Trehalose ameliorates autophagy dysregulation in aged cortex and acts as an exercise mimetic to delay brain aging in elderly mice

Pan, Shanyao; Guo, Shanshan; Dai, Jia-Ru; Gu, Yanrong; Wang, Guoxiang; Wang, Yulong; Qin, Zheng‐Hong; Li, Luo

doi:10.1016/j.fshw.2022.03.028

Cited by 3 publications

(5 citation statements)

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“…This study highlights several pharmacodynamic features of trehalose which are relevant to its use in pharmaceutical formulations. The desirable physicochemical and pharmacokinetic properties of trehalose observed in this study are consistent with several previous in vivo studies [6, 9, 38, 39, 46, 47] which validate its use as a pharmaceutical excipient. Among these desirable excipient properties are its lipophilicity, poor gastrointestinal permeability, slower metabolism, and negligible interference with the liver cytochrome p450 enzymes.…”

Section: Discussionsupporting

confidence: 91%

“…The GRAS label for trehalose is largely based on historical evidence of safety and a limited number of assessments using rodent and rabbit models. [6][7][8][9][38][39][40] Although excipients are assumed to be pharmacologically inert, this can largely be attributed to a lack of suitable bioassays to quantify their pharmacodynamic effects in parallel to historical evidence of their safety. However, no chemical entity can be considered truly inert, and this especially applies to pharmaceutical excipients which are often used in much higher concentrations than the API.…”

Section: Discussionmentioning

confidence: 99%

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A network pharmacology approach to assess the comparative pharmacodynamics of pharmaceutical excipient trehalose in human, mouse and rat

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Kumar

2023

Preprint

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Background: Trehalose is used as a pharmaceutical excipient due to its several desirable pharmacokinetic and historically evident safety features. However, information on the pharmacodynamic properties of trehalose is lacking. Hence this study evaluated the comparative pharmacodynamic properties of trehalose using a network pharmacology approach. Materials and methods: The specific targets of trehalose in human, mouse and rat were identified from the SwissTargetPrediction database, categorised and compared. The expression profile and subcellular localisation of the targets of trehalose in human was identified and correlated with the affinity of trehalose to these targets to assess its impact on the pharmacodynamic properties of trehalose. The affinity of trehalose to its metabolising enzyme in human, mouse, and rat was assessed by molecular docking and compared. Results: A significant difference in the target categories and target types of trehalose was observed in human, mouse, and rat. The affinity of trehalose to human (66.03 +/- 5.1 microM), rat (102.53 +/- 11.3 microM) and mouse (42.07 +/- 5.3 microM) trehalase was significantly different. Family A G protein coupled receptors were identified as the major target category of trehalose and cyclin dependent kinase 1 was observed as the high affinity target of trehalose in human and mouse. The correlation of target expression and affinity indicated minimal pharmacodynamic influence under physiological conditions. Conclusion: This study reports the selective targets of trehalose relevant to drug discovery and development protocols and highlights the limitations of rodent models in translating pharmacodynamic analysis of trehalose for development of human therapeutics.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A network pharmacology approach to assess the comparative pharmacodynamics of pharmaceutical excipient trehalose in human, mouse and rat

Friend

Kumar

2023

Preprint

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“…[41][42][43][44][45] This study highlights several pharmacodynamic features of trehalose which are relevant to its use in pharmaceutical formulations. The desirable physicochemical and pharmacokinetic properties of trehalose observed in this study are consistent with several previous in vivo studies, 6,9,38,39,46,47 which validate its use as a pharmaceutical excipient. Among these desirable excipient properties are its lipophilicity, poor gastrointestinal permeability, slower metabolism, and negligible interference with liver cytochrome p450 enzymes.…”

Section: Discussionsupporting

confidence: 90%

“…The GRAS label for trehalose is largely based on historical evidence of its safety and a limited number of assessments using rodent and rabbit models. [6][7][8][9][38][39][40] Although excipients are assumed to be pharmacologically inert, this can largely be attributed to a lack of suitable bioassays to quantify their pharmacodynamic effects in parallel to historical evidence of their safety. However, no chemical entity can be considered truly inert, and this especially applies to pharmaceutical excipients, which are often used in much higher concentrations than the API.…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Assess the Comparative Pharmacodynamics of Pharmaceutical Excipient Trehalose in Human, Mouse, and Rat

Friend,

Kumar

2023

Nature Cell and Science

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disaccharide formed from two α-glucose units joined by a 1-1 glycosidic bond. The alpha-1,1-isomer is quite common across fungi, plants, and insects, where it is suggested that trehalose is used as a natural energy storehouse or cryptobiotic. 11,12 Trehalose synthesis is absent in vertebrates, and there are no trehalose synthesis genes in vertebrates. 13 However, the trehalose-catabolizing enzyme trehalase (EC 3.2.1.28) is reported in vertebrates, including mammals,

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“…As a result of exposure to TRE, cells can retain more water during stress, protecting intracellular organelles from disruption by hydration/dehydration cycles [19]. Additionally, TRE reduces the accumulation of misfolded proteins and intracellular protein aggregates [20]. It has been shown that TRE reduces the accumulation of ubiquitinated proteins, can reduce skeletal muscle denervation, protect mitochondria, and (taken in general) it can be neuroprotective in the amyotrophic lateral sclerosis (ALS) mouse model, suggesting that it might be a therapeutic target for the treatment of ALS and several other types of neurodegenerative disease [21].…”

Section: Introductionmentioning

confidence: 99%

The effect of trehalose administration on the serum expression levels of microRNAs associated with lipid metabolism and autophagy process in patients with myocardial infarction - the post-hoc analysis of the TREAT-IR trial.

et al. 2023

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IntroductionThis study aimed to evaluate the TRE-induced changes in the serum expression levels of miRNAs associated with lipids metabolism and autophagy process in MI patients to assess the potential protective effects of TRE in these patients.Material and methodsThis post hoc investigation was performed on serum samples obtained from a pilot randomized, double blind, placebo-controlled clinical trial that recruited 14 men (aged 18-80) who had MI and systemic inflammation. The patients were randomized in a 2:1 ratio to either TRE (15 g/week, intravenous (IV) ad-ministration) (N=10) or placebo groups (equal volume of saline 0.9 %) (N=4) for a period of 12 weeks. To measure the relative serum expression levels of miRNA-155, miRNA-221, and miRNA-33, the SYBR Green qPCR method was used.ResultsmiRNA-155 showed significantly higher serum expression levels in the TRE group (2.772±0.73; P=0.009) when compared to the placebo group. Also, significant reductions in miRNA-155 (0.171±0.03; P=0.016), miRNA-221 (0.116±0.07; P=0.013), and miRNA-33a (0.076±0.07; P=0.025) were observed in the placebo group at the end of the study. Nevertheless, the reduction (normalized to the baseline) of the serum expres-sion levels of miRNA-221 (FC:0.87±0.20 vs FC:0.18±0.08; P=0.009) and miRNA-33a (FC:0.73±0.22 vs FC:0.13±0.08; P=0.025) were significantly less in TRE group than in the placebo group.ConclusionsIV TRE administration did not reduce the expression of miRNA-221 and miRNA33a as much as placebo. Keeping a steady state of the serum expression levels of these miRNAs associated with lipoproteins metabolism and autophagy in the TRE group might have protective effects in patients with MI.

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Trehalose ameliorates autophagy dysregulation in aged cortex and acts as an exercise mimetic to delay brain aging in elderly mice

Cited by 3 publications

References 57 publications

A network pharmacology approach to assess the comparative pharmacodynamics of pharmaceutical excipient trehalose in human, mouse and rat

A network pharmacology approach to assess the comparative pharmacodynamics of pharmaceutical excipient trehalose in human, mouse and rat

A Network Pharmacology Approach to Assess the Comparative Pharmacodynamics of Pharmaceutical Excipient Trehalose in Human, Mouse, and Rat

The effect of trehalose administration on the serum expression levels of microRNAs associated with lipid metabolism and autophagy process in patients with myocardial infarction - the post-hoc analysis of the TREAT-IR trial.

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