Metabolomic Analysis of Complex Chinese Remedies: Examples of Induced Nephrotoxicity in the Mouse from a Series of Remedies Containing Aristolochic Acid

Aristolochic acid nephropathy is caused by aristolochic acid (AA) and AA-containing herbs. In traditional Chinese medicine, a principle called “Jun-Chen-Zou-Shi” may be utilized to construct a remedial herbal formula that attempts to mitigate the toxicity of the main ingredient. This study usedBu-Fei-A-Jiao-Tang(BFAJT) to test if the compound remedy based on a principle of “Jun-Chen-Zou-Shi” can decrease the toxicity of AA-containing herbs. We compared the three toxicities of AA standard,Madouling(anAristolochiaherb), and a herbal formula BFAJT. AA standard was given for BALB/c mice at a dose of 5 mg/kg bw/day or 7.5 mg/kg bw/day for 10 days.Madoulingand BFAJT were given at an equivalence of AA 0.5 mg/kg bw/day for 21 days. Nephrotoxicity was evaluated by metabolomics and histopathology. The urinary metabolomics profiles were characterized by1H NMR spectroscopy. The spectral data was analyzed with partial least squares discriminant analysis, and the significant differential metabolites between groups were identified. The result showed different degrees of acute renal tubular injuries, and metabolomics analysis found that the kidney injuries were focused in proximal renal tubules. Both metabolomics and pathological studies revealed that AA standard,Madouling, and BFAJT were all nephrotoxicants. The compositions of the compound remedy did not diminish the nephrotoxicity caused by AA.

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Discriminant Analysis of Traditional Chinese Medicinal Properties Based on Holistic Chemical Profiling by 1H-NMR Spectrometry

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3141340 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Jie Zhang ◽

Wenna Guo ◽

Qiao Li ◽

Faxin Sun ◽

Xiaomeng Xu ◽

...

Keyword(s):

Discriminant Analysis ◽

Chinese Medicine ◽

Principal Component ◽

Linear Discriminant ◽

Chemical Profiling ◽

H Nmr ◽

Nmr Spectrometry ◽

Cinnamomi Cortex ◽

Medicinal Properties ◽

Leave One Out

Medicinal property, which is closely related to drug chemical profiling, is the essence of traditional Chinese medicine (TCM) theory and has always been the focus of modern Chinese medicine. Based on dozens of classic and commonly used TCM herbs with recognized medicinal properties, the present study just aimed to investigate the feasibility and reliability of medicinal property discriminant by using 1H-NMR spectrometry, which provided a mass of spectral data showing holistic chemical profile for multivariate analysis and data mining, including principal component analysis (PCA), Fisher linear discriminant analysis (FLDA), and canonical discriminant analysis (CDA). By using FLDA for two-class recognition, a large majority of test herbs (59/61) were properly discriminated as cold or hot group, and the only two exceptions were Chuanbeimu (Fritillariae Cirrhosae Bulbus) and Rougui (Cinnamomi Cortex), suggesting that medicinal properties interrelate with flavor and body tropism, and all these factors together bring up medicinal property and efficacy. While by performing CDA, 98.4% of the original grouped herbs and 77.0% of the leave-one-out cross-validated grouped cases were correctly classified. The findings demonstrated that discriminant analysis based on holistic chemical profiling data by 1H-NMR spectrometry may provide a powerful alternative to have a deeper understanding of TCM medicinal property.

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Nephroprotective Role of Zhibai Dihuang Wan in Aristolochic Acid-Intoxicated Zebrafish

BioMed Research International ◽

10.1155/2020/5204348 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Ping-Hsun Lu ◽

Hsun-Yao Lee ◽

Yan-Liang Liou ◽

Sheng-Fen Tung ◽

Ko-Li Kuo ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Aristolochic Acid ◽

Transgenic Zebrafish ◽

Herbal Formula ◽

Zebrafish Model ◽

Green Fluorescent ◽

Nephroprotective Effect ◽

Kidney Malformations

Zhibai Dihuang Wan (ZDW) is an eight-herbal formula of traditional Chinese medicine. Clinically, it regulated immune activity and was used to treat diabetes and renal disease. In this study, we aimed to explore the nephroprotective effect of ZDW in an aristolochic acid- (AA-) intoxicated zebrafish model. We used a green fluorescent kidney transgenic zebrafish to evaluate the nephroprotective effects of ZDW by recording subtle changes in the kidney. Our results demonstrated that ZDW treatment can attenuate AA-induced kidney malformations (60% for AA-treated, 47% for pretreatment with ZDW, and 17% for cotreatment ZDW with AA, n = 50 ). Furthermore, we found that the expression levels of tnfα and mpo were decreased either in pretreatment or cotreatment groups. In conclusion, our findings revealed that AA-induced nephrotoxicities can be attenuated by ZDW. Therefore, we believe that zebrafish represent an efficient model for screening AA-protective Chinese medicine.

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Aristolochic acid induces renal tubular injury and inhibits expression of bone morphogenetic protein-7 mRNA in renal tissue of rats

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20080514 ◽

2008 ◽

Vol 6 (5) ◽

pp. 502-507 ◽

Cited By ~ 2

Author(s):

HL Wang

Keyword(s):

Bone Morphogenetic Protein ◽

Aristolochic Acid ◽

Renal Tissue ◽

Tubular Injury ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein ◽

Renal Tubular

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Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

Cell Death and Disease ◽

10.1038/s41419-021-03709-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Bohan Chen ◽

Pei Wang ◽

Xianhui Liang ◽

Chunming Jiang ◽

Yan Ge ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Binding Protein ◽

Renal Tubules ◽

Genetic Ablation ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Renal Fibrogenesis ◽

Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

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Putative imbalanced amino acid metabolism in rainbow trout long term fed a plant-based diet as revealed by 1H-NMR metabolomics

Journal of Nutritional Science ◽

10.1017/jns.2021.3 ◽

2021 ◽

Vol 10 ◽

Author(s):

Catherine Deborde ◽

Blandine Madji Hounoum ◽

Annick Moing ◽

Mickaël Maucourt ◽

Daniel Jacob ◽

...

Keyword(s):

Amino Acids ◽

Rainbow Trout ◽

Amino Acid ◽

Amino Acid Content ◽

Proton Nuclear Magnetic Resonance ◽

Free Form ◽

Metabolomic Analysis ◽

Nmr Metabolomics ◽

H Nmr

Abstract The long-term effect of a plant (P)-based diet was assessed by proton nuclear magnetic resonance (1H-NMR) metabolomics in rainbow trout fed a marine fish meal (FM)–fish oil (FO) diet (M), a P-based diet and a control commercial-like diet (C) starting with the first feeding. Growth performances were not heavily altered by long-term feeding on the P-based diet. An 1H-NMR metabolomic analysis of the feed revealed significantly different soluble chemical compound profiles between the diets. A set of soluble chemical compounds was found to be specific either to the P-based diet or to the M diet. Pterin, a biomarker of plant feedstuffs, was identified both in the P-based diet and in the plasma of fish fed the P-based diet. 1H-NMR metabolomic analysis on fish plasma and liver and muscle tissues at 6 and 48 h post feeding revealed significantly different profiles between the P-based diet and the M diet, while the C diet showed intermediate results. A higher amino acid content was found in the plasma of fish fed the P-based diet compared with the M diet after 48 h, suggesting either a delayed delivery of the amino acids or a lower amino acid utilisation in the P-based diet. This was associated with an accumulation of essential amino acids and the depletion of glutamine in the muscle, together with an accumulation of choline in the liver. Combined with an anticipated absorption of methionine and lysine supplemented in free form, the present results suggest an imbalanced essential amino acid supply for protein metabolism in the muscle and for specific functions of the liver.

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Metabolomics study of the therapeutic mechanism of a Chinese herbal formula on collagen-induced arthritis mice

RSC Advances ◽

10.1039/c8ra05528a ◽

2019 ◽

Vol 9 (7) ◽

pp. 3716-3725 ◽

Cited By ~ 1

Author(s):

Zhen Jin ◽

Ji-da Zhang ◽

Xin Wu ◽

Gang Cao

Keyword(s):

Rheumatoid Arthritis ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Herbal Formula ◽

Collagen Induced Arthritis ◽

Chinese Herbal Formula ◽

Chinese Herbal ◽

Therapeutic Mechanism ◽

Metabolomics Study

Wenjinghuoluo (WJHL) prescription, the typical rheumatoid arthritis (RA) treatment compound in traditional Chinese medicine, shows favorable efficacy.

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High sucrose diet induces morphological, structural and functional impairments in the renal tubules of Drosophila melanogaster: A model for studying type-2 diabetes mediated renal tubular dysfunction

Insect Biochemistry and Molecular Biology ◽

10.1016/j.ibmb.2020.103441 ◽

2020 ◽

Vol 125 ◽

pp. 103441

Author(s):

Lavi Rani ◽

Sanjay Saini ◽

Neha Shukla ◽

Debapratim Kar Chowdhuri ◽

Naveen Kumar Gautam

Keyword(s):

Type 2 Diabetes ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Renal Tubules ◽

Functional Impairments ◽

Sucrose Diet ◽

High Sucrose Diet ◽

Renal Tubular ◽

High Sucrose

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Clinical Strategy for Optimal Traditional Chinese Medicine (TCM) Herbal Dose Selection in Disease Therapeutics: Expert Consensus on Classic TCM Herbal Formula Dose Conversion

The American Journal of Chinese Medicine ◽

10.1142/s0192415x1550086x ◽

2015 ◽

Vol 43 (08) ◽

pp. 1515-1524 ◽

Cited By ~ 14

Author(s):

Lin-Hua Zha ◽

Li-Sha He ◽

Feng-Mei Lian ◽

Zhong Zhen ◽

Hang-Yu Ji ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Measurement System ◽

Expert Consensus ◽

Dose Effect ◽

Herbal Formula ◽

Dose Selection ◽

Effect Relationship ◽

Weight Measurement ◽

Relationship Of

The clinical therapeutics of traditional Chinese medicine (TCM) constitutes a complicated process which involves theory, diagnosis, and formula prescription with specific herbal dosage. Zhang Zhong-Jing’s classic work, Treatise on Febrile and Miscellaneous Diseases, has been influencing TCM practice for almost 2000 years. However, during this extended period of time in Chinese history, the Chinese weight measurement system experienced noticeable changes. This change in the weight measurement system inevitably, and perhaps even negatively, affected TCM herbal dosage determination and treatment outcome. Thus, in modern society, a full understanding of the accuracy of herbal dose selection has a critical importance in the TCM daily practice of delivering the best treatment to the patients suffering from different illnesses. In the 973 Project of the Chinese National Basic Research Program, expert consensus on classic TCM formula dose conversion has been reached based on extensive literature review and discussion on the dose–effect relationship of classic TCM formulas. One “liang” (两) in classic TCM formulas is equivalent to 13.8[Formula: see text]g. However, based on many TCM basic and clinical studies of variable herbal formula prescriptions and herbal drug preparations, the rule of one liang equals 13.8[Formula: see text]g should be adjusted according to different disease conditions. Recommended by the committee on TCM formula dose–effect relationship of the China Association of Chinese Medicine and the World Federation of Chinese Medicine Societies, the following expert consensus has been reached: (i) One liang converts to 6–9[Formula: see text]g for the severely and critically ill patients. (ii) One liang converts to 3–6[Formula: see text]g for the patients suffering from chronic diseases. (iii) One liang converts to 1–3[Formula: see text]g in preventive medicine. The above conversions should be used as a future TCM practice guideline. Using this recommended guideline should enhance the effectiveness of daily TCM practice.

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Pleiotropic Actions of FGF23

Toxicologic Pathology ◽

10.1177/0192623317737469 ◽

2017 ◽

Vol 45 (7) ◽

pp. 904-910 ◽

Cited By ~ 20

Author(s):

Reinhold G. Erben

Keyword(s):

Vitamin D ◽

Fibroblast Growth Factor 23 ◽

Renal Tubules ◽

Hormone Production ◽

Membrane Expression ◽

Fgf Receptor ◽

Local Inhibition ◽

Organ Systems ◽

Key Enzyme ◽

Renal Tubular

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.

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