Metabolomics insights into diabetes nephropathy and protective effects of Radix Scutellariae on rats using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry

Men, Lihui; Pi, Zifeng; Zhou, Yuan; Liu, Yuan Yuan; Wei, Mengying; Song, Fengrui; Liu, Zhongying

doi:10.1039/c6ra28595c

Cited by 12 publications

(7 citation statements)

References 47 publications

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“…The metabolism of aromatic amino acids, especially phenylalanine and tyrosine, was considered to be correlated with CKD and DN [62,63]. Changes in phenylalanine metabolism showed a close association with chronic kidney failure, including extensive urinary excretion of its down products [64].…”

Section: Discussionmentioning

confidence: 99%

The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

Gao

Yang

et al. 2018

Acta Pharmacol Sin

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Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-β1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

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Section: Discussionmentioning

confidence: 99%

The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

Gao

Yang

et al. 2018

Acta Pharmacol Sin

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“…This study showed for the first time that in untreated AKU there is alteration to tyrosine, purine and TCA cycle metabolites ( Figure 5). These data add to a growing body of evidence from metabolomic studies that perturbations in tyrosine, purine and energy metabolism are linked in numerous diseases including Alzheimer's (Kaddurah-Daouk et al, 2011, depression (Weng et al, 2015) and diabetic nephropathy (Men et al, 2017).…”

Section: Associated Alteration To Tyrosine Purine and Tca Cycle Metamentioning

confidence: 67%

“…The increased xanthosine and decreased 2,3-cyclic AMP and inosine 5'-monophosphate reported here for Hgd -/mice is consistent with a shift in purine catabolism in response to oxidative conditions induced by HGA and ochronosis, as xanthosine is a direct precursor for xanthine and uric acid. Xanthosine is increased in urine from rats with other oxidative diseases, including chronic kidney disease (Zhang et al, 2015) and diabetes nephropathy, and markedly decreased following administration of nephroprotective therapy (Men et al, 2017). The alteration in purine metabolism perhaps most associated with pathology is elevated uric acid, the classic example being gout, in which elevated blood uric acid is the direct cause of a painful arthropathy.…”

Section: Alteration To Purine Metabolismmentioning

confidence: 99%

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Norman

Davison

Hughes

et al. 2020

Preprint

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Bullet point summaryWhat is already known  Increased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuria  The Hgd knockout mouse, created in our laboratory, accurately models human alkaptonuria What this study adds  Phase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acid  These data challenge misconceptions that phase I and II metabolism is solely for drug clearance Clinical significance  Phase I and II metabolic processes represent new treatment targets in inherited metabolic diseases  The molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism 3 4 Abstract Background and Purpose: alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted Hgd disruption. Experimental Approach: the first metabolomic analysis of the Hgd -/-AKU mouse model was performed. Urinary metabolites altered in Hgd -/were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU Key Results: comparison of Hgd -/-(AKU) versus Hgd +/-(heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways.Conclusion and Implications: AKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenouslyproduced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases.

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“…5-HTP is the immediate precursor of serotonin, which has been shown to inhibit apoptosis in multiple immune cell types under inflammatory conditions 64 . In terms of 3-MDI, reports exist in the literature regarding its detection in rat urine 65 , serum 66 and human breath 67 , but its function in MSCs upon inflammatory stimulation is yet unclear.…”

Section: Resultsmentioning

confidence: 99%

Sub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples

Bouza

et al. 2020

Nat Commun

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The human metabolome provides a window into the mechanisms and biomarkers of various diseases. However, because of limited availability, many sample types are still difficult to study by metabolomic analyses. Here, we present a mass spectrometry (MS)-based metabolomics strategy that only consumes sub-nanoliter sample volumes. The approach consists of combining a customized metabolomics workflow with a pulsed MS ion generation method, known as triboelectric nanogenerator inductive nanoelectrospray ionization (TENGi nanoESI) MS. Samples tested with this approach include exhaled breath condensate collected from cystic fibrosis patients as well as in vitro-cultured human mesenchymal stromal cells. Both test samples are only available in minimum amounts. Experiments show that picoliter-volume spray pulses suffice to generate high-quality spectral fingerprints, which increase the information density produced per unit sample volume. This TENGi nanoESI strategy has the potential to fill in the gap in metabolomics where liquid chromatography-MS-based analyses cannot be applied. Our method opens up avenues for future investigations into understanding metabolic changes caused by diseases or external stimuli.

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Metabolomics insights into diabetes nephropathy and protective effects of Radix Scutellariae on rats using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry

Abstract: UHPLC-Q-TOF-MS based metabolomics combined with multivariate statistical analysis for evaluating protective effects ofRadix Scutellariaeon DN rats.

Cited by 12 publications

References 47 publications

The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Sub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples

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