Natural Product Communications
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2025
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IF 1.4
Zhuowei Shen,Yanhong Chen,Kui Zeng,Haihong Hu,Jie Pan,Mingcheng Xu,Kaifeng He,Fengting Ou,Lushan Yu,Su Zeng,Lu Chen
Background6-hydroxykynurenic acid (6-HKA), isolated from Ginkgo biloba leaves, has demonstrated neurorestorative properties against cerebral ischemia in middle cerebral artery occlusion (MCAO) mice models. However, our previous studies showed that 6-HKA was difficult to penetrate the blood brain barrier (BBB) to exert its pharmacological effects in rats. Therefore, this study aims to investigate the pharmacokinetics and cerebral cortex distribution of 6-HKA in MCAO mice, to determine whether the ability of 6-HKA to cross the BBB is contingent upon barrier integrity.MethodsThis study established and validated the ultra-performance liquid chromatography tandem mass spectrometric (UPLC-MS/MS) methods for the quantification of 6-HKA in mouse plasma and brain, and investigated the pharmacokinetics and cerebral cortex distribution of 6-HKA in MCAO mice and sham-operated mice.ResultsThis study demonstrates that the mean residence time (MRT0−t) of 6-HKA in the MCAO group was significantly prolonged compared to the sham-operated group, and there was a higher distribution of 6-HKA in the ischemic cerebral cortex than in the contralateral normal cerebral cortex.ConclusionThis study illustrated that in MCAO mice, the prolonged MRT0−t of 6-HKA and the increased permeability of BBB made the accumulation of 6-HKA in the ischemic cerebral cortex, thereby enabling 6-HKA to exert neurorestorative effects.
研究领域:
神经科学
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药理学
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生物化学
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DOI
高影响因子
Molecular Medicine Reports
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2023
·Vol. 28
·期 5
·1-11
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IF 3.4
Yuwei Gao,Xiaohui Guo,Yunpeng Zhou,Jie Du,Chengbo Lu,Lei Zhang,Siyuan Sun,Shengfang Wang,Yang Li
Macrophage pyroptosis and related inflammatory responses play an important role in periodontitis. Kynurenic acid (KA) is hypothesized to have anti‑inflammatory potential, but whether KA can inhibit macrophage pyroptosis and the underlying mechanisms remain unclear. Lipopolysaccharide (LPS) was used to induce pyroptosis in THP‑1‑derived macrophages. KA or ML385 was used to pretreat macrophages, after which, cell viability, NOD‑like receptor protein 3 (NLRP3) inflammasome‑related protein expression, oxidative stress levels and nuclear factor erythroid 2‑related factor 2 (NRF2) expression were measured. The results showed that KA improved the LPS‑induced decrease in macrophage viability and lactate dehydrogenase release. KA prevented THP‑1 macrophage pyroptosis induced by LPS by reducing the expression of NLRP3, Gasdermin‑D, and Caspase1, and decreased the expression of inflammatory factors. KA suppressed NLRP3 inflammasome activation by inhibiting ROS overproduction and increasing Heme Oxygenase 1 and glutathione levels. Moreover, KA promoted NRF2 translocation from the cytoplasm to the nucleus. In addition, the anti‑pyroptotic and antioxidant effects of KA were reversed by ML385 inhibition of NRF2. In the present study, it was found that KA significantly suppressed macrophage pyroptosis induced by LPS. It was further demonstrated that the anti‑pyroptotic effects of KA were mediated by activation of the NRF2 pathway.
研究领域:
免疫学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TALANTA
·
2021
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IF 6.057
Lijun Xu,Dongguo Xue,Jialin Sai,Lu Zhou,Renjun Pei,Aihua Liu
Although enzyme mimics have been widely developed, limited catalytic efficiency is still a bottleneck, especially under neutral condition. Herein, we reported the bioactive quinaldic acid (QA) significantly boosted the peroxidase-like activity of Co 2+ in the presence of bicarbonate (HCO 3 − ). With 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonate) (ABTS) as the substrate, the catalytic activity of Co 2+ (1 μM) was increased by over 300 times upon adding 100 μM QA. The formed Co 2+ complex had much higher turnover number (5.52 min −1 ) than that of cobalt-based nanozymes (0.011–0.51 min −1 ) in decomposing H 2 O 2 . Based on this system, ultrasensitive colorimetric methods for the detection of Co 2+ , bicarbonate and urease activity were achieved with limits of detection of 4.6 nM, 40 μM and 0.00125 U/mL, respectively. For the first time, this work established an ultrasensitive method for the detection of urease activity by activating a peroxidase-like mimic with the produced HCO 3 − .
研究领域:
分析化学
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生物化学
·
催化
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Jianglin Hu,Jiayin Dai,Nan Sheng
Following its introduction as an alternative to perfluorooctanoic acid, hexafluoropropylene oxide dimer acid (HFPO-DA) has been extensively detected in various environmental matrices. Despite this prevalence, limited information is available regarding its hepatotoxicity biomarkers. In this study, toxicokinetic simulations indicated that under repeated treatment, HFPO-DA in mice serum reached a steady state by the 4th day. To assess its subacute hepatic effects and identify potential biomarkers, mice were administered HFPO-DA orally at doses of 0, 0.1, 0.5, 2.5, 12.5, or 62.5 mg/kg/d for 7 d. Results revealed that the lowest observed adverse effect levels were 0.5 mg/kg/d for hepatomegaly and 2.5 mg/kg/d for hepatic injury. Serum metabolomics analysis identified 34, 58, and 118 differential metabolites in the 0.1, 0.5, and 2.5 mg/kg/d groups, respectively, compared to the control group. Based on weighted gene coexpression network analysis, eight potential hepatotoxicity-related metabolites were identified; among them, kynurenic acid (KA) in mouse serum exhibited the highest correlation with liver injury. Furthermore, liver-targeted metabolomics analysis demonstrated that HFPO-DA exposure induced metabolic migration of the kynurenine pathway from KA to nicotinamide adenine dinucleotide, resulting in the activation of endoplasmic reticulum stress and the nuclear factor kappa-B signaling pathway. Notably, pretreatment with KA significantly attenuated liver injury induced by HFPO-DA exposure in mice, highlighting the pivotal roles of KA in the hepatotoxicity of HFPO-DA.
研究领域:
毒理学
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环境科学
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代谢学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Frontiers
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2024
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IF 7.4
Hang Yu,Jingmin Fan,Rui Xue,Jiawei Guan,Fangyuan Tian,Yu Xu,Linyun He,Ji Liu,Zhenzhu Du,Daqun Chen,Wei Yu,Wen Chen,Bo Han
Alhagi honey (AH) is produced in arid and hot areas of Central Asia, and its polysaccharides (AP) are widely known for their activity in the treatment of intestinal diseases such as diarrhea. However, the therapeutic potential and mechanism of AP in ulcerative colitis (UC) remain unclear. Here, AH polysaccharide-2 (AP2), a polysaccharide with the highest content in AP, was isolated and evaluated for its effects on dextran sulfate sodium (DSS)-induced UC in mice. AP2 was found to alleviate UC symptoms and regulate gut microbiota dysbiosis by decreasing Helicobacter levels and increasing Lactobacillus levels. Analysis of PICRUSt2 predicted that AP2 may regulate carbohydrate and amino acid metabolism, and metabolomic analysis confirmed that AP2 promotes the metabolism of tryptophan to produce kynurenic acid (kyna). Moreover, kyna acted as an aryl hydrocarbon receptor (AhR) ligand, which activated AhR to increase the expression of the tight junction proteins claudin-1 and occludin. Interestingly, AP2 showed similar effects in protecting the intestinal barrier and alleviating colitis as the AhR agonist 6-formylindolo[3,2- b ]carbazole, and the AhR antagonist CH223191 partially blocked the therapeutic effect of AP2 in UC mice, indicating that the anti-UC effect of AP2 was AhR dependent. These findings demonstrate that AP2 alleviates UC by regulating the gut microbiota and promoting tryptophan metabolism to generate kyna-activated AhR. The insights gained from this study could help in the future development of AP2 as a drug candidate or functional food for the treatment of UC.
研究领域:
胃肠病学
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免疫学
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微生物学
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药理学
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产品关联
DOI
高影响因子
FEBS Open Bio
·
2023
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IF 2.6
Di Wang,Wenbao Wang,Xue Bing,Chenguang Xu,Jiahua Qiu,Jiangang Shen,Jinwen Huang,Junda Li,Pi Liu,Biao Xie
Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein-coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS-induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35-mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35-mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS-induced damage. Furthermore, we provide compelling evidence suggesting that GPR35-mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS-induced colitis. In addition, five classes (Actinobacteria, Beta-/Gamma-proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera ( Corynebacterium , Allobaculum , Parabacteroides , Sutterella , Shigella , and Xenorhabdus ) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35-mediated KA sensing. Our findings highlight that GPR35-mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.
研究领域:
免疫学
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微生物学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2020
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IF 3.209
Zhipeng Wang,Hong Jiang,Xujiao Chen,Xinhua Song,Fengjing Xu,Fangchao Chen,Zhiguo Mao,Shouhong Gao,Wansheng Chen
A simple, rapid, reliable and sensitive ultra-high performance liquid chromatography tandem spectrometry (UHPLC-MS/MS) method was established for determination of eight serum protein-bound uremic toxins (hippuric acid, indoxyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, melatonin, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, 4-hydroxyhippuric acid) in serum from chronic kidney disease (CKD) dialysis patients. The chromatographic separation was achieved on an Atlantis T3 column (3 μm, 2.1 mm × 100 mm) using a gradient elution with acetonitrile (phase B) and 0.1% formic acid and 10 mmol/L ammonium acetate aqueous solution (phase A). The flow rate was 0.3 mL/min with analytical time of 5 min. The pretreatment procedure was developed with a simple protein precipitation and the hydrochlorothiazide was used as internal standard. The calibration ranges were set as 156.250-20000.000 ng/mL for indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; 78.125-10000.000 ng/mL for L-kynurenine, indole-3-acetic acid and 4-hydroxyhippuricacid; 1.562-200.000 ng/mL for kynurenic acid; 0.078-10.000 ng/mL for melatonin. The UHPLC-MS/MS method for quantification of eight protein-bound uremic toxins was successfully developed and validated, and its clinical practicability was assessed on 81 serum samples from CKD patients.
研究领域:
分析化学
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临床化学
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肾病学
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产品关联
DOI
PubMed
高影响因子
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