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The Clinical Experiences of Urine Metabolomics of Genitourinary Urothelial Cancer in a Tertiary Hospital in Taiwan

ABSTRACT: There are few studies which have addressed the impact of diagnostic urine metabolites and clinical outcomes associated with genitourinary urothelial (GU) cancer till this date. Furthermore, the longitudinal analysis of the dynamics of urine metabolites contributing to the detection of GU cancer has not yet been fully investigated; therefore, the discovery of novel diagnostic urine biomarkers is of our enormous interest. We explored the correlation of the urine metabolomics profiles to the GU cancers. The aqueous metabolites of the GU cancer and the control were also identified and analyzed through high-resolution1H nuclear magnetic resonance (NMR) spectroscopy. Compared with the control, the urine metabolites of the tumor were studied in relation to changes over time in a linear mixed model for repeated measures. The urine metabololites of eighty-two (58 males and 24 female) patients with GU cancers were systemically analyzed. The urine metabolite profile in GU cancer was significantly higher than those in the control group (p<0.05). Seven urine metabolites including histidine, propylene glycol, valine, leucine, acetylsalicylate, glycine and isoleucine as well as other pathways were identified statistically significantly associated with GU cancer detection with longitudinal analysis. We discovered that histidine, propylene glycol, valine, leucine, acetylsalicylate, glycine, isoleucine, succinic acid, lysine2-aminobutyric acid and acetic acid are involved significantly in the all types of the male patients in whom the urine metabolites of the upper tract urothelial carcinoma(UTUC) were found statistically significance compared with the control. We did not find any statistically significance in urine biomarkers between female and male patients. However, a statistically insignificant correlation was found among the grade and stage with the metabolites.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

SUBMITTER: Horng-Heng Juang

PROVIDER: MTBLS2824 | MetaboLights | 2021-07-28

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS2824	Other
	FILES	Other
	a_MTBLS2824_NMR___metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS2824_NMR___metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Abstract: Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however it remains unclear whether individual BCAAs can attenuate already established NASH and oxidative-inflammatory stress associated with it. Therefore, mice were first put on a run-in fast food diet (FFD) for 26 weeks, these obese mice were then treated with individual BCAAs valine or isoleucine (3% of FFD) for another 12 weeks and compared to FFD controls. Valine and isoleucine treatment did not affect obesity, dyslipidemia, gut permeability or fecal fatty acid excretion, although significantly reduced hyperinsulinemia compared with FFD. Valine and isoleucine significantly reduced ALT, CK-18M30, and liver steatosis with a particularly pronounced effect on the microvesicular component (-61% by valine and -71% by isoleucine). Hepatic 4-hydroxynonenal (4-HNE) immunoreactivity, a marker for oxidative stress-induced lipid peroxidation, was also significantly decreased. Functional genomics analysis demonstrated that valine and isoleucine upregulated BCAA metabolism, deactivated master regulators of anabolic pathways related to steatosis (e.g. SREBPF1) and activated master regulators of mitochondrial biogenesis (e.g. PPARGC1a) and lipid catabolism (e.g. ACOX1, AMPK). The correction of critical metabolic pathways by valine and isoleucine was accompanied by a significant decrease of liver inflammation, and suppression of many FFD-stimulated cytokine and chemokine pathways including IL-1β, TNFα and CCR2 signaling. In conclusion, the dietary intervention with either valine or isoleucine corrected multiple metabolic processes in liver and reduced steatosis and inflammation with profound effects on oxidative stress and inflammatory pathways. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.

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The Clinical Experiences of Urine Metabolomics of Genitourinary Urothelial Cancer in a Tertiary Hospital in Taiwan

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