheses ... ...

Abstract	Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and peripheral edema. The pathogenesis of NS has evolved through several hypotheses ranging from immune dysregulation theory and increased glomerular permeability theory to the current concept of podocytopathy. Podocytopathy is characterized by dysfunction or depletion of podocytes, which may be caused by unknown permeability factor, genetic disorders, drugs, infections, systemic disorders, and hyperfiltration. Over the last two decades, numerous studies have been done to explore the molecular mechanisms of podocyte injuries or NS and to develop the novel therapeutic strategies targeting podocytopathy for treatment of NS. Recent studies have shown that normal sphingolipid metabolism is essential for structural and functional integrity of podocytes. As a basic component of the plasma membrane, sphingolipids not only support the assembly of signaling molecules and interaction of receptors and effectors, but also mediate various cellular activities, such as apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation. This review briefly summarizes current evidence demonstrating the regulation of sphingolipid metabolism in podocytes and the canonical or noncanonical roles of podocyte sphingolipid signaling in the pathogenesis of NS and associated therapeutic strategies.
MeSH term(s)	Animals ; Humans ; Metabolic Networks and Pathways ; Nephrotic Syndrome/metabolism ; Nephrotic Syndrome/pathology ; Podocytes/metabolism ; Podocytes/pathology ; Signal Transduction ; Sphingolipids/metabolism
Chemical Substances	Sphingolipids
Language	English
Publishing date	2021-04-16
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000356
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Article ; Online: Regulatory role of mammalian target of rapamycin signaling in exosome secretion and osteogenic changes in smooth muscle cells lacking acid ceramidase gene.

Bhat, Owais M / Yuan, Xinxu / Kukreja, Rakesh C / Li, Pin-Lan

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Volume 35, Issue 7, Page(s) e21732

Abstract: Acid ceramidase (murine gene code: Asah1) (50 kDa) belongs to N-terminal nucleophile hydrolase family. This enzyme is located in the lysosome, which mediates conversion of ceramide (CER) into sphingosine and free fatty acids at acidic pH. CER plays an ... ...

Abstract	Acid ceramidase (murine gene code: Asah1) (50 kDa) belongs to N-terminal nucleophile hydrolase family. This enzyme is located in the lysosome, which mediates conversion of ceramide (CER) into sphingosine and free fatty acids at acidic pH. CER plays an important role in intracellular sphingolipid metabolism and its increase causes inflammation. The mammalian target of rapamycin complex 1 (mTORC1) signaling on late endosomes (LEs)/lysosomes may control cargo selection, membrane biogenesis, and exosome secretion, which may be fine controlled by lysosomal sphingolipids such as CER. This lysosomal-CER-mTOR signaling may be a crucial molecular mechanism responsible for development of arterial medial calcification (AMC). Torin-1 (5 mg/kg/day), an mTOR inhibitor, significantly decreased aortic medial calcification accompanied with decreased expression of osteogenic markers like osteopontin (OSP) and runt-related transcription factor 2 (RUNX2) and upregulation of smooth muscle 22α (SM22-α) in mice receiving high dose of Vitamin D (500 000 IU/kg/day). Asah1
MeSH term(s)	Acid Ceramidase/metabolism ; Animals ; Aorta/metabolism ; Calcium/metabolism ; Ceramides/metabolism ; Core Binding Factor Alpha 1 Subunit/metabolism ; Coronary Vessels/metabolism ; Exosomes/metabolism ; Lysosomes/metabolism ; Male ; Mammals/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multivesicular Bodies/metabolism ; Myocytes, Smooth Muscle/metabolism ; Osteogenesis/physiology ; Pulse Wave Analysis/methods ; Signal Transduction/physiology ; Sirolimus/metabolism ; Sphingolipids/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Vascular Calcification/metabolism
Chemical Substances	Ceramides ; Core Binding Factor Alpha 1 Subunit ; Sphingolipids ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Acid Ceramidase (EC 3.5.1.23) ; Asah1 protein, mouse (EC 3.5.1.23) ; Calcium (SY7Q814VUP) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202100385R
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Article: Impairment of Ceramide-Mediated Endothelial Instant Membrane Resealing During Diabetes Mellitus.

Chen, Yang / Li, Guangbi / Bhat, Owais M / Li, Xiang / Zhang, Yang / Li, Pin-Lan

Frontiers in physiology

2022 Volume 13, Page(s) 910339

Abstract: Recent studies have indicated that instant cell membrane resealing (ICMR) controls the activation of NOD-like receptor pyrin domain containing 3 (Nlrp3) inflammasomes in endothelial cells, thereby initiating and promoting vascular inflammation. It ... ...

Abstract	Recent studies have indicated that instant cell membrane resealing (ICMR) controls the activation of NOD-like receptor pyrin domain containing 3 (Nlrp3) inflammasomes in endothelial cells, thereby initiating and promoting vascular inflammation. It remains unknown whether this impaired ICMR occurs under diabetic condition or hyperglycemia contributing to endothelial dysfunction leading to vascular inflammation, a hallmark of diabetic vascular injury. The present study aims to examine whether ICMR occurs during in control and diabetic mice and to explore related molecular mechanisms associated with acid sphingomyelinase (ASM)-mediated ceramide production. Using confocal microscopy, we demonstrated that mouse aortic endothelial cells (MAECs) exposed to high glucose levels exhibited much more retarded ICMR after laser-induced membrane injury, compared to that in control cells. The high glucose-induced impairment of membrane resealing in MAECs was prevented when these cells were pretreated with sphingomyelin or C24-ceramide. Mechanistically, high glucose treatment decreased association of membrane ceramide with annexin A5, an essential element of membrane repair machinery. Consistently, the association of ceramide with annexin A5 was significantly reduced in the coronary arterial endothelium of mice with streptozotocin-induced diabetes mellitus compared to that in non-diabetic control mice. Moreover, a marked reduction of the association of ceramide with annexin A5 was observed in coronary arterial endothelium of ASM knockout mice regardless of their diabetic status. Lastly, high glucose treatment or ASM gene deletion substantially impaired ICMR in coronary arterial endothelium of mice receiving membrane puncturing agents. Collectively, our data suggest that ceramide-mediated ICMR in vascular endothelial cells is impaired during diabetes mellitus due to dissociation of ceramide with annexin A5 and ASM play a critical role in this ICMR.
Language	English
Publishing date	2022-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.910339
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