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Article ; Online: Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.

Di Lucente, Jacopo / Persico, Giuseppe / Zhou, Zeyu / Jin, Lee-Way / Ramsey, Jon J / Rutkowsky, Jennifer M / Montgomery, Claire M / Tomilov, Alexey / Kim, Kyoungmi / Giorgio, Marco / Maezawa, Izumi / Cortopassi, Gino A

Communications biology

2024 Volume 7, Issue 1, Page(s) 195

Abstract: The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by ...

Abstract	The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD's 'main actor' is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD's 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB's enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer's Disease.
MeSH term(s)	Humans ; Mice ; Animals ; Aged ; Long-Term Potentiation ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Diet, Ketogenic ; Mice, Transgenic ; Mice, Inbred C57BL ; Neuronal Plasticity
Chemical Substances	Amyloid beta-Protein Precursor
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05860-z
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Article ; Online: Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.

Jiang, Joy X / Tomilov, Alexey / Montgomery, Claire / Hui, Chun Kui / Török, Natalie J / Cortopassi, Gino

Journal of biochemical and molecular toxicology

2021 Volume 35, Issue 10, Page(s) e22876

Abstract: Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH-thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc ...

Abstract	Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH-thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.
MeSH term(s)	Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Choline Deficiency/complications ; Diet/adverse effects ; Disease Models, Animal ; Fast Foods/adverse effects ; Leukocytes, Mononuclear/metabolism ; Liver/injuries ; Liver/metabolism ; Liver Cirrhosis/blood ; Liver Cirrhosis/complications ; Liver Cirrhosis/drug therapy ; Liver Cirrhosis/etiology ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/blood ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/drug therapy ; Non-alcoholic Fatty Liver Disease/etiology ; Phosphorylation/drug effects ; Protective Agents/administration & dosage ; Shc Signaling Adaptor Proteins/antagonists & inhibitors ; Shc Signaling Adaptor Proteins/metabolism ; Signal Transduction/drug effects ; Therapeutics ; Ubiquinone/administration & dosage ; Ubiquinone/analogs & derivatives
Chemical Substances	Protective Agents ; Shc Signaling Adaptor Proteins ; Ubiquinone (1339-63-5) ; Methionine (AE28F7PNPL) ; Aspartate Aminotransferases (EC 2.6.1.1) ; Alanine Transaminase (EC 2.6.1.2) ; idebenone (HB6PN45W4J)
Language	English
Publishing date	2021-08-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1410020-4
ISSN	1099-0461 ; 1095-6670
ISSN (online)	1099-0461
ISSN	1095-6670
DOI	10.1002/jbt.22876
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Article ; Online: Small molecules bind human mTOR protein and inhibit mTORC1 specifically.

Allen, Sonia A / Tomilov, Alexey / Cortopassi, Gino A

Biochemical pharmacology

2018 Volume 155, Page(s) 298–304

Abstract: Inhibition of mTOR activity (mechanistic target of rapamycin) is an anti-cancer therapeutic strategy. mTOR participates in two functional complexes, mTORC1 and mTORC2. Since mTORC1 is specifically activated in multiple tumors, novel molecules that ... ...

Abstract	Inhibition of mTOR activity (mechanistic target of rapamycin) is an anti-cancer therapeutic strategy. mTOR participates in two functional complexes, mTORC1 and mTORC2. Since mTORC1 is specifically activated in multiple tumors, novel molecules that inhibit mTORC1 could be therapeutically important. To identify potentially novel modulators of mTOR pathways, we screened 1600 small molecule human drugs for mTOR protein binding, using novel biolayer interferometry technology. We identified several small molecules that bound to mTOR protein in a dose-dependent manner, on multiple chemical scaffolds. As mTOR participates in two major complexes, mTORC1 and mTORC2, the functional specificities of the binders were measured by S6Kinase and Akt phosphorylation assays. Three novel 'mTOR general' binders were identified, carvedilol, testosterone propionate, and hydroxyprogesterone, which inhibited both mTORC1 and mTORC2. By contrast, the piperazine drug cinnarizine dose-dependently inhibited mTORC1 but not mTORC2, suggesting it as a novel mTORC1-specific inhibitor. Some of cinnarizine's chemical analogs also inhibited mTORC1 specifically, whereas others did not. Thus we report the existence of a novel target for some related piperazines including cinnarizine and hydroxyzine, i.e. specific inhibition of mTORC1 activity. Since mTOR inhibition is a general anti-cancer strategy, and mTORC1 is specifically activated in some tumors, we suggest the piperazine scaffold, including cinnarizine and hydroxyzine, could be proposed for rational therapy in tumors in which mTORC1 is specifically activated. Related piperazines have shown toxicity to cancer cells in vitro as single agents and in combination chemotherapy. Thus piperazine-based mTOR inhibitors could become a novel chemotherapeutic strategy.
MeSH term(s)	Animals ; Carvedilol/metabolism ; Carvedilol/pharmacology ; Cinnarizine/metabolism ; Cinnarizine/pharmacology ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Protein Binding/drug effects ; Protein Binding/physiology ; Sirolimus/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Carvedilol (0K47UL67F2) ; Cinnarizine (3DI2E1X18L) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2018-07-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2018.07.013
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Zs.A 19: Show issues

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Article ; Online: The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.

Jin, Lee-Way / Di Lucente, Jacopo / Ruiz Mendiola, Ulises / Suthprasertporn, Nopparat / Tomilov, Alexey / Cortopassi, Gino / Kim, Kyoungmi / Ramsey, Jon J / Maezawa, Izumi

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

2023 Volume 37, Issue 11, Page(s) e23261

Abstract: Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet ...

Abstract	Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aβ oligomer (AβO)-stimulated human iPS-derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1-2 mM. AβO stimulated glycolytic transcripts, suppressed genes in the β-oxidation pathway, and induced over-expression of AD-relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AβO also triggered mitochondrial Ca
MeSH term(s)	Humans ; Animals ; Mice ; 3-Hydroxybutyric Acid/pharmacology ; Microglia ; Amyloid beta-Peptides ; Ketone Bodies ; Inflammation ; Alzheimer Disease
Chemical Substances	3-Hydroxybutyric Acid (TZP1275679) ; Amyloid beta-Peptides ; Ketone Bodies
Language	English
Publishing date	2023-10-25
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.202301254R
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Article ; Online: Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations.

Datta, Sandipan / Tomilov, Alexey / Cortopassi, Gino

Mitochondrion

2016 Volume 30, Page(s) 177–186

Abstract: Inherited mitochondrial complex I mutations cause blinding Leber's hereditary optic neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient ... ...

Abstract	Inherited mitochondrial complex I mutations cause blinding Leber's hereditary optic neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models.
MeSH term(s)	Adenosine Triphosphate/biosynthesis ; Cell Line ; Drug Evaluation, Preclinical ; Electron Transport Complex I/metabolism ; Humans ; Metabolic Networks and Pathways/drug effects ; Optic Atrophy, Hereditary, Leber/drug therapy ; Papaverine/metabolism ; Pyridines/metabolism
Chemical Substances	Pyridines ; zolpidem (7K383OQI23) ; Adenosine Triphosphate (8L70Q75FXE) ; Papaverine (DAA13NKG2Q) ; Electron Transport Complex I (EC 1.6.5.3)
Language	English
Publishing date	2016
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2056923-3
ISSN	1872-8278 ; 1567-7249
ISSN (online)	1872-8278
ISSN	1567-7249
DOI	10.1016/j.mito.2016.08.002
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Article ; Online: Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition.

Tomilov, Alexey / Allen, Sonia / Hui, Chun Kiu / Bettaieb, Ahmed / Cortopassi, Gino

Pharmacological research

2018 Volume 137, Page(s) 89–103

Abstract: When insulin binds insulin receptor, IRS1 signaling is stimulated to trigger the maximal insulin response. p52Shc protein competes directly with IRS1, thus damping and diverting maximal insulin response. Genetic reduction of p52Shc minimizes competition ... ...

Abstract	When insulin binds insulin receptor, IRS1 signaling is stimulated to trigger the maximal insulin response. p52Shc protein competes directly with IRS1, thus damping and diverting maximal insulin response. Genetic reduction of p52Shc minimizes competition with IRS1, and improves insulin signaling and glucose control in mice, and improves pathophysiological consequences of hyperglycemia. Given the multiple benefits of Shc reduction in vivo, we investigated whether any of 1680 drugs used in humans may function as Shc inhibitors, and thus potentially serve as novel anti-diabetics. Of the 1680, 30 insulin sensitizers were identified by screening in vitro, and of these 30 we demonstrated that 7 bound Shc protein. Of the 7 drugs, idebenone dose-dependently bound Shc protein in the 50-100 nM range, and induced insulin sensitivity and cytoprotection in this same 100 nM range that clinically dosed idebenone reaches in human plasma. By contrast we observe mitochondrial effects of idebenone in the 5,000 nM range that are not reached in human dosing. Multiple assays of target engagement demonstrate that idebenone physically interacts with Shc protein. Idebenone sensitizes mice to insulin in two different mouse models of prediabetes. Genetic depletion of idebenone's target eliminates idebenone's ability to insulin-sensitize in vivo. Thus, idebenone is the first-in-class member of a novel category of insulin-sensitizing and cytoprotective agents, the Shc inhibitors. Idebenone is an approved drug and could be considered for other indications such as type 2 diabetes and fatty liver disease, in which insulin resistance occurs.
MeSH term(s)	Animals ; Cell Line ; Cytoprotection ; Diabetes Mellitus, Experimental/drug therapy ; Drug Repositioning ; Female ; High-Throughput Screening Assays ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin/pharmacology ; Insulin Resistance ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Docking Simulation ; Receptor, Insulin/metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1/antagonists & inhibitors ; Src Homology 2 Domain-Containing, Transforming Protein 1/metabolism ; Ubiquinone/analogs & derivatives ; Ubiquinone/pharmacology
Chemical Substances	Hypoglycemic Agents ; Insulin ; SHC1 protein, human ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Ubiquinone (1339-63-5) ; Receptor, Insulin (EC 2.7.10.1) ; idebenone (HB6PN45W4J)
Language	English
Publishing date	2018-10-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2018.09.024
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Zs.A 721: Show issues

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Article ; Online: Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer.

Allen, Sonia A / Datta, Sandipan / Sandoval, Jose / Tomilov, Alexey / Sears, Thomas / Woolard, Kevin / Angelastro, James M / Cortopassi, Gino A

Mitochondrion

2019 Volume 50, Page(s) 19–24

Abstract: AMP-activated protein kinase (AMPK) is a eukaryotic energy sensor and protector from mitochondrial/energetic stress that is also a therapeutic target for cancer and metabolic disease. Metformin is an AMPK inducer that has been used in cancer therapeutic ... ...

Abstract	AMP-activated protein kinase (AMPK) is a eukaryotic energy sensor and protector from mitochondrial/energetic stress that is also a therapeutic target for cancer and metabolic disease. Metformin is an AMPK inducer that has been used in cancer therapeutic trials. Through screening we isolated cetylpyridinium chloride (CPC), a drug known to dose-dependently inhibit mitochondrial complex 1, as a potent and dose-dependent AMPK stimulator. Mitochondrial biogenesis and bioenergetics changes have also been implicated in glioblastoma, which is the most aggressive form of brain tumors. Cetylpyridinium chloride has been administered in humans as a safe drug-disinfectant for several decades, and we report here that under in vitro conditions, cetylpyridinium chloride kills glioblastoma cells in a dose dependent manner at a higher efficacy compared to current standard of care drug, temozolomide.
MeSH term(s)	Adenylate Kinase/metabolism ; Animals ; Anti-Infective Agents, Local/pharmacology ; Antineoplastic Agents/pharmacology ; Cell Line ; Cell Survival ; Cetylpyridinium/pharmacology ; Glioma/drug therapy ; Hepatocytes/drug effects ; Humans ; Mice ; Neoplastic Stem Cells/drug effects
Chemical Substances	Anti-Infective Agents, Local ; Antineoplastic Agents ; Cetylpyridinium (CUB7JI0JV3) ; Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2019-10-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2056923-3
ISSN	1872-8278 ; 1567-7249
ISSN (online)	1872-8278
ISSN	1567-7249
DOI	10.1016/j.mito.2019.09.009
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Article ; Online: Shc Is Implicated in Calreticulin-Mediated Sterile Inflammation in Alcoholic Hepatitis.

Li, Yuan / Jiang, Joy X / Fan, Weiguo / Fish, Sarah R / Das, Suvarthi / Gupta, Parul / Mozes, Gergely / Vancza, Lorand / Sarkar, Sutapa / Kunimoto, Koshi / Chen, Dongning / Park, Hyesuk / Clemens, Dahn / Tomilov, Alexey / Cortopassi, Gino / Török, Natalie J

Cellular and molecular gastroenterology and hepatology

2022 Volume 15, Issue 1, Page(s) 197–211

Abstract: Background & aims: Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We ... ...

Abstract	Background & aims: Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells. Methods: Liver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice. Results: Shc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury. Conclusions: Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.
MeSH term(s)	Mice ; Animals ; bcl-2-Associated X Protein ; Hepatitis, Alcoholic ; Caspase 8 ; Calreticulin ; NAD ; Mice, Knockout ; Ethanol ; Inflammation ; Collagen
Chemical Substances	bcl-2-Associated X Protein ; Caspase 8 (EC 3.4.22.-) ; Calreticulin ; NAD (0U46U6E8UK) ; Ethanol (3K9958V90M) ; Collagen (9007-34-5)
Language	English
Publishing date	2022-09-17
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.
ZDB-ID	2819778-1
ISSN	2352-345X ; 2352-345X
ISSN (online)	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2022.09.005
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Article ; Online: In Vitro

Datta, Sandipan / He, Guochun / Tomilov, Alexey / Sahdeo, Sunil / Denison, Michael S / Cortopassi, Gino

Environmental health perspectives

2017 Volume 125, Issue 8, Page(s) 87015

Abstract: Background: Quaternary ammonium salts (QUATS), such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAK), are frequently used in antiseptic formulations, including toothpastes, mouthwashes, lozenges, throat and nasal sprays, and as biocides. ...

Abstract	Background: Quaternary ammonium salts (QUATS), such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAK), are frequently used in antiseptic formulations, including toothpastes, mouthwashes, lozenges, throat and nasal sprays, and as biocides. Although in a recent ruling, the U.S. Food and Drug Administration (FDA) banned CPC from certain products and requested more data on BAK's efficacy and safety profile, QUATS, in general, and CPC and BAK, in particular, continue to be used in personal health care, food, and pharmaceutical and cleaning industries. Objectives: We aimed to assess CPC's effects on mitochondrial toxicity and endocrine disruption Method: Mitochondrial O Results: CPC inhibited both mitochondrial O Conclusions: Mitochondrial inhibition
MeSH term(s)	Anti-Infective Agents, Local/toxicity ; Cell Line, Tumor ; Cetylpyridinium/toxicity ; Humans ; Mitochondria/drug effects
Chemical Substances	Anti-Infective Agents, Local ; Cetylpyridinium (CUB7JI0JV3)
Language	English
Publishing date	2017--22
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP1404
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Zs.MO 379: Show issues

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Article: Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells.

Sandoval, Jose A / Tomilov, Alexey / Datta, Sandipan / Allen, Sonia / O'Donnell, Robert / Sears, Thomas / Woolard, Kevin / Kovalskyy, Dmytro / Angelastro, James M / Cortopassi, Gino

Pharmaceuticals (Basel, Switzerland)

2020 Volume 13, Issue 12

Abstract: Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian ... ...

Abstract	Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.
Language	English
Publishing date	2020-11-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph13120419
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In stock of ZB MED Cologne/Königswinter

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Full text online

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

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Kategorien

Order via subito

Full text online

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito