Untargeted LC-MS-based metabonomics revealed that aristolochic acid I induces testicular toxicity by inhibiting amino acids metabolism, glucose metabolism, β-oxidation of fatty acids and the TCA cycle in male mice

Cui, Yuan; Han, Jing; Ren, Juan; Chen, Huiming; Xu, Bo; Song, Naining; Li, Haishan; Liang, Aihua; Shen, Guolin

doi:10.1016/j.taap.2019.04.014

Cited by 33 publications

(17 citation statements)

References 47 publications

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“…Similarly, T2823 has been investigated in the treatment of cisplatin-induced hepatotoxicity via TLR4/NF-κBp50 signalling and BAMBI modulation of TGF-β activity [ 39 ]. T2801 plays multiple role as a nephrotoxin, a carcinogenic agent, a mutagen, a toxin and a metabolite too [ 40 , 41 , 42 , 43 , 44 ] (available experimental data regarding the other biological activities of the compounds and the activity profile is shown in Table S3 ).…”

Section: Resultsmentioning

confidence: 99%

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

et al. 2021

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The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.

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Section: Resultsmentioning

confidence: 99%

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

et al. 2021

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“…Recent studies have shown that metabolomics can identify and profile functional metabolites to reveal the varied pathological mechanisms of AAs-induced nephrotoxicity, which including the inhibition of amino acid metabolism, fatty acid metabolism, glucose metabolism and the TCA (Krebs) cycle [34][35][36][37]. However, the targeting mechanism of action is unclear.…”

Section: Discussionmentioning

confidence: 99%

Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics

Zhang¹,

Luo²,

Chen³

et al. 2022

Int. J. Biol. Sci.

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Aristolochic acid (AA), mainly derived from herbal Aristolochia and Asarum plants, was listed as a human carcinogen class I in 2002. Aristolochic acid nephropathy (AAN) is a rapidly progressive tubulointerstitial nephritis and urothelial cancer caused by AA. However, the targeting molecular mechanisms of AAs-induced nephrotoxicity are largely unclear. This study aims to dissect targeting molecular mechanisms of AA-induced nephrotoxicity. Activity-based protein profiling (ABPP) in combination with cellular thermal shift assay (CETSA) was performed to identify the AAs binding target proteins. Our data indicated that several key enzymes in the metabolic process and mitochondrial respiration including IDH2 and MDH2 (Krebs cycle), PKM and LDH (aerobic respiration), FASN (fatty acid beta-oxidation), HK2 (glucose metabolism), and ATP synthase were identified as directly binding targets of AAs. Metabolomics and oxygen consumption rate (OCR) experiments further confirmed that AAs targeting proteins disrupted metabolic biosynthesis processes and impaired mitochondrial functions. Ultimately, AAs induced renal cells apoptosis by disturbing various biological processes. Cumulatively, AAs may directly bind to key proteins involved in the metabolic process and mitochondrial homeostasis, and finally induce aristolochic acid nephropathy. Our findings provide novel insight into underlying mechanisms of AAs-induced kidney toxicity, which may help to develop therapeutic strategies for AAN.

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“…Several groups were successful in identifying potential biomarkers in several diseases using FD-LC-MS/MS [46,47]. Using untargeted LC-MS-based metabonomics can elucidate the mechanism of AA-induced testicular toxicity [48].…”

Section: Discussionmentioning

confidence: 99%

The Ginsenoside Rg1 Rescues Mitochondrial Disorders in Aristolochic Acid-Induced Nephropathic Mice

Chou

Huang

Lin

et al. 2021

Life

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Chronic exposure to aristolochic acid (AA) leads to renal interstitial fibrosis and nephropathy. In this study, we aimed to investigate the renoprotective effects of Panax ginseng extract (GE) and ginsenoside saponin (GS) on AA-induced nephropathy (AAN) in mice. Eighty female C3H/He mice were randomly divided into eight groups, including normal; AA (3 μg/mL for 56 days); AA with GE (125, 250, or 500 mg/kg/d for 14 days); and AA with important GE ingredients, Rg1, Rb1, or Rd (5 mg/kg/d for 14 days). Compared with the AA group, renal injuries were significantly decreased in the GE (250 mg/kg/d), Rb1, and Rg1 treatment groups. Rg1 exhibited the best renoprotection among all GS-treated groups. There were 24 peaks significantly altered among normal, AA, and AA + Rg1 groups, and four mitochondrial proteins were identified, including acyl-CoA synthetase medium-chain family member 2, upregulated during skeletal muscle growth 5 (Usmg5), mitochondrial aconitase 2 (ACO2), and cytochrome c oxidase subunit Va preprotein (COX5a). We demonstrated for the first time that the AAN mechanism and renoprotective effects of Rg1 are associated with expression of mitochondrial proteins, especially ACO2, Usmg5, and COX5a.

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Untargeted LC-MS-based metabonomics revealed that aristolochic acid I induces testicular toxicity by inhibiting amino acids metabolism, glucose metabolism, β-oxidation of fatty acids and the TCA cycle in male mice

Cited by 33 publications

References 47 publications

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics

The Ginsenoside Rg1 Rescues Mitochondrial Disorders in Aristolochic Acid-Induced Nephropathic Mice

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