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Article ; Online: Mitochondria isolated from lipid droplets of white adipose tissue reveal functional differences based on lipid droplet size.

Brownstein, Alexandra J / Veliova, Michaela / Acin-Perez, Rebeca / Villalobos, Frankie / Petcherski, Anton / Tombolato, Alberto / Liesa, Marc / Shirihai, Orian S

Life science alliance

2023 Volume 7, Issue 2

Abstract: Recent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), which were termed PeriDroplet Mitochondria (PDM). PDM can be isolated from BAT by differential centrifugation and salt washes. ... ...

Abstract	Recent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), which were termed PeriDroplet Mitochondria (PDM). PDM can be isolated from BAT by differential centrifugation and salt washes. Contrary to BAT, this approach has so far not led to the successful isolation of PDM from white adipose tissue (WAT). Here, we developed a method to isolate PDM from WAT with high yield and purity by an optimized proteolytic treatment that preserves the respiratory function of mitochondria. Using this approach, we show that, contrary to BAT, WAT PDM have lower respiratory and ATP synthesis capacities compared with WAT cytoplasmic mitochondria (CM). Furthermore, by isolating PDM from LDs of different sizes, we found a negative correlation between LD size and the respiratory capacity of their PDM in WAT. Thus, our new isolation method reveals tissue-specific characteristics of PDM and establishes the existence of heterogeneity in PDM function determined by LD size.
MeSH term(s)	Lipid Droplets/metabolism ; Energy Metabolism ; Adipose Tissue, White/metabolism ; Adipose Tissue, Brown/metabolism ; Mitochondria/metabolism
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202301934
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Blood immune cells from people with HIV on antiviral regimens that contain tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) have differential metabolic signatures.

Ritou, Eleni / Satta, Sandro / Petcherski, Anton / Daskou, Maria / Sharma, Madhav / Vasilopoulos, Hariclea / Murakami, Eisuke / Shirihai, Orian S / Kelesidis, Theodoros

Metabolism: clinical and experimental

2023 Volume 141, Page(s) 155395

Abstract: Background: Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate ...

Abstract	Background: Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) may alter mitochondrial function and energy production in immune cells in HIV Methods: Cellular bioenergetics were determined in PBMCs from HIV-1 Results: PBMCs from HIV-1 Conclusions: Compared to TDF, TAF may alter bioenergetics in immune cells from PWH in vitro and in vivo. The clinical significance in terms of the differential impact caused by TAF versus TDF on mitochondrial function and energy production in immune cells, a regulator of immune function, requires further studied in HIV, preexposure prophylaxis and hepatitis B.
MeSH term(s)	Humans ; Adenine/therapeutic use ; Alanine/pharmacology ; Alanine/therapeutic use ; Anti-HIV Agents/therapeutic use ; HIV Infections/drug therapy ; Leukocytes, Mononuclear ; Tenofovir/therapeutic use
Chemical Substances	Adenine (JAC85A2161) ; Alanine (OF5P57N2ZX) ; Anti-HIV Agents ; Tenofovir (99YXE507IL)
Language	English
Publishing date	2023-01-14
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80230-x
ISSN	1532-8600 ; 0026-0495
ISSN (online)	1532-8600
ISSN	0026-0495
DOI	10.1016/j.metabol.2022.155395
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Article ; Online: The biology of lipid droplet-bound mitochondria.

Veliova, Michaela / Petcherski, Anton / Liesa, Marc / Shirihai, Orian S

Seminars in cell & developmental biology

2020 Volume 108, Page(s) 55–64

Abstract: Proper regulation of cellular lipid storage and oxidation is indispensable for the maintenance of cellular energy homeostasis and health. Mitochondrial function has been shown to be a main determinant of functional lipid storage and oxidation, which is ... ...

Abstract	Proper regulation of cellular lipid storage and oxidation is indispensable for the maintenance of cellular energy homeostasis and health. Mitochondrial function has been shown to be a main determinant of functional lipid storage and oxidation, which is of particular interest for the adipose tissue, as it is the main site of triacylglyceride storage in lipid droplets (LDs). Recent studies have identified a subpopulation of mitochondria attached to LDs, peridroplet mitochondria (PDM) that can be separated from cytoplasmic mitochondria (CM) by centrifugation. PDM have distinct bioenergetics, proteome, cristae organization and dynamics that support LD build-up, however their role in adipose tissue biology remains largely unexplored. Therefore, understanding the molecular basis of LD homeostasis and their relationship to mitochondrial function and attachment in adipocytes is of major importance.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Endocrine System/metabolism ; Humans ; Lipid Droplets/metabolism ; Lipid Droplets/ultrastructure ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Molecular Targeted Therapy
Language	English
Publishing date	2020-05-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2020.04.013
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Article: Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.

bioRxiv : the preprint server for biology

2024

Abstract: Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP- ... ...

Abstract	Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.26.586649
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Article ; Online: Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.

Zeng, Jialiu / Acin-Perez, Rebeca / Assali, Essam A / Martin, Andrew / Brownstein, Alexandra J / Petcherski, Anton / Fernández-Del-Rio, Lucía / Xiao, Ruiqing / Lo, Chih Hung / Shum, Michaël / Liesa, Marc / Han, Xue / Shirihai, Orian S / Grinstaff, Mark W

Nature communications

2023 Volume 14, Issue 1, Page(s) 2573

Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal ... ...

Abstract	Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
MeSH term(s)	Mice ; Animals ; Non-alcoholic Fatty Liver Disease/metabolism ; Autophagy ; Liver/metabolism ; Lysosomes/metabolism ; Hydrogen-Ion Concentration
Language	English
Publishing date	2023-05-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38165-6
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Article ; Online: A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.

Palermo, Amelia / Li, Shen / Ten Hoeve, Johanna / Chellappa, Akshay / Morris, Alexandra / Dillon, Barbara / Ma, Feiyang / Wang, Yijie / Cao, Edward / Shabane, Byourak / Acín-Perez, Rebeca / Petcherski, Anton / Lusis, A Jake / Hazen, Stanley / Shirihai, Orian S / Pellegrini, Matteo / Arumugaswami, Vaithilingaraja / Graeber, Thomas G / Deb, Arjun

Communications biology

2023 Volume 6, Issue 1, Page(s) 1115

Abstract: The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity ... ...

Abstract	The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.
MeSH term(s)	Mice ; Animals ; SARS-CoV-2 ; Diet, Ketogenic ; COVID-19 ; Inflammation ; Cytokines
Chemical Substances	Cytokines
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05478-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Ellagic Acid and Its Microbial Metabolite Urolithin A Alleviate Diet‐Induced Insulin Resistance in Mice

Yang, Jieping / Guo, Yuanqiang / Henning, Susanne M / Chan, Brenda / Long, Jianfeng / Zhong, Jin / Acin‐Perez, Rebeca / Petcherski, Anton / Shirihai, Orian / Heber, David / Li, Zhaoping

Molecular nutrition & food research. 2020 Oct., v. 64, no. 19

2020

Abstract: SCOPE: This work aims at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet‐induced IR. METHODS AND RESULTS: DBA2J mice are fed a high fat/ ... ...

Abstract	SCOPE: This work aims at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet‐induced IR. METHODS AND RESULTS: DBA2J mice are fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA (EA+UA) are added to the HF/HS‐diet for another 8 weeks. UA significantly decreases fasting glucose and increases adiponectin compared with HF/HS‐controls. During intraperitoneal insulin tolerance test, EA+UA significantly improve insulin‐mediated glucose lowering effects at 15 and 120 min and reduce blood triglycerides compared with HF/HS‐controls. Serum free fatty acids are significantly decreased by EA, UA, and EA+UA. Differential expression of genes related to mitochondrial function by EA, UA, and EA+UA in liver and skeletal muscle is observed. Primary hepatocytes from IR‐mice have higher proton leak, basal and ATP‐linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduce the proton leak in hepatocytes from IR‐mice. CONCLUSION: EA and UA induce different metabolic benefits in IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism.
Keywords	adiponectin ; blood serum ; ellagic acid ; food research ; gene expression regulation ; glucose ; hepatocytes ; high carbohydrate diet ; insulin resistance ; insulin tolerance test ; liver ; metabolism ; mitochondria ; oxygen consumption ; skeletal muscle
Language	English
Dates of publication	2020-10
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	2160372-8
ISSN	1613-4133 ; 1613-4125
ISSN (online)	1613-4133
ISSN	1613-4125
DOI	10.1002/mnfr.202000091
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: ENDO-LYSOSOME-TARGETED NANOPARTICLE DELIVERY OF ANTIVIRAL THERAPY FOR CORONAVIRUS INFECTIONS

Petcherski, Anton / Tingley, Brett M / Martin, Andrew / Adams, Sarah / Brownstein, Alexandra J / Steinberg, Ross A / Shabane, Byourak / Garcia, Gustavo / Veliova, Michaela / Arumugaswami, Vaithilingaraja / Colby, Aaron H / Shirihai, Orian S / Grinstaff, Mark W

bioRxiv

Abstract: SARS-CoV-2 can infect cells through endocytic uptake, a process which can be targeted by inhibition of lysosomal proteases. However, clinically this approach fared poorly with an oral regimen of hydroxychloroquine that was accompanied by significant ... ...

Abstract	SARS-CoV-2 can infect cells through endocytic uptake, a process which can be targeted by inhibition of lysosomal proteases. However, clinically this approach fared poorly with an oral regimen of hydroxychloroquine that was accompanied by significant toxicity due to off-target effects. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, 100-150 nm in diameter, and possess a negative surface charge which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2-WA1 and its Omicron variant in a human lung epithelium model. This study demonstrates that organelle-targeted delivery is an effective means to inhibit viral infection.
Keywords	covid19
Language	English
Publishing date	2023-05-09
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.05.08.539898
Database	COVID19

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Article ; Online: The ApoA-I mimetic peptide 4F attenuates in vitro replication of SARS-CoV-2, associated apoptosis, oxidative stress and inflammation in epithelial cells.

Kelesidis, Theodoros / Madhav, Sharma / Petcherski, Anton / Cristelle, Hugo / O'Connor, Ellen / Hultgren, Nan W / Ritou, Eleni / Williams, David S / Shirihai, Orian S / Reddy, Srinivasa T

Virulence

2021 Volume 12, Issue 1, Page(s) 2214–2227

Abstract: An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against ... ...

Abstract	An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry. 4 F also reduced associated cellular apoptosis and secretion of IL-6 in both SARS-CoV-2 infected Vero-E6 and Calu3 cells. Thus, 4 F attenuates
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Antiviral Agents/pharmacology ; Apoptosis/drug effects ; Basigin/metabolism ; Cytokines/metabolism ; Epithelial Cells ; Heparan Sulfate Proteoglycans/metabolism ; Humans ; Inflammation ; Interferons/metabolism ; Oxidative Stress/drug effects ; Peptides/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Attachment/drug effects ; Virus Internalization/drug effects ; Virus Replication/drug effects
Chemical Substances	Antioxidants ; Antiviral Agents ; Cytokines ; Heparan Sulfate Proteoglycans ; Peptides ; Spike Glycoprotein, Coronavirus ; apolipoprotein A-I mimetic peptide 4F ; spike protein, SARS-CoV-2 ; Basigin (136894-56-9) ; Interferons (9008-11-1)
Language	English
Publishing date	2021-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2657572-3
ISSN	2150-5608 ; 2150-5594
ISSN (online)	2150-5608
ISSN	2150-5594
DOI	10.1080/21505594.2021.1964329
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models.

Petcherski, Anton / Sharma, Madhav / Satta, Sandro / Daskou, Maria / Vasilopoulos, Hariclea / Hugo, Cristelle / Ritou, Eleni / Dillon, Barbara Jane / Fung, Eileen / Garcia, Gustavo / Scafoglio, Claudio / Purkayastha, Arunima / Gomperts, Brigitte N / Fishbein, Gregory A / Arumugaswami, Vaithilingaraja / Liesa, Marc / Shirihai, Orian S / Kelesidis, Theodoros

bioRxiv : the preprint server for biology

2022

Abstract: To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against ... ...

Abstract	To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern One-sentence summary: Mitoquinone/mitoquinol mesylate has potent antiviral and anti-inflammatory activity in preclinical models of SARS-CoV-2 infection.
Language	English
Publishing date	2022-06-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.02.22.481100
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