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Article ; Online: Effects of soluble guanylate cyclase stimulator on renal function in ZSF-1 model of diabetic nephropathy.

Hu, Lufei / Chen, Yinhong / Zhou, Xiaoyan / Hoek, Maarten / Cox, Jason / Lin, Ken / Liu, Yang / Blumenschein, Wendy / Grein, Jeff / Swaminath, Gayathri

PloS one

2022 Volume 17, Issue 1, Page(s) e0261000

Abstract: Background: Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC ... ...

Abstract	Background: Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. Materials and methods: The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. Results: While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. Conclusion: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy.
MeSH term(s)	Animals ; Blood Pressure/drug effects ; CHO Cells ; Cricetulus ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/physiopathology ; Disease Models, Animal ; Drug Therapy, Combination ; Enalaprilat/administration & dosage ; Enalaprilat/pharmacology ; Enzyme Activators/administration & dosage ; Enzyme Activators/pharmacology ; Gene Expression Profiling ; Kidney Function Tests ; Male ; Nitric Oxide/metabolism ; Oxidative Stress ; Pilot Projects ; Rats ; Signal Transduction/drug effects ; Soluble Guanylyl Cyclase/metabolism ; Treatment Outcome
Chemical Substances	Enzyme Activators ; Nitric Oxide (31C4KY9ESH) ; Soluble Guanylyl Cyclase (EC 4.6.1.2) ; Enalaprilat (GV0O7ES0R3)
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0261000
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Article ; Online: APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress.

Wakashin, Hidefumi / Heymann, Jurgen / Roshanravan, Hila / Daneshpajouhnejad, Parnaz / Rosenberg, Avi / Shin, Myung Kyun / Hoek, Maarten / Kopp, Jeffrey B

BMC nephrology

2020 Volume 21, Issue 1, Page(s) 371

Abstract: Background: Apolipoprotein L1, APOL1, is a trypanosome lytic factor present in human and certain other primates. APOL1 gene variants, present in individuals of recent sub-Saharan African descent, increase risk for glomerular disease and associate with ... ...

Abstract	Background: Apolipoprotein L1, APOL1, is a trypanosome lytic factor present in human and certain other primates. APOL1 gene variants, present in individuals of recent sub-Saharan African descent, increase risk for glomerular disease and associate with the disease progression, but the molecular mechanisms have not been defined. Objectives: We focus on the mechanism how APOL1 variant proteins enhance podocyte injury in the stressed kidney. Methods: First, we investigated the expression of APOL1 protein isoform and the localization of APOL1 protein in the kidney. Next, we examined the role of APOL1 in the podocyte stress and the inflammatory signaling in the kidney after hemi-nephrectomy. Results: We identified a novel RNA variant that lacks a secretory pathway signal sequence and we found that the predicted APOL1-B3 protein isoform was expressed in human podocytes in vivo and by BAC-APOL1 transgenic mice. APOL1-B3-G2 transgenic mice, carrying a renal risk variant, manifested podocyte injury and increased pro-IL-1β mRNA in isolated glomeruli and increased IL-1β production in the remnant kidney after uninephrectomy. APOL1-B3 interacted with NLRP12, a key regulator of Toll-like receptor signaling. Conclusions: These results suggest a possible mechanism for podocyte injury by which one of the APOL1 protein isoforms, APOL1-B3 and its renal risk variants, enhances inflammatory signaling.
MeSH term(s)	Animals ; Apolipoprotein L1/genetics ; Apolipoprotein L1/metabolism ; Humans ; In Vitro Techniques ; Inflammation/genetics ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Mice ; Mice, Transgenic ; Nephrectomy ; Podocytes/metabolism ; Podocytes/pathology ; Protein Isoforms ; RNA, Messenger/metabolism ; Stress, Physiological/genetics
Chemical Substances	Apolipoprotein L1 ; IL1B protein, mouse ; Interleukin-1beta ; Intracellular Signaling Peptides and Proteins ; NLRP12 protein, mouse ; Protein Isoforms ; RNA, Messenger
Language	English
Publishing date	2020-08-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2041348-8
ISSN	1471-2369 ; 1471-2369
ISSN (online)	1471-2369
ISSN	1471-2369
DOI	10.1186/s12882-020-01995-3
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Article ; Online: Lack of APOL1 in proximal tubules of normal human kidneys and proteinuric APOL1 transgenic mouse kidneys.

Blessing, Natalya A / Wu, Zhenzhen / Madhavan, Sethu M / Choy, Jonathan W / Chen, Michelle / Shin, Myung K / Hoek, Maarten / Sedor, John R / O'Toole, John F / Bruggeman, Leslie A

PloS one

2021 Volume 16, Issue 6, Page(s) e0253197

Abstract: The mechanism of pathogenesis associated with APOL1 polymorphisms and risk for non-diabetic chronic kidney disease (CKD) is not fully understood. Prior studies have minimized a causal role for the circulating APOL1 protein, thus efforts to understand ... ...

Abstract	The mechanism of pathogenesis associated with APOL1 polymorphisms and risk for non-diabetic chronic kidney disease (CKD) is not fully understood. Prior studies have minimized a causal role for the circulating APOL1 protein, thus efforts to understand kidney pathogenesis have focused on APOL1 expressed in renal cells. Of the kidney cells reported to express APOL1, the proximal tubule expression patterns are inconsistent in published reports, and whether APOL1 is synthesized by the proximal tubule or possibly APOL1 protein in the blood is filtered and reabsorbed by the proximal tubule remains unclear. Using both protein and mRNA in situ methods, the kidney expression pattern of APOL1 was examined in normal human and APOL1 bacterial artificial chromosome transgenic mice with and without proteinuria. APOL1 protein and mRNA was detected in podocytes and endothelial cells, but not in tubular epithelia. In the setting of proteinuria, plasma APOL1 protein did not appear to be filtered or reabsorbed by the proximal tubule. A side-by-side examination of commercial antibodies used in prior studies suggest the original reports of APOL1 in proximal tubules likely reflects antibody non-specificity. As such, APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies in the APOL1-mediated kidney diseases.
MeSH term(s)	Alleles ; Animals ; Apolipoprotein L1/genetics ; Apolipoprotein L1/metabolism ; Endothelial Cells/metabolism ; Humans ; Kidney ; Kidney Tubules, Proximal/metabolism ; Liver/metabolism ; Mice ; Mice, Transgenic ; Podocytes/metabolism ; Proteinuria/genetics ; Proteinuria/metabolism
Chemical Substances	Apolipoprotein L1
Language	English
Publishing date	2021-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0253197
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Article ; Online: Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte.

Heymann, Jurgen / Winkler, Cheryl A / Hoek, Maarten / Susztak, Katalin / Kopp, Jeffrey B

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2017 Volume 32, Issue suppl_1, Page(s) i65–i70

Abstract: APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies ... ...

Abstract	APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies for these conditions may achieve therapeutic targets, reduction in proteinuria and control of blood pressure, respectively, but often fail to halt the progressive decline in kidney function. It appears that current therapies fail to address certain underlying critical pathologic processes that are driven, particularly in podocytes and microvascular cells, by the APOL1 renal risk genetic variants. Mechanisms hypothesized to be responsible for APOL1 variant-associated cell injury can be summarized in five domains: increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress. We briefly review the available evidence for these five mechanisms and suggest possible novel therapeutic approaches.
MeSH term(s)	Apolipoprotein L1 ; Apolipoproteins/antagonists & inhibitors ; Glomerulosclerosis, Focal Segmental/drug therapy ; Glomerulosclerosis, Focal Segmental/metabolism ; Glomerulosclerosis, Focal Segmental/pathology ; Humans ; Hypertension, Renal/drug therapy ; Hypertension, Renal/metabolism ; Hypertension, Renal/pathology ; Lipoproteins, HDL/antagonists & inhibitors ; Nephritis/drug therapy ; Nephritis/metabolism ; Nephritis/pathology
Chemical Substances	APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Lipoproteins, HDL
Language	English
Publishing date	2017-04-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gfw402
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Zs.A 2198: 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: An analysis of CAF-1-interacting proteins reveals dynamic and direct interactions with the KU complex and 14-3-3 proteins.

Hoek, Maarten / Myers, Michael P / Stillman, Bruce

The Journal of biological chemistry

2011 Volume 286, Issue 12, Page(s) 10876–10887

Abstract: CAF-1 is essential in human cells for the de novo deposition of histones H3 and H4 at the DNA replication fork. Depletion of CAF-1 from various cell lines causes replication fork arrest, activation of the intra-S phase checkpoint, and global defects in ... ...

Abstract	CAF-1 is essential in human cells for the de novo deposition of histones H3 and H4 at the DNA replication fork. Depletion of CAF-1 from various cell lines causes replication fork arrest, activation of the intra-S phase checkpoint, and global defects in chromatin structure. CAF-1 is also involved in coordinating inheritance of states of gene expression and in chromatin assembly following DNA repair. In this study, we generated cell lines expressing RNAi-resistant versions of CAF-1 and showed that the N-terminal 296 amino acids are dispensable for essential CAF-1 function in vivo. N-terminally truncated CAF-1 p150 was deficient in proliferating cell nuclear antigen (PCNA) binding, reinforcing the existence of two PCNA binding sites in human CAF-1, but the defect in PCNA binding had no effect on the recruitment of CAF-1 to chromatin after DNA damage or to resistance to DNA-damaging agents. Tandem affinity purification of CAF-1-interacting proteins under mild conditions revealed that CAF-1 was directly associated with the KU70/80 complex, part of the DNA-dependent protein kinase, and the phosphoserine/threonine-binding protein 14-3-3 ζ. CAF-1 was a substrate for DNA-dependent protein kinase, and the 14-3-3 interaction in vitro is dependent on DNA-dependent protein kinase phosphorylation. These results highlight that CAF-1 has prominent interactions with the DNA repair machinery but that the N terminus is dispensable for the role of CAF-1 in DNA replication- and repair-coupled chromatin assembly.
MeSH term(s)	14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism ; Antigens, Nuclear/genetics ; Antigens, Nuclear/metabolism ; Cell Line ; Chromatin Assembly Factor-1/genetics ; Chromatin Assembly Factor-1/metabolism ; Chromatin Assembly and Disassembly/physiology ; DNA Damage/physiology ; DNA Repair/physiology ; DNA Replication/physiology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Histones/genetics ; Histones/metabolism ; Humans ; Ku Autoantigen ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Proliferating Cell Nuclear Antigen/genetics ; Proliferating Cell Nuclear Antigen/metabolism ; Protein Binding
Chemical Substances	14-3-3 Proteins ; Antigens, Nuclear ; Chromatin Assembly Factor-1 ; DNA-Binding Proteins ; Histones ; Multiprotein Complexes ; Proliferating Cell Nuclear Antigen ; YWHAH protein, human ; Xrcc6 protein, human (EC 3.6.4.12) ; Ku Autoantigen (EC 4.2.99.-)
Language	English
Publishing date	2011-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.217075
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Article ; Online: Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

Hung, Adriana M / Assimon, Victoria A / Chen, Hua-Chang / Yu, Zhihong / Vlasschaert, Caitlyn / Triozzi, Jefferson L / Chan, Helen / Wheless, Lee / Wilson, Otis / Shah, Shailja C / Mack, Taralynn / Thompson, Trevor / Matheny, Michael E / Chandrasekar, Saranya / Mozaffari, Sahar V / Chung, Cecilia P / Tsao, Philip / Susztak, Katalin / Siew, Edward D /

Estrada, Karol / Gaziano, J Michael / Graham, Robert R / Tao, Ran / Hoek, Maarten / Robinson-Cohen, Cassianne / Green, Eric M / Bick, Alexander G

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 11, Page(s) 1889–1899

Abstract: Significance statement: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of ... ...

Abstract	Significance statement: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. Background: African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. Methods: We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. Results: In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. Conclusions: APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.
MeSH term(s)	Humans ; Apolipoprotein L1/genetics ; Apolipoproteins/genetics ; Cross-Sectional Studies ; Genetic Predisposition to Disease ; Genotype ; Ion Channels/genetics ; Population Health ; Renal Insufficiency, Chronic/genetics ; Black or African American/genetics
Chemical Substances	APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Ion Channels
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; 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	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000219
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Zs.A 3344: Show issues

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Article ; Online: APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice.

Ryu, Jung-Hwa / Ge, Mengyuan / Merscher, Sandra / Rosenberg, Avi Z / Desante, Marco / Roshanravan, Hila / Okamoto, Koji / Shin, Myung K / Hoek, Maarten / Fornoni, Alessia / Kopp, Jeffrey B

PloS one

2019 Volume 14, Issue 4, Page(s) e0211559

Abstract: Apolipoprotein L1 (APOL1) genetic variants G1 and G2, compared to the common allele G0, are major risk factors for non-diabetic kidney disease in African descent populations. APOL1 is a minor protein component of HDL, as well as being expressed in ... ...

Abstract	Apolipoprotein L1 (APOL1) genetic variants G1 and G2, compared to the common allele G0, are major risk factors for non-diabetic kidney disease in African descent populations. APOL1 is a minor protein component of HDL, as well as being expressed in podocytes and vascular cells. Reverse cholesterol transport involves the transport of cholesterol to HDL by cellular ATP-binding cassette; ABCA1 and ABCG1 with subsequent delivery from peripheral tissues to the liver. With impaired reverse cholesterol transport, lipid accumulation occurs and macrophages morphologically transform into foam cells, releasing inflammatory factors. We asked whether the APOL1 risk variants alter peripheral cholesterol metabolism and specifically affect macrophage cholesterol efflux. Tissues and bone marrow (BM)-derived monocytes were isolated from wild-type mice (WT) and from BAC/APOL1 transgenic (APOL1-G0, APOL1-G1, and APOL1-G2) mice, which carry a bacterial artificial chromosome that contains the human APOL1 genomic region. Monocytes were differentiated into macrophages using M-CSF, and then polarized into M1 and M2 macrophages. Cholesterol content, cholesterol efflux, and ABCA1 and ABCG1 mRNA expression were measured. Kidney, spleen, and bone marrow-derived macrophages from APOL1-G1 and -G2 mice showed increased cholesterol accumulation and decreased ABCA1 and ABCG1 mRNA levels. BM-derived macrophages from APOL1-G1 and -G2 mice showed significantly reduced cholesterol efflux compared to WT or APOL1-G0 macrophages. Taken together, the evidence suggests that APOL1-G1 and -G2 risk variants impaired reverse cholesterol transport through decreased expression of cholesterol efflux transporters suggesting a possible mechanism to promote macrophage foam cell formation, driving inflammation in the glomerulus and renal interstitium.
MeSH term(s)	Animals ; Apolipoprotein L1/genetics ; Apolipoprotein L1/metabolism ; Biological Transport ; Cells, Cultured ; Cholesterol/metabolism ; Genetic Variation ; Humans ; Kidney/metabolism ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Transgenic ; Spleen/metabolism
Chemical Substances	APOL1 protein, human ; Apolipoprotein L1 ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2019-04-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0211559
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Article ; Online: PAN-AMPK Activation Improves Renal Function in a Rat Model of Progressive Diabetic Nephropathy.

Zhou, Xiaoyan / Muise, Eric S / Haimbach, Robin / Sebhat, Iyassu K / Zhu, Yonghua / Liu, Franklin / Souza, Sandra C / Kan, Yanqing / Pinto, Shirly / Kelley, David E / Hoek, Maarten

The Journal of pharmacology and experimental therapeutics

2019 Volume 371, Issue 1, Page(s) 45–55

Abstract: Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated ... ...

Abstract	Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for chronic kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, that was shown to have beneficial effects in preclinical models. In this study we investigated the effects of MK-8722 in a progressive rat model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We found that MK-8722 administration in a therapeutic paradigm is profoundly renoprotective, as demonstrated by a reduction in proteinuria (63% decrease in MK-8722 10 mg/kg per day compared with vehicle group) and a significant improvement in glomerular filtration rate (779 and 430
MeSH term(s)	Aged ; Animals ; Blood Glucose/metabolism ; Blood Pressure ; Cells, Cultured ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/metabolism ; Female ; Glomerular Filtration Rate ; Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Kidney/drug effects ; Kidney/metabolism ; Male ; Middle Aged ; Mitochondria/drug effects ; Protein Kinases/metabolism ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Rats ; Rats, Zucker ; Triglycerides/blood
Chemical Substances	Blood Glucose ; Hypoglycemic Agents ; Imidazoles ; MK-8722 ; Pyridines ; Triglycerides ; Protein Kinases (EC 2.7.-) ; AMP-activated protein kinase kinase (EC 2.7.1.-)
Language	English
Publishing date	2019-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.119.258244
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Article ; Online: Mobilisation and analyses of publicly available SARS-CoV-2 data for pandemic responses.

Rahman, Nadim / O'Cathail, Colman / Zyoud, Ahmad / Sokolov, Alexey / Oude Munnink, Bas / Grüning, Björn / Cummins, Carla / Amid, Clara / Nieuwenhuijse, David F / Visontai, Dávid / Yuan, David Yu / Gupta, Dipayan / Prasad, Divyae K / Gulyás, Gábor Máté / Rinck, Gabriele / McKinnon, Jasmine / Rajan, Jeena / Knaggs, Jeff / Skiby, Jeffrey Edward /

Stéger, József / Szarvas, Judit / Gueye, Khadim / Papp, Krisztián / Hoek, Maarten / Kumar, Manish / Ventouratou, Marianna A / Bouquieaux, Marie-Catherine / Koliba, Martin / Mansurova, Milena / Haseeb, Muhammad / Worp, Nathalie / Harrison, Peter W / Leinonen, Rasko / Thorne, Ross / Selvakumar, Sandeep / Hunt, Sarah / Venkataraman, Sundar / Jayathilaka, Suran / Cezard, Timothée / Maier, Wolfgang / Waheed, Zahra / Iqbal, Zamin / Aarestrup, Frank Møller / Csabai, Istvan / Koopmans, Marion / Burdett, Tony / Cochrane, Guy

Microbial genomics

2024 Volume 10, Issue 2

Abstract: The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively ... ...

Abstract	The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug reuse studies and design. The European COVID-19 Data Platform was launched to support this data sharing, and has resulted in the deposition of several million SARS-CoV-2 raw reads. In this paper we describe (1) open data sharing, (2) tools for submission, analysis, visualisation and data claiming (e.g. ORCiD), (3) the systematic analysis of these datasets, at scale via the SARS-CoV-2 Data Hubs as well as (4) lessons learnt. This paper describes a component of the Platform, the SARS-CoV-2 Data Hubs, which enable the extension and set up of infrastructure that we intend to use more widely in the future for pathogen surveillance and pandemic preparedness.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; Pandemics ; COVID-19/epidemiology ; Genomics ; Information Dissemination
Language	English
Publishing date	2024-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2835258-0
ISSN	2057-5858 ; 2057-5858
ISSN (online)	2057-5858
ISSN	2057-5858
DOI	10.1099/mgen.0.001188
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Article ; Online: Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

Ullman, Julie C / Mellem, Kevin T / Xi, Yannan / Ramanan, Vyas / Merritt, Hanne / Choy, Rebeca / Gujral, Tarunmeet / Young, Lyndsay E A / Blake, Kerrigan / Tep, Samnang / Homburger, Julian R / O'Regan, Adam / Ganesh, Sandya / Wong, Perryn / Satterfield, Terrence F / Lin, Baiwei / Situ, Eva / Yu, Cecile / Espanol, Bryan /

Sarwaikar, Richa / Fastman, Nathan / Tzitzilonis, Christos / Lee, Patrick / Reiton, Daniel / Morton, Vivian / Santiago, Pam / Won, Walter / Powers, Hannah / Cummings, Beryl B / Hoek, Maarten / Graham, Robert R / Chandriani, Sanjay J / Bainer, Russell / DePaoli-Roach, Anna A / Roach, Peter J / Hurley, Thomas D / Sun, Ramon C / Gentry, Matthew S / Sinz, Christopher / Dick, Ryan A / Noonberg, Sarah B / Beattie, David T / Morgans, David J / Green, Eric M

Science translational medicine

2024 Volume 16, Issue 730, Page(s) eadf1691

Abstract: Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are ...

Abstract	Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.
MeSH term(s)	Mice ; Animals ; Glycogen Storage Disease Type II/drug therapy ; Glycogen Synthase/metabolism ; Glycogen Synthase/pharmacology ; Mice, Knockout ; Glycogen/metabolism ; Muscle, Skeletal/metabolism ; Enzyme Replacement Therapy/methods
Chemical Substances	Glycogen Synthase (EC 2.4.1.11) ; Glycogen (9005-79-2)
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adf1691
Database	MEDical Literature Analysis and Retrieval System OnLINE

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