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Article ; Online: Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet.

Lin, Li / Basu, Rashmita / Chatterjee, Debolina / Templin, Andrew T / Flak, Jonathan N / Johnson, Travis S

2023 Volume 13, Issue 1, Page(s) 12919

Abstract: High-fat diet (HFD) is associated with Alzheimer's disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of ... ...

Abstract	High-fat diet (HFD) is associated with Alzheimer's disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer's microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.
MeSH term(s)	Mice ; Humans ; Animals ; Astrocytes/metabolism ; Diet, High-Fat/adverse effects ; Diabetes Mellitus, Type 2/metabolism ; Microglia/metabolism ; Alzheimer Disease/metabolism
Language	English
Publishing date	2023-08-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-39890-0
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Article: β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances.

Mukherjee, Noyonika / Lin, Li / Contreras, Christopher J / Templin, Andrew T

Metabolites

2021 Volume 11, Issue 11

Abstract: ... associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process ...

Abstract	β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.
Language	English
Publishing date	2021-11-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo11110796
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Article ; Online: Human islet amyloid polypeptide-induced β-cell cytotoxicity is linked to formation of α-sheet structure.

Hsu, Cheng-Chieh / Templin, Andrew T / Prosswimmer, Tatum / Shea, Dylan / Li, Jinzheng / Brooks-Worrell, Barbara / Kahn, Steven E / Daggett, Valerie

Protein science : a publication of the Protein Society

2023 Volume 33, Issue 2, Page(s) e4854

Abstract: Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet β-cells. Several factors contribute to β-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with ... ...

Abstract	Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet β-cells. Several factors contribute to β-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated β-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated β-cell loss.
MeSH term(s)	Humans ; Mice ; Animals ; Diabetes Mellitus, Type 2 ; Islet Amyloid Polypeptide/genetics ; Islet Amyloid Polypeptide/chemistry ; Insulin-Secreting Cells ; Amyloid/chemistry ; Amyloid beta-Peptides
Chemical Substances	Islet Amyloid Polypeptide ; Amyloid ; Amyloid beta-Peptides
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4854
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Biomechanical characteristics of proficient free-throw shooters-markerless motion capture analysis.

Cabarkapa, Dimitrije / Cabarkapa, Damjana V / Miller, Jonathan D / Templin, Tylan T / Frazer, Lance L / Nicolella, Daniel P / Fry, Andrew C

Frontiers in sports and active living

2023 Volume 5, Page(s) 1208915

Abstract: The winning game outcome in basketball is partially contingent on the team's ability to secure and make more free-throw shooting attempts, especially close to the end of the game. Thus, the purpose of the present study was to perform a comprehensive ... ...

Abstract	The winning game outcome in basketball is partially contingent on the team's ability to secure and make more free-throw shooting attempts, especially close to the end of the game. Thus, the purpose of the present study was to perform a comprehensive biomechanical analysis of the free-throw shooting motion to examine differences between (a) proficient (≥70%) and non-proficient shooters (<70%) and (b) made and missed free-throw shoots within the proficient group of shooters. Thirty-four recreationally active males with previous basketball playing experience attempted ten consecutive free-throw shots (4.57 m), with a 10-15 s rest interval between each shot. An innovative three-dimensional markerless motion capture system (SwRI Enable, San Antonio, TX, USA) composed of nine high-definition cameras recording at 120 Hz was used to capture and analyze the biomechanical parameters of interest. Independent
Language	English
Publishing date	2023-08-02
Publishing country	Switzerland
Document type	Journal Article
ISSN	2624-9367
ISSN (online)	2624-9367
DOI	10.3389/fspor.2023.1208915
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Article ; Online: RIPK3 promotes islet amyloid-induced β-cell loss and glucose intolerance in a humanized mouse model of type 2 diabetes.

Mukherjee, Noyonika / Contreras, Christopher J / Lin, Li / Colglazier, Kaitlyn A / Mather, Egan G / Kalwat, Michael A / Esser, Nathalie / Kahn, Steven E / Templin, Andrew T

Molecular metabolism

2024 Volume 80, Page(s) 101877

Abstract: Objective: Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely ...

Abstract	Objective: Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and β-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced β-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation. Methods: We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3 Results: We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3 Conclusions: In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced β-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and β-cell loss and improve glucose homeostasis in the pathogenesis of T2D.
MeSH term(s)	Animals ; Humans ; Mice ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Caspase 3/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Glucose ; Glucose Intolerance ; Inflammation ; Islet Amyloid Polypeptide/genetics ; Islet Amyloid Polypeptide/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Caspase 3 (EC 3.4.22.-) ; Glucose (IY9XDZ35W2) ; Islet Amyloid Polypeptide ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2024-01-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2024.101877
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Article ; Online: Probing the Meaning of Persistent Propeptide Release in Type 1 Diabetes.

Kahn, Steven E / Templin, Andrew T / Hull, Rebecca L / Verchere, C Bruce

Diabetes care

2019 Volume 42, Issue 2, Page(s) 183–185

MeSH term(s)	Diabetes Mellitus, Type 1 ; Humans ; Peptide Hormones ; Proinsulin ; Protein Precursors
Chemical Substances	Peptide Hormones ; Protein Precursors ; Proinsulin (9035-68-1)
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ZDB-ID	441231-x
ISSN	1935-5548 ; 0149-5992
ISSN (online)	1935-5548
ISSN	0149-5992
DOI	10.2337/dci18-0054
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Zs.A 1434: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity.

Contreras, Christopher J / Mukherjee, Noyonika / Branco, Renato C S / Lin, Li / Hogan, Meghan F / Cai, Erica P / Oberst, Andrew A / Kahn, Steven E / Templin, Andrew T

Molecular metabolism

2022 Volume 65, Page(s) 101582

Abstract: Objective: Type 1 diabetes (T1D) is characterized by autoimmune-associated β-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with β-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the ... ...

Abstract	Objective: Type 1 diabetes (T1D) is characterized by autoimmune-associated β-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with β-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the molecular mechanisms of β-cell TNF receptor signaling have not been fully characterized. Based on work in other cell types, we hypothesized that receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) regulate TNFα-induced β-cell death in concert with caspase activity. Methods: We evaluated TNFα-induced cell death, caspase activity, and TNF receptor pathway molecule expression in immortalized NIT-1 and INS-1 β-cell lines and primary mouse islet cells in vitro. Our studies utilized genetic and small molecule approaches to alter RIPK1 and RIPK3 expression and caspase activity to interrogate mechanisms of TNFα-induced β-cell death. We used the β-cell toxin streptozotocin (STZ) to determine the susceptibility of Ripk3 Results: Expression of TNF receptor signaling molecules including RIPK1 and RIPK3 was identified in NIT-1 and INS-1 β cells and isolated mouse islets at the mRNA and protein levels. TNFα treatment increased NIT-1 and INS-1 cell death and caspase activity after 24-48 h, and BV6, a small molecule inhibitor of inhibitor of apoptosis proteins (IAPs) amplified this TNFα-induced cell death. RIPK1 deficient NIT-1 cells were protected from TNFα- and BV6-induced cell death and caspase activation. Interestingly, small molecule inhibition of caspases with zVAD-fmk (zVAD) did not prevent TNFα-induced cell death in either NIT-1 or INS-1 cells. This caspase-independent cell death was increased by BV6 treatment and decreased in RIPK1 deficient NIT-1 cells. RIPK3 deficient NIT-1 cells and RIPK3 kinase inhibitor treated INS-1 cells were protected from TNFα+zVAD-induced cell death, whereas RIPK3 overexpression increased INS-1 cell death and promoted RIPK3 and MLKL interaction under TNFα+zVAD treatment. In mouse islet cells, BV6 or zVAD treatment promoted TNFα-induced cell death, and TNFα+zVAD-induced cell death was blocked by RIPK3 inhibition and in Ripk3 Conclusions: RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity in immortalized and primary islet β cells. TNF receptor signaling molecules such as RIPK1 and RIPK3 may represent novel therapeutic targets to promote β-cell survival and glucose homeostasis in T1D.
MeSH term(s)	Animals ; Caspases/metabolism ; Cell Death ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 1 ; Glucose ; Humans ; Hyperglycemia ; Inhibitor of Apoptosis Proteins/metabolism ; Insulins/metabolism ; Mice ; RNA, Messenger ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Streptozocin ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Inhibitor of Apoptosis Proteins ; Insulins ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; Streptozocin (5W494URQ81) ; RIPK1 protein, human (EC 2.7.11.1) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1) ; Caspases (EC 3.4.22.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-08-24
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2022.101582
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Article ; Online: Loss of apoptosis repressor with caspase recruitment domain (ARC) worsens high fat diet-induced hyperglycemia in mice.

Templin, Andrew T / Schmidt, Christine / Hogan, Meghan F / Esser, Nathalie / Kitsis, Richard N / Hull, Rebecca L / Zraika, Sakeneh / Kahn, Steven E

The Journal of endocrinology

2021 Volume 251, Issue 2, Page(s) 125–135

Abstract: Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its ... ...

Abstract	Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC-/- mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC-/- mice. Non-fasting plasma glucose was not different between ARC-/- and WT mice prior to HFD feeding, and ARC-/- mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC-/- mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC-/- mice returned to baseline and was not different from WT mice. At this final time point, no differences were observed between genotypes in plasma glucose or insulin under fasted conditions or following intravenous glucose administration. However, HFD-fed ARC-/- mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins/physiology ; Blood Glucose ; Diet, High-Fat/adverse effects ; Hyperglycemia/etiology ; Insulin Secretion ; Insulin-Secreting Cells/physiology ; Mice ; Muscle Proteins/physiology
Chemical Substances	Apoptosis Regulatory Proteins ; Blood Glucose ; Muscle Proteins ; Nol3 protein, mouse
Language	English
Publishing date	2021-09-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-20-0612
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Article: Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice.

Esser, Nathalie / Schmidt, Christine / Barrow, Breanne M / Cronic, Laura / Hackney, Daryl J / Mongovin, Stephen M / Hogan, Meghan F / Templin, Andrew T / Castillo, Joseph J / Hull, Rebecca L / Zraika, Sakeneh

Frontiers in endocrinology

2022 Volume 13, Page(s) 888867

Abstract: Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism ...

Abstract	Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sensitivity, and beta-cell mass were determined. Sacubitril and valsartan, but not sacubitril/valsartan, lowered fasting and fed glucose levels and increased insulin release in diabetic mice. None of the drugs altered insulin sensitivity or beta-cell mass, but all reduced body weight gain. Effects of the drugs on insulin release were reproduced in angiotensin II-treated islets from lean C57BL/6J mice, suggesting the insulin response to each of the drugs is due to a direct effect on islets and mechanisms therein. In summary, sacubitril and valsartan each exert beneficial insulinotropic, glycemic and weight-reducing effects in obese and/or diabetic mice when administered alone; however, when combined, mechanisms within the islet contribute to their inability to enhance insulin release.
MeSH term(s)	Aminobutyrates/pharmacology ; Angiotensin Receptor Antagonists/pharmacology ; Animals ; Biphenyl Compounds ; Body Weight ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; Glucose ; Insulin Resistance ; Insulins ; Mice ; Mice, Inbred C57BL ; Neprilysin/pharmacology ; Receptors, Angiotensin ; Tetrazoles/pharmacology ; Valsartan/pharmacology
Chemical Substances	Aminobutyrates ; Angiotensin Receptor Antagonists ; Biphenyl Compounds ; Insulins ; Receptors, Angiotensin ; Tetrazoles ; sacubitril (17ERJ0MKGI) ; Valsartan (80M03YXJ7I) ; Neprilysin (EC 3.4.24.11) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-06-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.888867
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Article ; Online: RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity

Christopher J. Contreras / Noyonika Mukherjee / Renato C.S. Branco / Li Lin / Meghan F. Hogan / Erica P. Cai / Andrew A. Oberst / Steven E. Kahn / Andrew T. Templin

Molecular Metabolism, Vol 65, Iss , Pp 101582- (2022)

2022

Abstract	Objective: Type 1 diabetes (T1D) is characterized by autoimmune-associated β-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with β-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the molecular mechanisms of β-cell TNF receptor signaling have not been fully characterized. Based on work in other cell types, we hypothesized that receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) regulate TNFα-induced β-cell death in concert with caspase activity. Methods: We evaluated TNFα-induced cell death, caspase activity, and TNF receptor pathway molecule expression in immortalized NIT-1 and INS-1 β-cell lines and primary mouse islet cells in vitro. Our studies utilized genetic and small molecule approaches to alter RIPK1 and RIPK3 expression and caspase activity to interrogate mechanisms of TNFα-induced β-cell death. We used the β-cell toxin streptozotocin (STZ) to determine the susceptibility of Ripk3+/+ and Ripk3−/− mice to hyperglycemia in vivo. Results: Expression of TNF receptor signaling molecules including RIPK1 and RIPK3 was identified in NIT-1 and INS-1 β cells and isolated mouse islets at the mRNA and protein levels. TNFα treatment increased NIT-1 and INS-1 cell death and caspase activity after 24–48 h, and BV6, a small molecule inhibitor of inhibitor of apoptosis proteins (IAPs) amplified this TNFα-induced cell death. RIPK1 deficient NIT-1 cells were protected from TNFα- and BV6-induced cell death and caspase activation. Interestingly, small molecule inhibition of caspases with zVAD-fmk (zVAD) did not prevent TNFα-induced cell death in either NIT-1 or INS-1 cells. This caspase-independent cell death was increased by BV6 treatment and decreased in RIPK1 deficient NIT-1 cells. RIPK3 deficient NIT-1 cells and RIPK3 kinase inhibitor treated INS-1 cells were protected from TNFα+zVAD-induced cell death, whereas RIPK3 overexpression increased INS-1 cell death and promoted RIPK3 and MLKL interaction under ...
Keywords	RIPK1 ; RIPK3 ; β-cell death ; Type 1 diabetes ; TNFα ; Caspase ; Internal medicine ; RC31-1245
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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