CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Jie Liu,Ailing Hui,Jinghe Wang,Qingfeng Hu,Shengnan Li,Yuanli Chen,Zeyu Wu,Wencheng Zhang
Neuroinflammation is considered as an important pathological mechanism in neurodegenerative diseases. The natural isoquercitrin (IQ) was reported to have potential anti-neuroinflammatory activity. The acylation of glycoside in IQ enhanced its hydrophobicity, which was expected to enhance the protective effect against inflammation. In this study, three carboxylic acids with anti-neuroinflammatory effects including cinnamic acid, ibuprofen (IBU) and acetylsalicylic acid were introduced into the 6''-OH of IQ through the corresponding vinyl esters intermediates ( 8a-8c ). Ultimately, the acylated IQ derivatives (Compound 9a-9c ) were obtained with 35–42% yields using immobilized lipase Novozym 435 as catalyst. Subsequently, their anti-neuroinflammatory activities were evaluated in lipopolysaccharide (LPS)-induced BV2 cells. Compound 9b improved cell viability in the range of ≤50 μM and significantly decreased NO, PGE 2 production and TNF-α, IL-1β release and oxidative stress level with a concentration-dependent manner. Also, it could downregulate iNOS, COX-2, TNF-α and IL-1β expression levels, approximately 40% reduction were achieved when 15 μM compound 9b was employed. In addition, compound 9b resisted phosphorylation and degradation of IkBαs, suppressing the activation of NF-κB signaling pathway, exhibiting excellent neuroinflammatory inhibition. Moreover, the administration of compound 9b (30, 60 mg/kg) alleviated behavioral disorders and neuronal damages in LPS-induced neuroinflammatory mice. Meanwhile, the decreased TNF-α, IL-1β release, expression and the inhibited glial cells activation were obtained in compound 9b -treated group, which was superior to that of IQ or IBU. Overall, these findings demonstrated that compound 9b , formed by the introduction of ibuprofen into IQ, can serve as a novel promising therapeutic agent for anti-neuroinflammation.
研究领域:
药理学
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神经科学
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炎症
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Lin Xiao-mian,Luo Wu,Wang Heng,Li Rong-zhen,Huang Yi-shan,Chen Lian-kuai,Wu Xiao-ping
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Meilan Xue,Xuehan Zhang,Yifan Zhou,Jiayi Yan,Haiqi Gao,Yixian Bai,Jing Shi,Yuhan Liu,Yan Xu,Nan Zhang,Lu Li,Shaobo Shi,Hui Liang
This study was aimed to reveal the neuroprotective effect of sulfated fucooligosaccharides (FOS) in an aging mouse model induced by d-galactose. The results showed that FOS treatment ameliorated inflammation, improved behavioral decline in memory and cognition, and exerted neuroprotective effects. FOS reduced microglia activation by decreasing the expression of P38 mitogen-activated protein kinase (P38 MAPK), cyclic-AMP response binding protein (CREB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). In addition, FOS improved intestinal mucosal barrier damage and reduced the release of lipopolysaccharide. FOS increased the diversity of the gut flora and promoted a significant enrichment of the Akkermansia genus. FOS also increased the butyric acid level and reduced the expression of histone deacetylase 3 (HDAC3), Toll-like receptor 4 (TLR4), and nuclear factor kappa-B (NF-κB). Fecal microbiota transplantation from the FOS-treated mice showed a similar effect to FOS treatment in inhibiting neuroinflammation and reduced d-galactose-induced cognitive dysfunction. The results suggested that FOS supplementation ameliorated d-galactose-induced neuron damage and exerted neuroprotective effects through the gut–brain axis.
研究领域:
神经科学
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衰老研究
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免疫学
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胃肠病学
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微生物学
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药理学
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生物化学
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DOI
PubMed
高影响因子
Acta Biomaterialia
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2022
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IF 10.633
Kai Sun,Jiaying Yu,Jinzhong Hu,Jian Chen,Jia Song,Zhixin Chen,Zhuoer Cai,Zhuoxuan Lu,Liming Zhang,Zhifei Wang
The delivery of salicylic acid or its derivatives to tumor tissue in the form of nanomedicine is critical for the studies on their potential synergistic mechanism in tumor therapy and chemoprevention considering the dangerous bleeding in the high-dose oral administration. To deepen the understanding of their role in adjusting immunosuppressive tumor microenvironment (ITM), herein, we firstly developed a hypoxia-sensitive Fe-5,5′-azosalicylic acid nanoscale coordination polymer nanomedicines (FeNCPs) via a “old drugs new tricks” strategy for synergistic chemodynamic therapy (CDT) and remodulation of ITM to elevate antitumor immunotherapy effect. PEGylated FeNCPs could be reductively cleaved to release 5-aminosalicylic acid (5-ASA) and ferric ions by azo-reductase under hypoxic conditions, which could induce tumor cell death by Fenton reaction-catalysis enhanced CDT and 5-ASA-converted carboxylquinone to promote the production of •OH. Meanwhile, cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E 2 (PGE 2 ), as immune negative regulatory molecules, can promote tumor progression and immune tolerance . The released 5-ASA as a COX inhibitor could suppress the expression of PGE 2 , and Fe 3+ was employed to reeducate M2-like tumor-associated macrophages (TAMs) to M1-like phenotype, which could initiate antitumor immune response to reach better antitumor immunotherapy. This work broadens the application of salicylic acid derivatives in antitumor immunotherapy, and provides a new strategy for their “old drugs new tricks”. Statement of Significance Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE 2 ), as immune negative regulatory molecules, facilitate the differentiation of immune cells into immunosuppressive cells to build the immunosuppressive tumor microenvironment, which can promote tumor progression and immune tolerance. Thus, down-regulation of COX-2/PGE 2 expression may be a key approach to tumor treatments. Meanwhile, as a class of inhibitors of COX-2/PGE 2 , the potential mechanism of aspirin or 5-aminosalicylic acid has been a mystery in tumor therapy and chemoprevention. To expand the application of aspirin family nanomedicine in biomedicine , herein, we firstly developed a hypoxia-sensitive Fe-5,5′-azosalicylic acid nanoscale coordination polymer nanomedicines via a “old drugs new tricks” strategy for synergistic chemodynamic therapy and remodulation of immunosuppressive tumor microenvironment to elevate antitumor immunotherapy effect.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
ChemMedChem
·
2023
·Vol. 18
·期 23
·e202300468
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IF 3.4
Jingjie Fang,Ziyi Shang,Kumaravel Kaliaperumal,Zhiran Ju,Fen-Er Chen
Graphical This study presents a design strategy, synthesis, and evaluation of balanced COX inhibitors derived from natural anti-inflammatory ascidian metabolites and celecoxib, highlighting their potential therapeutic value in the context of inflammation. The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m , exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6 m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), IL-1β, as well as decreased production of prostaglandin E 2 (PGE 2 ), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.
研究领域:
药理学
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药物化学
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炎症研究
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药物设计
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DOI
PubMed
高影响因子
Translational Andrology and Urology
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2024
·Vol. 13
·期 9
·1971
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IF 1.9
Jiahao Jiang,Fei Xiao,Lanxin Yang,Yan Zeng,Jing Chen,Hengcheng Zhu,Lingqi Liu
Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain and various discomforts. Astaxanthin (AST) has multiple functions, including anti-inflammatory property, but it is unclear whether AST plays a key role in CP/CPPS and how it works. This study aimed to investigate the protective effect of AST on CP/CPPS in rats and the underlying mechanism. Methods A CP/CPPS rat model was induced by intraprostatic injection of carrageenan and the blood specimens and prostates were harvested for further research after oral administration of AST for 4 weeks. Results Tactile allodynia test showed that AST ameliorated chronic pelvic pain in a dose-depended manner. In addition, histological evaluation indicated that AST alleviated CP/CPPS rat prostate histological inflammation. Meanwhile, AST suppressed the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Besides, AST inhibited the activities of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). Furthermore, AST decreased the activation of the nuclear factor-κB (NF-κB) signaling pathway. Conclusions Our study has shown that AST exerts an anti-inflammatory and protective effect against CP/CPPS and the function is mediated at least through the suppression of NF-κB signaling pathway. These results provide evidence of AST as the potential agents for the treatment of CP/CPPS.
研究领域:
泌尿科
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药理学
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炎症研究
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2021
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IF 4.36
Ali Attiq,Juriyati Jalil,Khairana Husain,Hazni Falina Mohamad,Abrar Ahmad
Ethnopharmacological relevance Numerous Alphonsea species including Alphonsea elliptica (mempisang) leaves and fruits are indigenously used in inflammatory conditions such as postpartum swelling and rheumatism in southeast Asian countries. In our previous in-vitro findings, A. elliptica methanol extract exhibited platelet-activating factor inhibition, suggesting the presence of phyto-constituents with anti-inflammatory potential. Aim of the study However, so far there is no literature available on the anti-inflammatory activity of this species. Henceforth, based on the above background and our previous laboratory findings, we hypothesize that phytoconstituents of A. elliptica could possess anti-inflammatory potential against inflammatory mediators including prostaglandin-E 2 (PGE 2 ), cyclooxegenase-2 (COX-2) and cytokines (IL-1β and IL-6). Materials and methods Vacuum and column chromatography techniques were employed for the isolation of phytoconstituents. The structure elucidation was carried out using HRESI-MS, 1 H and 13 C-NMR analysis and compared with the published literature. For cytotoxicity analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed on peripheral blood mononuclear cells. In-vitro anti-inflammatory activities were evaluated against the levels of PGE 2 , COX-2, IL-1β and IL-6 in lipopolysaccharide (LPS)-induced human plasma using enzyme-linked immunosorbent assay and radioimmunoassay . Results Unprecedentedly, chromatographic purification of methanolic leaves extract afforded five flavones namely vitexin , isovitexin , orientin, isoorientin , schaftoside with three flavanols ; kaempferol , myricetin and rutin from A elliptica . In cell viability analysis, isolates did not present cytotoxicity up to 50 μM. In anti-inflammatory evaluation, orientin and isoorientin exhibited strong (≥70%), while isovitexin and vitexin produced strong to moderate (50–69%) PGE 2 , COX-2, IL-1β and IL-6 inhibition at 25 and 50 μM. Isoorientin, orientin, isovitexin, and vitexin showed significant (p < 0.05) and concentration-dependent PGE 2 inhibition with IC 50 values (μM) of 11.40, 14.71, 17.70 and 20.58 against indomethacin (8.80). Furthermore, isoorientin, orientin, isovitexin, and vitexin produced significant concentration-dependent inhibition with IC 50 values (μM) of COX-2: 7.13, 9.51, 12.81, 16.61; IL-1β 4.80, 6.20, 10.85, 14.51; IL-6: 4.01, 5.90, 11.51 and 14.88 as compared to dexamethasone : 5.29, 2.93, 3.72, respectively (p < 0.05). Conclusion Conclusively, isolated phytoconstituents are reported for the first time from the A. elliptica. Moreover, isovitexin, vitexin orientin and isoorientin abrogated LPS-induced inflammatory responses in human plasma at non-cytotoxic concentrations.
研究领域:
药理学
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民族药理学
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生物化学
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免疫学
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植物化学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2020
·
IF 3.69
Baolian Ma,Shilin Yang,Ting Tan,Junmao Li,Xiaoyong Zhang,Hui Ouyang,Mingzhen He,Yulin Feng
Ethnopharmacological relevance Akebiae Fructus, a Tujia minority folk medicine and a well-known traditional Chinese medicine for soothing the liver, regulating Qi, promoting blood circulation and relieving pain, is widely used in the treatment of primary dysmenorrhea . However, little is known about its underlying mechanism. Aim of the study To explore the effect of Akebiae Fructus on primary dysmenorrhea model induced by estradiol benzoate and oxytocin, and to provide better understanding of the mechanism of Akebiae Fructus for primary dysmenorrhea treatment. Materials and methods The primary dysmenorrhea mouse model was used in this study. Except for the control group and the normal administration group, the mice of other groups were subcutaneously injected with estradiol benzoate (10 mg/kg/d) for 10 consecutive days. From the 5th day of the ten-day model period, the positive control groups were given 0.075 g/kg ibuprofen and 7.5 g/kg Leonurus granule, the drug groups were given 0.2 g/kg, 0.4 g/kg, 0.8 g/kg Akebiae Fructus extract, the normal administration group was given 0.8 g/kg Akebiae Fructus extract, and the same volume saline was given in the control group. On the tenth day, oxytocin (10 U/kg) was peritoneally injected after estradiol benzoate injected 1 h. After the oxytocin injection, writhing behavior was observed for 30 min. Then the uterine tissue was collected to measure the level of PGF 2α and PGE 2 , and for histological analysis and transcriptomics analysis. Meanwhile, plasma and urine samples were collected for metabolomic analysis. Results Akebiae Fructus inhibited the writhing, decreased the PGF 2α level and ameliorated the morphological changes. 32 potential metabolic biomarkers in plasma and 17 in urine were found for primary dysmenorrhea, and after Akebiae Fructus treatment, 25 metabolites in plasma and 14 in urine were restored. These altered metabolites were mainly involved in lipid, amino acid and organic acid metabolism. For the transcriptomic study, a total of 2244 differentially expressed genes (1346 up-regulated and 898 down-regulated) were obtained between the control and model group, and 148 differentially expressed genes (DEGs) were found related with Akebiae Fructus treatment of primary dysmenorrhea. Correlation analysis was carried out based on the transcriptomic and metabolomic data. 5 differentially expressed genes (Plpp3, Sgpp2, Arg1, Adcy8, Ak5) were found related with the enrichment metabolic pathways. The mechanism by which Akebiae Fructus ameliorates primary dysmenorrhea may account for the regulation of the gene expression to control the key enzymes in the sphingolipid metabolism, arginine and proline metabolism, glycerophospholipid metabolism and purine metabolism, inhibiting the abnormal secretion of PGF 2α , alleviating the uterine contraction and reducing inflammation and pain. Conclusions Akebiae Fructus could effectively alleviate the symptoms of primary dysmenorrhea, regulate metabolic disorders , and control the related gene expression in primary dysmenorrhea. The study may provide clues for further study of Akebiae Fructus treatment on primary dysmenorrhea.
研究领域:
药理学
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中药学
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分子生物学
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代谢组学
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转录组学
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疼痛管理
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Xiaoliang Deng,Xianquan Feng,Xiaohui Tang,Zhihui Zheng,Da Zheng,Enqin Zheng,Lingjun Zeng,Shiying Xu,Boxin Chen,Qian Zhang,Zhihong Liu,Hongtao Song
The clinical efficacy of immunotherapy in triple-negative breast cancer (TNBC) faces dual barriers: poor immunogenicity and a suppressive tumor microenvironment. While low-temperature photothermal therapy (LTPTT) has emerged as a potential immunostimulatory strategy, its efficacy is counteracted by heat shock protein (HSP) induction and COX-2/PGE2-mediated immunosuppression. To address these challenges, we developed a multifunctional immunophotothermal nanoplatform (IAC NPs) through rational engineering of human serum albumin for combinatorial delivery of indocyanine green as a photothermal converter, atovaquone for HSP70-mediated thermoresistance blockade, and celecoxib for COX-2/PGE2 pathway inhibition. The IAC NPs achieved tumor-targeted delivery and NIR-activated immunogenic phototherapy while coinhibiting HSP70 (via atovaquone’s mitochondrial complex III blockade) and the COX-2/PGE2 immunosuppressive axis (via celecoxib). The triple medications’ synergistic action improved the expression of effector memory T cells, boosted the maturation of dendritic cells, encouraged the infiltration of CD4+ and CD8+ T cells, and reduced regulatory T cells. In vivo, the IAC NPs mediated profound suppression of both primary tumors and metastatic dissemination while exhibiting optimal biocompatibility for clinical translation. Our work validates a nanoenabled self-delivery system that augments the efficacy of LTPTT immunotherapy against TNBC by orchestrating coordinated inhibition of HSPs and inflammatory responses.
研究领域:
癌症免疫治疗
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纳米医学
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光热治疗
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分子靶向治疗
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肿瘤微环境
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药物递送系统
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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）