PHYTOMEDICINE
·
2026
·
IF 8.3
Qi Wu,Ziyi Chen,Zong Hou,Zhiqiang Liu,Rong Sun,Shu Liu
Background Polygoni Multiflori Radix (PMR) and its processed form, Polygoni Multiflori Radix Praeparata (PMRP), are two widely used traditional Chinese medicines (TCM). However, in recent years, frequent reports have emerged regarding their hepatotoxicity. Despite numerous studies, the underlying mechanisms of hepatotoxicity and key toxic components remain poorly understood. Purpose This study aimed to comprehensively elucidate the hepatotoxic processes of PMR and PMRP and identify the principal toxic components. Methods In vivo toxicity tests were carried out to assess the toxicity levels and characteristics of PMR and PMRP. The integration of untargeted serum metabolomics, liver spatial transcriptomics, and liver spatial metabolomics was first employed to elucidate the toxicity mechanisms, which were further validated through metabolite and sensitive index levels and by evaluating protein expression. Mass spectrometry and cytotoxicity tests were utilised to determine the primary toxic components. Results The findings revealed that PMR and PMRP primarily regulate tryptophan metabolism, the tricarboxylic acid (TCA) cycle, purine metabolism, and glutathione metabolism. Furthermore, PMR and PMRP can inhibit the expression of bile acid transporters, causing obstruction of bile acid secretion. These modulations trigger oxidative stress, which subsequently leads to cholestasis. The accumulation of bile acids further intensifies oxidative stress, creating a vicious cycle. Furthermore, emodin was identified as the primary toxic component. Conclusion PMR and PMRP can induce cholestatic liver injury. They exert hepatotoxic effects by establishing a vicious cycle between cholestasis and oxidative stress, with emodin being the key component responsible for this toxicity.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2026
·
IF 17.3
XuanLin Zhao,Tao Wang,QiLong Zhou,ZeLiang Wei,Ying Zhang,XiaoYi Wu,YuDa Zhu,XiuXian Yu,HongLi Jiang,XinRui Xu,Kun Zhang,Guang Xin,Wen Huang
Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder lacking effective targeted therapies. Mitochondrial dysfunction, marked by ATP depletion and excessive ROS production, lies at the heart of disease initiation and progression. This study presents a hierarchically targeted nanotherapeutic, Cu-CDs/Kyna@RM (RMCK), in which copper-doped, mitochondria-targeting carbon dots (Cu-CDs) are grafted with kynurenic acid (Kyna) and encapsulated within red blood cell-macrophage hybrid membranes. Upon systemic administration, RMCK homes to inflamed pancreatic tissue, where it sequentially releases Cu-CDs to target mitochondria, scavenge ROS, liberate Kyna, and restore mitochondrial function. It markedly improves survival, lowers serum amylase/lipase, attenuates pancreatic edema and necrosis, and prevents secondary lung injury, outperforming free Kyna therapy. In vitro, RMCK significantly reduces sodium taurocholate (STC)-induced acinar cell injury, measured by decreased cell necrosis and LDH release. Mechanistic studies including transcriptomics, immunohistochemistry, and functional assays reveal that RMCK amplifies GPR35-NF-κB inhibition to curb cytokine storms, prevents mtDNA-driven inflammasome activation, and alleviates hypoxia to downregulate HIF-1α and upregulate PPARγ for restored fatty acid oxidation. By integrating organ- and organelle-level targeting with ROS scavenging and mitochondrial energy remodeling, RMCK delivers synergistic, precision therapy for AP and offers a versatile platform for other inflammatory diseases characterized by mitochondrial dysfunction.
✓ 已验证
产品关联
DOI
高影响因子
PLoS One
·
2025
·Vol. 20
·期 6
·e0325189
·
IF 2.6
Yu Wang,Chaofan Chen,Yushan Li,Ran Li,Jinghan Wang,Chao Wu,Haonan Chen,Yingchao Shi,Shengfang Wang,Chuanyu Gao
Kaempferol exhibits various biological activities, including antioxidant and anti-inflammatory effects. Its role in modulating lipid metabolism and inhibiting inflammatory responses to suppress the progression of atherosclerosis has been confirmed. However, its impact on macrophage pyroptosis and the underlying mechanisms remain unclear. This study aims to investigate the effects of kaempferol (Kae) on lipopolysaccharide (LPS)-induced macrophage pyroptosis and its potential mechanisms. In the experiments, we used the CCK8 assay to evaluate cell viability, ROS detection kits to measure intracellular reactive oxygen species (ROS) levels, Western Blot to detect the expression of proteins such as NOD-like receptor family pyrin domain-containing 3 (NLRP3), nuclear factor erythroid 2-related factor 2 (NRF2), gasdermin D (GSDMD), and heme oxygenase-1 (HO-1), and immunofluorescence to observe NRF2 nuclear translocation. The results showed that kaempferol alleviated LPS-induced cell viability decline and lactate dehydrogenase (LDH) release, inhibited excessive ROS generation, and suppressed NLRP3 inflammasome activation by increasing glutathione (GSH) and HO-1 levels, thereby reducing the expression of inflammatory factors. Additionally, kaempferol promoted NRF2 nuclear translocation, and the application of the NRF2 inhibitor ML385 reversed its antioxidant and anti-inflammatory effects. In vivo experiments further confirmed that kaempferol inhibited oxidative stress and reduced macrophage pyroptosis by activating the NRF2 pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Qiuyang Huang,Xiaoling Zang,Zhiwei Zhang,Hang Yu,Baoyan Ding,Zhuangzhuang Li,Simin Cheng,Xin Zhang,Mustafa R.K. Ali,Xue Qiu,Zhihua Lv
The discovery of new anti-cancer drugs targeting the PD-1/PD-L1 pathway has been a research hotspot in recent years. In this study, biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 to PD-1. We screened dozens of potential cancer related endogenous compounds. Surprisingly, cyclic adenosine monophosphate (cAMP) was found to have a direct inhibitory effect on the PD-1/PD-L1 binding with an in vitro IC 50 value of about 36.4 ± 9.3 μM determined by homogeneous time-resolved fluorescence (HTRF) assay. cAMP could recover the proliferation of Jurkat T cells co-cultured with DU-145 cells and may suppress PD-L1 expression of DU-145 cells. cAMP was demonstrated to bind and induce PD-L1 dimerization by FRET assay, and also predicted by MD simulations and molecular docking. The finding of cAMP as a potential inhibitor directly targeting the PD-1/PD-L1 interaction could advance our understanding of the activity of endogenous compounds regulating PD-L1.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cells
·
2022
·Vol. 11
·期 22
·3689
·
IF 7.666
Hao Liu,Jun-Tao Zhang,Chen-Ye Mou,Yue Hao,Wei Cui
Background: D-amino acid oxidase (DAAO) is a flavoenzyme that specifically catalyzes the deamination of many neutral and basic D-amino acids. This study aims to explore the pathological increment of hippocampal DAAO and its potential relationship with delayed hippocampal neuronal death. Methods: Ischemia–reperfusion was induced in mice through middle cerebral artery occlusion (MCAO). Neurological deficit scores and hippocampal neuronal death were assessed in MCAO mice. Immunofluorescent staining was applied to identify activated astrocytes and evaluate DAAO expression. TUNEL and Nissl staining were utilized to identify cell apoptosis of hippocampal neurons. Results: Hippocampal astrocytic DAAO was strikingly increased following ischemic stroke, with the greatest increase on day 5 after surgery, followed by the manifestation of neurobehavioral deficits. Astrocytic DAAO was found to be mainly expressed in the hippocampal CA2 region and linked with subsequent specific neural apoptosis. Thus, it is supposed that the activation of astrocytic DAAO in ischemic stroke might contribute to neuronal death. An intravenous, twice-daily administration of 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN, 10 mg/kg) markedly relieved behavioral status and delayed hippocampal neuronal death by 38.0% and 41.5%, respectively, compared to the model group treated with saline. In transfected primary astrocytes, DAAO overexpression inhibits cell activity, induces cytotoxicity, and promotes hippocampal neuronal death at least partly by enhancing H2O2levels with subsequent activation of TRP calcium channels in neurons. Conclusions: Our findings suggest that increased hippocampal DAAO is causally associated with the development of delayed neuronal death after MCAO onset via astrocyte–neuron interactions. Hence, targeting DAAO is a promising therapeutic strategy for the management of neurological disorders.Keywords:D-amino acid oxidase;middle cerebral artery occlusion;neuronal death;transient receptor potential channel;hydrogen peroxide
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2022
·
IF 3.318
Xiaoxu Cheng,Zifeng Pi,Zhong Zheng,Shu Liu,Fengrui Song,Zhiqiang Liu
Wu-tou decoction (WTD) is a traditional Chinese medicine (TCM) formula which has been used for treating rheumatoid arthritis (RA) for a thousand years. However, the underlying mechanism of WTD in treating RA is still unclear. In recent years, more and more attention has been paid to the role of gut microbiota and microbiota-derived metabolites in the treatment of RA. Hence, this study aims to investigate the roles of microbiota and microbial metabolites in the treatment of RA with WTD. Firstly, the therapeutic effects of WTD on adjuvant-induced arthritis (AIA) rats were evaluated. Then, the 16S rRNA sequencing analysis was used to clarify the changes of the intestinal microbiota and obtain the key microbiota affected by WTD. The important microbial metabolites were quantitated to explore the metabolic characteristics of WTD against RA by targeted metabolomics method. Finally, correlation analysis was performed to investigate the functional correlation among the gut microbiota, metabolites and RA-related serum indexes. The results indicated that WTD could relieve arthritis and reverse gut microbiota dysbiosis. The variation of short-chain fatty acids, bile acids, tryptophan metabolites and amino acids, which are important microbial metabolites, were reversed by WTD intervention. The correlation studies proved that WTD could regulate inflammation and intestinal barrier function partially by modulating Bacteroides, Prevotella, Akkermansia and their associated acetic acid, butyric acid, cholic acid and indole propionic acid. The anti-RA effects of WTD were partially mediated by gut microbiota and microbial metabolites. This study provides a new insight for treating RA and highlights the importance of gut microbiota in the treatment of diseases.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2023
·Vol. 11
·期 5
·2277-2287
·
IF 3.9
Shuyuan Cao,Shengjie Hu,Ping Jiang,Zhan Zhang,Lei Li,Qian Wu
Sulforaphane (SFN) is a promising phytochemical with a wide range of antitumor activities. A comprehensive understanding of the effects of SFN on breast cancer based on the metabolome and microbiome is limited. Thus, we treated MCF-7 cell-transplanted nude mice with 50 mg/kg SFN. SFN inhibits breast cancer cell proliferation. SFN increased the levels of sulfate-related metabolites and glutathione-related metabolites and decreased tryptophan metabolites and methyl-purine metabolites in urinary metabolic profile. SFN indirectly affected the activation of aryl hydrocarbon receptor by tryptophan metabolism. The ratio of SAM to methionine was decreased by SFN while the global DNA methylation was downregulated in tumor tissue. SFN decreased the sulfate-reducing bacterium Desulfovibrio , which is related to reduced methylation capacity, and increased the genus Lactobacillus related to tryptophan metabolites with antitumor activities. In conclusion, we provide a perspective on the metabolome and microbiome to elucidate the antitumor activities of SFN.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 17
·3336-3349
·
IF 6.583
Hao Liu,Meng-Jing Zhao,Zi-Ying Wang,Qiao-Qiao Han,Hai-Yun Wu,Xiao-fang Mao,Yong-Xiang Wang
Background and Purpose d -Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d -amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. Experimental Approach A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. Key Results The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED 50 values of 3.9–4.5 mg·kg −1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Conclusions and Implications Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2019
·
IF 2.983
Xue-Mei Han,Yan-Jie Qin,Ying Zhu,Xin-Lin Zhang,Nan-Xi Wang,Ying Rang,Xue-Jia Zhai,Yong-Ning Lu
Sensitive and comprehensive measurement of systemic metabolites of tryptophan, phenylalanine and glutamate metabolism in biological samples is effective for understanding the pathogenesis of depression and other neurological diseases. Therefore, this study developed an underivatized liquid chromatography tandem mass spectrometry (LC–MS/MS) method for simultaneous monitoring the 3 components of glutamate metabolism in rat hippocampus and 11 components of tryptophan and phenylalanine metabolism in rat hippocampus, plasma and urine, and applied it to investigate their changes in rats induced by chronic unpredictable mild stress (CUMS). The investigated analytes are as follows: tryptophan, serotonin, 5-hydroxyindoleacetic acid, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, quinolinic acid, phenylalanine, tyrosine, tyramine, glutamate, glutamine and gamma-aminobutyric acid. The method was verified to be sensitive and effective with satisfactory linearity, accuracies in the range of 78.2%–120.4%, and precisions less than 17.8% for all identified analytes. A series of significant changes in CUMS-induced rats can be detected: tryptophan, serotonin and tyrosine levels decreased and quinolinic acid increased in both hippocampus and plasma. In addition, the kynurenine/tryptophan ratios increased in hippocampus and plasma, the kynurenic acid/quinolinic acid ratios of plasma and urine were significantly reduced. These findings demonstrated that the CUMS procedure could lead to the central and peripheral imbalances of tryptophan and phenylalanine metabolism. In conclusion, a LC–MS/MS method for simultaneous measurement of several neurotransmitters in rat hippocampus, plasma and urine was developed and successfully applied to investigation of the central and peripheral changes in CUMS-induced rats. The method would be expected to provide applicability to the study of the mechanisms of depression and other related diseases associated with these neurotransmitters.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2016
·
IF 4.839
Dezhen Wang,Xinru Wang,Ping Zhang,Yao Wang,Renke Zhang,Jin Yan,Zhiqiang Zhou,Wentao Zhu
Epidemiological studies indicate that exposure to persistent organic pollutants is positively associated with the prevalence of obesity. To delineate the potential role of technical-grade chlordane in obesity development, chlordane metabolism and chlordane-induced metabolic changes were investigated in mice fed high-fat diet (HFD) over a 6-week period. Gas chromatography–electron capture detector analysis showed that HFD induced more accumulation of technical chlordane in the liver, muscle and adipose tissue . The enantioselectivities of oxychlordane in selected tissues were also influenced by HFD. 1 H NMR-based liver metabolome indicated that technical chlordane can enhance the metabolic alterations induced by HFD. Compared with the low-fat diet (LFD) group, no differences were observed in the LFD + chlordane group. However, as many as 16 metabolites were significantly different between the HFD group and HFD + chlordane group. Moreover, compared to the LFD + chlordane group, the abundances of 24 metabolites significantly increased or decreased in the HFD + chlordane group. Twenty metabolites were altered in the HFD group compared to the LFD group. Tryptophan profiling suggested that both chlordane and HFD can disturb tryptophan catabolism. These interactions between technical chlordane and HFD suggest that technical chlordane is a candidate obesogen.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2017
·
IF 6.337
Dan-Qian Chen,Gang Cao,Hua Chen,Dan Liu,Wei Su,Xiao-Yong Yu,Nosratola D. Vaziri,Xiu-Hua Liu,Xu Bai,Li Zhang,Ying-Yong Zhao
Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL AND ENVIRONMENTAL SCIENCES
·
2020
·
IF 2.656
Yu Meng WANG,Wei Yi WANG,Li Yan SUN,Qiang LI,Zhi Jun ZHAO,Jian HU,Rong Yu ZHANG,Li Hua WANG
Objective To explore potential serum biomarkers of children with Kashin-Beck Disease (KBD) and the metabolic pathways to which the biomarkers belong. Methods A two-stage metabolomic study was employed. The discovery cohort included 56 patients, 51 internal controls, and 50 external controls. The metabolites were determined by HPLC-(Q-TOF)-MS and confirmed by Human Metabolome Databases (HMDB) and Metlin databases. MetaboAnalyst 3.0 and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used to analyze the metabolic pathways of the candidate metabolites. The use of HPLC-(Q-TRAP)-MS enabled quantitative detection of the target metabolites which were chosen using the discovery study and verified in another independent verification cohort of 31 patients, 41 internal controls, and 50 external controls. Results Eight candidate metabolites were identified out in the discovery study, namely kynurenic acid, N-α-acetylarginine, 6-hydroxymelatonin, sphinganine, ceramide, sphingosine-1P, spermidine, and glycine. These metabolites exist in sphingolipid, glutathione, and tryptophan metabolic pathways. In the second-stage study, five candidate metabolites were validated, including kynurenic acid, N-α-acetylarginine, sphinganine, spermidine, and sphingosine-1P. Except for spermidine, all substances exhibited low expression in the case group compared with the external control group, and the difference in levels of sphinganine, spermidine, and sphingosine-1P was statistically significant. Conclusion The direction of change of levels of sphinganine, spermidine, and sphingosine-1P in the two-stage study cohorts was completely consistent, and the differences were statistically significant. Therefore, these substances can be used as potential biomarkers of KBD. Furthermore, these results raise the possibility that sphingolipid metabolic pathways may be closely related to KBD.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）