Advanced Science
·
2026
·
IF 14.1
Yongyuan Kang,Pai Peng,Liang Song,Qiaoxuan Wang,Zilong Zhong,Dongchao Qiu,Yunfan Liu,Kefei Zhao,Xiaofei Dong,Changyou Gao
Lactate plays a central role in regulating wound metabolism and has been implicated in fibrosis through mechanisms such as histone lactylation and endothelial-to-mesenchymal transition. However, strategies to modulate lactate-driven metabolic imbalance and oxidative stress remain limited. Herein, a metabolism-regulating and inflammation-modulatory artificial enzyme, Metazyme, was developed, which exhibited dual lactate oxidase (LOX)-like and catalase (CAT)-like activities to oxidize lactate and decompose hydrogen peroxide (H 2 O 2 ), enabling efficient oxygen recycling. Embedding Metazyme into a rod-shaped microgel matrix yielded MetaRgel, a localized and sustained catalytic platform for wound microenvironment modulation. The MetaRgel reduced lactate and reactive oxygen species (ROS) levels, relieved hypoxia, and downregulated glycolysis-related enzymes such as pyruvate kinase (PKM2) and pyruvate dehydrogenase kinase isoform 1 (PDK1) in vitro and thereby suppressed the pro-inflammatory cytokine interleukin-6 (IL-6) and the fibrotic mediator transforming growth factor-β1 (TGF-β1). In a rat full-thickness wound model in vivo, the MetaRgel significantly accelerated healing, enhanced granulation and collagen organization, and notably reduced glycolytic enzyme activity as well as the fibrotic marker α-smooth muscle actin (α-SMA) and hypoxia-inducible factor 1α (HIF-1α). The targeting of lactate-centered metabolic dysregulation with cascade artificial enzymes offers a promising approach to interrupt inflammation-metabolism-fibrosis crosstalk and promote scarless skin regeneration.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Yanzhuo Liu,Chenfan Duan,Honglei Chen,Chenlong Wang,Xiaoxiao Liu,Miao Qiu,Honglin Tang,Feng Zhang,Xiaoyang Zhou,Jing Yang
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib , leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) in the synovial fluid macrophages. In addition, leonurine decreased representative M1 marker (iNOS and CD86) expression, NLRP3 inflammasome activation and M1 cytokine (TNF-α and IL-1β) production. In the in vitro cultured RAW264.7 and human monocyte-derived macrophages (MDMs), blockade of COX-2/mPGES-1 and 5-LOX by leonurine inhibited macrophage M1 polarization and NLRP3 inflammasome activation in response to MSU crystals, and thus down-regulated IL-1β and TNF-α with STAT1 and NF-κB inactivation. Conversely, these effects were partially abolished by overexpression of COX-2, mPGES-1, 5-LOX or STAT1. Furthermore, leonurine prevented a positive feedback loop between COX-2/mPGES-1/5-LOX and IL-1β/TNF-α in MSU crystal-induced inflammation. Together, simultaneous down-regulation of COX-2/mPGES-1 and 5-LOX by leonurine ameliorates MSU crystal-induced inflammation through decreasing IL-1β and TNF-α production. Our study may provide novel multi-target agents toward the arachidonic acid (AA) network for gouty arthritis therapy.
研究领域:
药理学
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免疫学
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风湿病学
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炎症性疾病
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Wenjia Guo,Haifeng Huang,Hong Wang,Xiaodan Tan,Yujun Tu,Chao Gu,Pu Xiang,Lin Chen,Zhe Peng,Yang Yang,Dongzhi Ran,Yin Luo,Junqing Yang
The objective of this study was to explore the effects and underlying mechanisms of miR-690 on hepatic steatosis in db/db mice. Our findings revealed that miR-690 was downregulated in the liver of db/db mice and high-glucose (HG)-treated NCTC1469 cells. In vivo, miR-690 overexpression alleviated hyperglycemia, hyperlipidemia, and hyperinsulinemia, improved liver function, and mitigated steatosis and pathological damage. In vitro , miR-690 enhanced cell viability and glucose uptake while reducing lipid deposition. Mechanistically, bioinformatics analysis identified 15-LOX and NF-KappaB P65 as potential miR-690 targets, with their expression levels inversely correlated with miR-690. Furthermore, treatment with miR-690 agomir downregulated 15-LOX and NF-KappaB P65, although dual-luciferase reporter assays confirmed that 15-LOX is indirectly targeted by miR-690. Additionally, miR-690 agomir increased LC3BII/I and Beclin1 levels while decreased P62 and p-mTOR (Ser2448)/mTOR and induced autophagosome formation. Moreover, overexpression of 15-LOX or NF-KappaB P65 reversed the protective effects of miR-690 on autophagy. Collectively, these results suggest that miR-690 exerts hepatoprotective effects against diabetic hepatic steatosis by activating autophagy via modulating 15-LOX and NF-KappaB P65, providing experimental evidence for its potential use in the treatment of hepatic steatosis in diabetes, and new insight into diabetes drug development for targeting miR-690.
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Food Chemistry-X
·
2024
·
IF 6.5
Yue Tang,Chenguang Zhou,Zhiyang Yu,Meng Jiang,Yan Chen,Haiyan Wang,Zhen Yang
The aim of this study was to explore the formation of volatile lipid oxidation products by the lipoxygenase (LOX)-hydroperoxide lyase (HPL)-mediated pathway in oat, barley and soy bean. LOX activity was found only in barley and soy bean samples, but the lipase and HPL activity was detected in all samples. HPL showed particularly high activity with 13-hydroperoxides, while the activity was quite low when using 9-hydroperoxides, especially in the oat and barley. The optimum pH for HPL in different samples was similar, i.e., pH 6–7. In this condition, the volatile compounds formed dramatically with aldehydes and furans as the dominant products. Furthermore, a remarkable enzymatic degradation of lipids occurred during the preparation of food models with highly refined rapeseed oil (RO) and rapeseed oil fatty acid (ROFA) emulsions, where the ROFAs were more prone to oxidation than RO. This study shows the significance of lipid-degrading enzymes in plant-food flavour formation.
研究领域:
植物学
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食品科学
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BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Jie Zhao,Xiangyu Piao,Yue Wu,Shanshan Liang,Fang Han,Qian Liang,Shujuan Shao,Dewei Zhao
Cepharanthine (CEP) is a potential candidate for treatment of cerebral ischemia/reperfusion (I/R) injury, due to its anti-inflammatory and anti-oxidative properties. To investigate the effect of CEP on cerebral I/R injury, we established a mouse model of transient middle cerebral artery occlusion (tMCAO) and a microglia cell model of oxygen and glucose deprivation/reoxygenation (OGD/R). Administration of CEP attenuated neurological deficits, reduced infarct volume and edema, and decreased microglia activation in MCAO mice. Immunofluorescence staining showed an up-regulation in NLR Family Pyrin Domain Containing 3 (NLRP3) immunoreactivity in Iba1-labled microglia together with total Iba1 and NLRP3 expression in the brain following tMCAO, while down-regulated by CEP treatment. In both tMCAO-induced mice and OGD/R-treated BV-2 cells, CEP exhibited dose-dependent inhibition on the expression of NLRP3, ASC and cleaved caspase-1. Importantly, CEP attenuated tMCAO or OGD/R-induced overproduction of M1 microglia-regulated pro-inflammation cytokines IL-1β and IL-18, suggesting that CEP might involve in suppressing microglia polarization to M1 phenotype in vivo and in vitro . Moreover, CEP dose-dependently inhibited tMCAO-induced arachidonate 15 lipoxygenase (ALOX15) together with Iba1-labled microglia. The subsequent ALOX15-mediated oxidative stress was decreased by CEP treatment in vivo and in vitro , as evidenced by reduced ROS generation and MDA level, and increased SOD activity. Taken together, we demonstrate that CEP attenuates cerebral I/R injury probably by inhibiting microglia activation and NLRP3 inflammasome-induced inflammation and reducing oxidative stress via suppressing 12/15-LOX signaling.
研究领域:
神经科学
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药理学
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炎症生物学
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氧化应激
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PubMed
高影响因子
DEVELOPMENTAL CELL
·
2025
·
IF 8.7
Qi Zhang,Yezhen Tan,Qiyang Liang,Liangyou Gu,Yue Shi,Yan Huang,Xiubin Li,Jie Qi,Cheng Peng,Hanfeng Wang,Yaohui Wang,Kan Liu,Tianwei Cai,Yudan He,Qingbo Huang,Xu Zhang,Baojun Wang,Xin Ma,Weimin Ci
Preoperative downstaging of renal cell carcinoma with a tumor thrombus (RCC-TT) makes thrombectomy feasible. However, treatment resistance is common and may partly be attributed to the tumor-promoting role of the tumor microenvironment (TME). Herein, we sequenced, integrated, and comprehensively analyzed multi-center, multi-omics data from 164 RCC-TT patients and identified two clinically relevant RCC-TT subtypes. We find that the poor-prognosis subtype (TT1) exhibits enhanced extracellular-matrix (ECM) remodeling driven by epithelial LOX expression. Spatial transcriptomics (ST) shows the co-localization of GPNMB + macrophages, THBS2 + fibroblasts, and LOX + malignant cells around tumor nests in TT1 tumors, reinforcing tumor immune barriers (TIBs). Our extensive validations using cell lines, syngeneic mouse models, multiplex immunofluorescence staining, and large-scale RCC cohorts underscore the potential of LOX inhibition in disrupting TIBs, sensitizing RCC to immunotherapy, and overcoming treatment-induced phenotypic plasticity. This study provides insights into the biological underpinnings and prognosis assessment of RCC-TT, demonstrating targetable ECM-remodeling vulnerabilities.
研究领域:
肿瘤学
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分子生物学
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免疫学
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生物信息学
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病理学
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高影响因子
Natural Products and Bioprospecting
·
2024
·Vol. 14
·期 1
·1-12
·
IF 4.8
Shi Yuru,Zhang Xiaoqian,Pei Shengji,Wang Yuhua
Adenosma buchneroides Bonati, also known as fleagrass, is an important medicinal plant used by the Akha (Hani) people of China for treating inflammation-related skin swelling, acne, and diarrhoea, among other conditions. In this study, we aimed to evaluate the anti-inflammatory activities and explore the molecular mechanisms of fleagrass on treating skin swelling and acne. The results demonstrated that fleagrass inhibited the enzymatic activities of 5-LOX and COX-2 in vitro, and decreased the release of NO, IL-6, TNF-α, and IL-10 in the LPS-induced RAW264.7 macrophages. The levels of proteins associated with the nuclear factor-kappa B (NF-κB) pathway were examined by western blotting and immunofluorescence, demonstrating that fleagrass downregulated the expression of TLR4, MyD88, NF-κB/p65, and iNOS and blocked the nuclear translocation of NF-κB/p65. Furthermore, fleagrass exhibited acute anti-inflammatory activity in paw oedema models. The results confirm that fleagrass exhibits remarkable anti-inflammatory activity and can be used in alleviating inflammation, suggesting that fleagrass has the potential to be a novel anti-inflammatory agent. Graphical Abstract
研究领域:
民族药理学
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药理学
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炎症
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药用植物
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 4.833
Zhang Li,Zhong-Chang Wang,Xin Li,Muhammad Abbas,Song-Yu Wu,Shen-Zhen Ren,Qi-Xing Liu,Yi Liu,Peng-Wen Chen,Yong-Tao Duan,Peng-Cheng Lv,Hai-Liang Zhu
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC 50 = 6.43–10.97 μ M for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib ( A33 : IC 50 = 194.01 μ M vs. celecoxib : IC 50 = 97.87 μ M for 293T cells), and excellent inhibitory activities on COX-2 (IC 50 = 0.17 μ M) and 5-LOX (IC 50 = 0.68 μ M). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo . In general, compound A33 could be a promising candidate for cancer therapy.
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FOOD CHEMISTRY
·
2023
·
IF 8.8
Ben Niu,Yingchang Fei,Ruiling Liu,Hangjun Chen,Xiangjun Fang,Weijie Wu,Honglei Mu,Haiyan Gao
The effect of oxyresveratrol on postharvest quality and membrane lipid metabolism of shiitake mushroom was investigated. The result exhibited that oxyresveratrol retarded browning, maintained firmness and alleviated occurrence of decay of shiitake mushroom. The oxidation and hydrolysis of membrane phospholipids were suppressed by oxyresveratrol treatment, which was associated with reduced LOX and PLD activities and increased SOD and CAT activities. The membrane lipidomics of shiitake mushroom was determined by LC-MS. 385 lipid species and 13 fatty acids in membrane lipids were identified by multiple reaction monitoring method. Compared with control group, the phospholipic acid and lysophospholipid reduced by 29.24% and 21.29% in oxyresveratrol-treated group, respectively, which alleviated hydrolysis of phospholipid. Meanwhile, oxyresveratrol maintained the unsaturation of fatty acids and alleviated oxidation of phospholipid. These results demonstrated that oxyresveratrol could play a dual role of inhibiting the oxidation and hydrolysis of phospholipids to mitigate cellular damage of shiitake mushroom.
研究领域:
食品科学
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采后生理学
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脂质组学
·
植物生物化学
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2020
·
IF 4.873
Liu Tang,Xiao-Lei Li,Zi-Xin Deng,Yao Xiao,Ya-Hong Cheng,Jing Li,Hong Ding
Conjugated linoleic acid (CLA), commonly found in beef, lamb and dairy products, has been reported to exhibit anti-inflammatory and antipruritus effects and to inhibit the release of chemical mediators such as histamine and eicosanoid in laboratory rodents. The chief objective of the study is to assess the efficacy of CLA on atopic dermatitis (AD) in mice and to explore possible mechanisms with CLA treatments . To develop a new therapy for AD, the anti-AD potential of CLA was investigated by inducing AD-like skin lesions in mice using 2,4-dinitrofluorobenzene. We evaluated dermatitis severity; histopathological changes; serum levels of T helper (Th) cytokines (interferon-γ, interleukin-4); changes in protein expression by western blotting and immunohistochemistry staining for cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), toll like receptor 4 (TLR-4), myeloid differentiation factor 88 (MyD88), nuclear factor-κB (NF-κB) and tumor necrosis factor α (TNF-α); and production of the proinflammatory lipid mediators, such as prostaglandin E 2 and leukotriene B4 , in the skin lesions. Treatment with CLA ameliorated the development of AD-like clinical symptoms and effectively inhibited epidermal hyperplasia and infiltration of mast cells and CD4 + T cells in the AD mouse skin. Total serum immunoglobulin E levels and the expression levels of Th1/Th2 cytokines and lipid mediators in dorsal skin were dramatically suppressed by CLA. Furthermore, CLA down-regulated the expressions of COX-2, 5-LOX, TLR4, MyD88, NF-κB and TNF-α. Taken together, our findings demonstrate the potential usefulness of CLA as an anti-inflammatory dietary supplement or drug for the prevention and management of AD skin diseases by modulating the COX-2/5-LOX and TLR4/MyD88/NF-κB signaling pathways .
研究领域:
免疫学
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药理学
·
皮肤科
·
分子生物学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2021
·
IF 3.575
Likun Yan,Xiao Zhang,Jie Fu,Qiang Liu,Xiaohua Lei,Zhenyu Cao,Ju Zhang,Yaoli Shao,Qing Tong,Wei Qin,Xinxu Liu,Chun Liu,Zhiqiang Liu,Zhenghao Li,Jueliang Lu,Xundi Xu
Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP superfamily. Previous studies have demonstrated that TRPV3 is associated with myocardial fibrosis. However, the role of TRPV3 in hepatic fibrosis and its underlying mechanisms are still unclear. This study aimed to elucidate the underlying effects of TRPV3 on hepatic fibrosis at multiple biological levels. First, immunohistochemical staining was performed to examine TRPV3 expression in human hepatic cirrhosis tissues. Then, we established a CCl 4 -induced hepatic fibrosis mouse model. The TRPV3 selective agonist drofenine and its inhibitor, forsythoside B, were intraperitoneally injected to investigate the relationship between TRPV3 and liver fibrosis progression. Finally, in vitro studies were performed using hepatic stellate cells (HSCs) to discover the potential molecular biological mechanisms. Immunohistochemistry revealed TRPV3 overexpression in liver cirrhosis. In the liver fibrosis groups, TRPV3 inhibitor treatment significantly reduced liver fibrosis, while TRPV3 agonist exacerbated its progression. In HSCs, knocking down TRPV3 with siRNA impaired DNA synthesis and cell proliferation and increased cell apoptosis. Furthermore, we found that knockdown of TRPV3 could reduce the lectin like oxidized lowdensity lipoprotein receptor-1 (LOX-1) protein levels. Our research suggests that lower expression or functional levels of TRPV3 can ameliorate the inflammatory response and fibrotic tissue proliferation.
研究领域:
药理学
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肝病学
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分子生物学
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高影响因子
Food Chemistry: Molecular Sciences
·
2026
·
IF 4.8
Yongbang Si,Yongna Song,Dong Huang,Yifei Chen,Jun Sun,Zezhong Wu,Rui Ma,Guoliang Sun,Yuqiong Meng
Driven by sustainability, plant oils are increasingly used to replace fish oil in aquafeeds, thereby altering muscle fatty acid composition and potentially affecting volatile profiles. Lipoxygenases (LOXs) participate in fatty-acid bioconversion, but the role of 5-lipoxygenase (5-LOX) in non-immune fish muscle remains unclear. We hypothesized that acute intragastric exposure to plant-derived C18 fatty acids would be associated with changes in muscle 5-LOX protein abundance and volatile profiles in triploid rainbow trout. Using an acute oral gavage model, trout received oleic, linoleic, or α-linolenic acid, alone or with the selective 5-LOX inhibitor zileuton. Muscle samples were analyzed for 5-LOX mRNA expression, detectable protein abundance, and volatile profiles. Detectable 5-LOX protein abundance was low under basal conditions and changed after fatty-acid administration, with linoleic acid showing the clearest increase. Several major volatiles also changed across treatments. Under acute fatty-acid exposure, zileuton reduced hexanal concentration by 85.7% (221.2 to 31.6 ng/g) and decreased the nonanal odor activity value by 34.4%. These results indicate that acute plant-derived C18 fatty acid exposure was associated with changes in detectable muscle 5-LOX protein abundance and volatile profiles in triploid rainbow trout. The inhibitor-associated volatile changes further support the possibility that multiple oxidative processes may be involved under these acute conditions.
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