EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 6.7
Yue Wu,Jin-Hui Shi,Guang-Hao Zhu,Yuan Xiong,Jia-Hao Gong,Hui-Zhen Wei,Zhao-Bin Guo,Zi-Ru Dai,Xiao-Bo Sun,Guang-Bo Ge
Human cytochrome P450 1B1 (hCYP1B1), an extrahepatic cytochrome P450 enzyme over-expressed in various tumors, has been validated as a promising target for preventing and treating cancers. Herein, two series of chalcone derivatives were synthesized to discover potent hCYP1B1 inhibitors without AhR agonist effect. Structure-activity relationship (SAR) studies demonstrated that 4′-trifluoromethyl on the B-ring strongly enhanced the anti-hCYP1B1 effects, identifying A9 as a promising lead compound. Further SAR analysis on A9 derivatives (modified A-ring of 4′-trifluoromethylchalcone) showed that introducing 2-methoxyl improved the anti-hCYP1B1 effect and selectivity , while introducing a methoxyl at the C-4 site was beneficial for avoiding AhR activation. Ultimately, five 4′-trifluoromethyl chalcones were identified as potent hCYP1B1 inhibitors (IC 50 < 10 nM), while B18 exhibits the most potent anti-hCYP1B1 effect (IC 50 = 3.6 nM), suitable metabolic stability and good cell-permeability. B18 also acted as an AhR antagonist and could down-regulate hCYP1B1 in living systems. Mechanistic studies showed that B18 potently inhibited hCYP1B1 in a competitive inhibition manner ( K i = 3.92 nM), while docking simulations revealed that B18 could tightly bind to the catalytic cavity of hCYP1B1 mainly via hydrophobic and hydrogen-bonding interactions. Furthermore, B18 could potently inhibit hCYP1B1 in living cells and showed remarkable anti-migration ability on MFC-7 cells. Taken together, this study deciphered the SARs of chalcones as hCYP1B1 inhibitors and provided several potent hCYP1B1 inhibitors as promising candidates for the development of more efficacious anti-migration agents.
研究领域:
药理学
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药物化学
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肿瘤学
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药物发现
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PubMed
高影响因子
MOLECULAR MEDICINE
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2023
·Vol. 29
·期 1
·1-13
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IF 5.7
Zhuang Huangming,Ren Xunshan,Jiang Fuze,Zhou Panghu
Background Osteoarthritis (OA) is a common chronic disease characterized by chronic inflammation and extracellular matrix degradation. Indole-3-propionic acid (IPA) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in a variety of diseases. In this study, we further investigated the potential therapeutic role of IPA in OA and the underlying mechanism.Methods IL-1β was utilized to induce chondrocyte inflammation. Then, the cytotoxicity of IPA on rat chondrocytes was assessed. Meanwhile, RT-qPCR, Griess reaction, ELISA, Western blot and immunofluorescence were performed to evaluate the expression of inflammatory factors and stromal proteins, and the NF-κB pathway in chondrocytes treated with IL-1β alone, with IPA or with aryl hydrocarbon receptor (AhR) knockdown. An OA rat model was established by anterior cruciate ligament transection, and hematoxylin-eosin staining, Safranin-O/Fast Green staining and immunochemistry were applied to estimate OA severity.Results IPA did not affect cellular viability at concentrations up to 80 µM. IPA significantly inhibited the IL-1β-induced expression of inflammatory factors (Nitric oxide, PGE2, TNF-α, IL-6, iNOS and COX-2) and matrix-degrading enzymes (MMP-3, MMP-13 and ADAMTS-5), upregulated the expression of anabolic markers (aggrecan and collagen-II) and inactivated the NF-κB pathway. However, AhR knockdown could abolish the above protection capabilities and the suppression of the NF-κB pathway induced by IPA. Furthermore, IPA significantly reduced serum inflammatory cytokines expression, cartilage destruction and synovitis in vivo, demonstrating its protective role in OA progression.Conclusion IPA improved IL-1β-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.
研究领域:
药理学
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风湿病学
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分子生物学
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炎症研究
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Di Lei,Tingting Chen,Cuifang Fan,Qingzhen Xie
Benz[a]anthracene (BaA), a hazardous polycyclic aromatic hydrocarbon classified by the EPA, is a probable reproductive toxicant. Epidemiological studies suggest that BaA exposure may be a risk factor for recurrent miscarriage (RM). However, the underlying mechanisms are not well understood. This study identified DEC1 as a key gene through RNA-seq and single-cell RNA sequencing analysis. DEC1 expression was found to be downregulated in villous tissues from women with RM and in primary extravillous trophoblasts (EVTs) exposed to BaA. BaA suppressed DEC1 expression by promoting abnormal methylation patterns. Further analysis revealed that ARHGAP5 is a direct target of DEC1 in EVTs, where DEC1 inhibits trophoblast invasion by directly regulating ARHGAP5 transcription. Additionally, BaA destabilized matrix metalloproteinase 2 (MMP2) by activating the aryl hydrocarbon receptor (AhR) and promoting E3 ubiquitin ligase MID1-mediated degradation. In a mouse model, BaA induced miscarriage by modulating the DEC1/ARHGAP5 and MID1/MMP2 axes. Notably, BaA-induced miscarriage in mice was prevented by DEC1 overexpression or MID1 knockdown. These findings indicate that BaA exposure leads to miscarriage by suppressing the DEC1/ARHGAP5 pathway and enhancing the MID1/MMP2 pathway in human EVTs.
研究领域:
生殖毒理学
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分子生物学
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细胞生物学
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表观遗传学
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动物模型
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高影响因子
Reproductive Sciences
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2024
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IF 2.6
Zhou Nan,Lv Wenqiang,Chen Linna,Chen Kexin,He Qing,Xie Guangyan,Ma Jiachen,Cao Yijuan,Zhang Bei,Zhou Xueyan
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS. Graphical Abstract
研究领域:
内分泌学
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药理学
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生殖生物学
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分子生物学
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高影响因子
PHARMACOLOGICAL RESEARCH
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2026
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IF 12.2
Jiahui Xie,Yueran Ren,Minlin Lai,Jiayu Liang,Jingru Liang,Yifeng Zheng,Huidi Wang,Jiafeng Zhang,Boxin Zhao,Wei Song,Jia Yin
Clinical and animal data show peripheral-central crosstalk: microbial tryptophan metabolism regulate cognition under CCH. • This study highlights microbial tryptophan metabolism, especially ILA, as a promising therapeutic target for cognition. • This study identifies the ILA–AHR–AQP4 pathway as a key mediator of glymphatic restoration, which improves cognition. Microbial tryptophan metabolites regulate cognitive function, but their role in vascular cognitive impairment (VCI) induced by chronic cerebral hypoperfusion (CCH) remains poorly understood. In the CCH cohort, we observed gut microbiota dysbiosis and reduced levels of microbial tryptophan metabolites, including indole-3-lactic acid (ILA), in cognitively impaired CCH patients, with these metabolites serving as protective factors. In mice with bilateral carotid artery stenosis, gut microbiota dysbiosis and ILA reduction preceded cognitive decline and were accompanied by astrocytic aryl hydrocarbon receptor (AHR) inactivation, aquaporin-4 (AQP4) depolarization, and glymphatic dysfunction. Fecal microbiota transplantation (FMT) reconstituted the gut microbiota and salvaged cognition. The cognitive improvement following FMT depended on the restoration of the glymphatic system. Tryptophan supplementation increased cerebral ILA concentrations, activated astrocytic AHR, and polarized AQP4, thereby rescuing glymphatic function and enabling cognitive recovery. Notably, ILA supplementation alone was sufficient to restore AQP4 polarization and cognitive function. Mechanistically, we identified dioxin-responsive elements within the promoters of the AQP4 polarization-associated genes alpha-syntrophin ( Snta1 ) and dystroglycan 1 ( Dag1 ). ILA supplementation activated AHR in astrocytes and upregulated the expression of these genes, whereas AHR-specific antagonist pretreatment inhibited the upregulation of Snta1 and Dag1 induced by ILA. These findings demonstrate an ILA–AHR–AQP4 axis linking microbial tryptophan metabolism to the glymphatic system, which is important for cognitive restoration and indicates a novel therapeutic insight for VCI associated with CCH. Given the exploratory nature of the clinical cohorts, the findings warrant validation in larger independent cohorts. (Trial registration: ClinicalTrials. gov. ID number: NCT04688138). Download: Download high-res image (318KB) Download: Download full-size image
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Gut Microbes
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2026
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IF 11
Xueli Qiu,Lijun Wu,Fengxian Jiang,Huajian Shan,Lei Sheng,Bo Tian,Heng Wang,Hao Cui,Lide Tao,Chenyang Wu,Yuqian Yao,Chao Wang,Xiaozhong Zhou,Yingzi Zhang,Jinyu Bai
Postmenopausal osteoporosis (PMOP) has a high incidence in middle-aged and elderly women, leading to an increased risk of fractures and elevated rates of disability and mortality. In this work, we identified the reduction of indole-3-propionic acid (IPA) as a potential key factor contributing to the decline in bone mass observed in postmenopausal women. Mechanistically, IPA activates AhR, leading to the stabilization of key proteins in Wnt and NF-κB pathways that regulate bone formation and resorption. We evaluated efficacy in vivo using eight-week-old female C57BL/6 mice subjected to bilateral ovariectomy (OVX), with treatments initiated one week postsurgery, and performed complementary in vitro assays. Intraperitoneal IPA (20 mg/kg, 3× per week for 8 weeks) increased the trabecular bone mineral density (Tb.BMD) by ~68% versus OVX controls, whereas engineered Clostridium sporogenes that enhances IPA biosynthesis led to an even greater increase of ~118%. Together, these findings highlight the gut–bone axis as a central framework linking microbiota-derived IPA to skeletal remodeling and provide preclinical proof-of-concept for an engineered C. sporogenes–IPA strategy with therapeutic potential in PMOP.
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Advanced Science
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2025
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IF 14.1
Zhaoxuan Wang,Weijiao Xu,Lei Zhao,Lin Zhong,Wendan Yu,Shengmin Wang,Lu Sun,Tao Guo,Fengzhou Li,Zhuoshi Li,Lei Fang,Shiqing Wang,Guohui Zhang,Guoqing Xue,Wei Guo,Shilei Zhao,Chundong Gu
Lung adenocarcinoma (LUAD) displays marked intratumoral heterogeneity with distinct histological patterns. The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single-cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)-expressing tumor-associated macrophages (TAMs) and tryptophan 2,3-dioxygenase (TDO2)-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co-localization in peritumoral stroma, forming an immune-excluded niche. Mechanistically, TDO2⁺ myCAFs promoted monocyte-to-IL4I1⁺ TAM differentiation via the kynurenine-aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1⁺ TAMs and TDO2⁺ myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole-3-carboxaldehyde), contributing to CD8⁺ T cell exhaustion and anti-PD-1 therapeutic resistance. IL4I1⁺ TAMs and TDO2⁺ myCAFs conformably mediate ferroptosis resistance through the AhR-NRF2-GPX4-SLC7A11 pathway. Notably, AhR antagonist CH-223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH-223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti-PD-1 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1⁺ TAMs and TDO2⁺ myCAFs synergistically establish an immunosuppressive, ferroptosis-resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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肿瘤微环境
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癌症代谢
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转化医学
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高影响因子
Journal of Advanced Research
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2026
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IF 17.1
Yuting Zhang,Ruopeng Yin,Wang Dong,Li Sun,Tao Wang,Jingzu Sun,Huanqin Dai,Yanliang Bi,Liangliang Wang,Hongwei Liu
Introduction Sepsis is a life-threatening syndrome of organ dysfunction driven by a dysregulated immune response. Effective therapeutic strategies to restore immune homeostasis remain limited. Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila have emerged as potential immunomodulatory postbiotics, yet their therapeutic potential in sepsis and the underlying mechanisms remain unexplored. Objectives This study aims to investigate whether ALOS confers protection in experimental models of sepsis induced by toxic lipopolysaccharides (LPS) or cecal ligation and puncture (CLP), and the mechanism by which ALOS exerts its anti-inflammatory and regulatory effects. Methods In LPS or CLP-induced mouse sepsis models and a porcine sepsis model, ALOS (0.2 mg/kg, i.p.) was administered once every two days before challenge or half an hour post-surgery. Survival rates, physiological and biochemical parameters were assessed. Based on 16S rRNA gene amplicon sequencing and barrier function assessment, the changes of the colonic microbiota and metabolites and anti-inflammatory capacity were analyzed. The anti-inflammatory and immunomodulatory mechanisms of ALOS were investigated through dendritic cell phenotyping, transcriptomic analysis, inhibitor assays, and conditioned medium experiments. Finally, the safety of ALOS was evaluated in C57BL/6J mice following one-week administration (0.2 mg/kg, i.p.). Results ALOS pretreatment significantly suppresses sepsis, reduces the proportion of pro-inflammatory Th17 cells, and increases regulatory T cells (Treg). Mechanistically, ALOS induced semi‑mature dendritic cells with upregulated IDO1 expression, leading to enhanced production of kynurenine (Kyn). Kyn activated the aryl hydrocarbon receptor (AhR) to drive Treg differentiation. The protective effect of ALOS was completely reversed by NLG919, whereas Kyn administration mimicked the therapeutic benefit. ALOS also produced therapeutic protection on sepsis. In a porcine sepsis model, pretreatment of ALOS exerted systemic anti‑inflammatory effects and protected multiple organs. Conclusion This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Jianyu Qu,Jian Fu,Yuanbin Wang,Xin Jiang,Ying Ma,Jine Yi,Jing Wu,Yunhuan Liu,Kehe Huang,Ji Wang,Zhihang Yuan,Lixin Wen,Shuiping Liu
Arsenic is an environmental contaminant with potent renal toxicity. Accumulating evidence has indicated that gut microbiota dysbiosis plays an important role in kidney disease. However, the role of gut microbiota in arsenic-exposure-induced renal injury remains unclear. In our study, chronic exposure to NaAsO2 and fecal microbiota transplantation (FMT) from NaAsO2-exposed mice increased intestinal permeability and elevated renal indoxyl sulfate (IS), a key metabolite of gut microbiota, which promoted renal fibrosis and activated the AhR/NLRP3 inflammasome signaling pathway. Moreover, AST-120, a non-specific adsorbent, alleviated chronic NaAsO2 exposure-induced renal fibrosis by reducing the IS level in mice. In HK-2 cells, IS mediated NaAsO2-induced fibrosis via the AhR/NLRP3 inflammasome signaling pathway. Collectively, we confirmed that chronic exposure to NaAsO2 caused renal fibrosis and intestinal barrier dysfunction. Meanwhile, the gut–kidney axis plays a significant role in the mechanism of NaAsO2-induced renal fibrosis, providing a new therapeutic target for the prevention and treatment of arseniasis.
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高影响因子
PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Weiling Tan,Yufang Fu,Wanyu Hu,Yating Lin,Jingni Cai,Xuelin Huang,Yinyi OuYang,Sheng Lin,Ling Ye
Loganic acid (LA), a major iridoid glycoside from Gentiana macrophylla Pall., possesses anti-inflammatory and immunomodulatory properties, but its therapeutic potential in rheumatoid arthritis (RA) and its interaction with the gut microbiota remain poorly defined. Here, we show that LA markedly and dose-dependently attenuates disease severity in collagen-induced arthritis mice, as evidenced by reduced clinical arthritis scores, systemic inflammatory cytokines, and synovial tissue damage. LA reshaped the gut microbiota, and fecal microbiota transplantation from LA-treated donors partially reproduced its protective effects, indicating a causal contribution of the altered microbial community. In particular, LA selectively enriched OTUs annotated as Lactobacillus murinus ( L. murinus ) and increased levels of the microbial tryptophan metabolite indole-3-acetic acid (IAA). Both LA and IAA activated aryl hydrocarbon receptor (AhR) signaling, suppressed tumor necrosis factor-α-induced inflammatory responses in human synoviocytes, and, in vivo, enhanced IAA–AhR–interleukin-10 (IL-10) signaling in arthritic joints. Pharmacological inhibition of AhR with CH223191 substantially reversed LA's therapeutic effects, demonstrating that AhR signaling plays a critical role in its anti-arthritic activity. Collectively, these findings demonstrate that LA protects against RA through a dual mechanism: direct activation of AhR in joint tissues and indirect reinforcement of AhR signaling through an L. murinus -associated microbial IAA axis. This study highlights a gut microbiota–metabolite–AhR pathway as a key mediator of LA's anti-arthritic effects and supports LA as a promising microbiota-informed therapeutic candidate for RA.
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高影响因子
PEST MANAGEMENT SCIENCE
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2025
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IF 3.8
Anxiang Zhuang,Xu Zhao,Xiaoxue Lu,Shengyi Wang,Xi Zeng,Xiaoyu Li,Siquan Yu,Meiqi Xie,Yang Mei,Haibin Yuan,Xiangkun Meng
BACKGROUND The aryl hydrocarbon receptor (AhR) and its dimerization partner ARNT are well-established regulators of xenobiotic metabolism in vertebrates, but their functional roles in insect detoxification remain poorly characterized. This study investigates the involvement of TcAhR/TcARNT in the detoxification of insecticides and plant allelochemicals in the red flour beetle, Tribolium castaneum . RESULTS We found that the expressions of TcAhR and TcARNT were significantly induced upon exposure to imidacloprid, deltamethrin, or (−)-4-terpineol. RNA interference (RNAi)-mediated silencing of TcAhR and TcARNT dramatically increased larval susceptibility to these chemicals, and concurrently suppressed the activities of key detoxification enzymes, including P450s, CarEs, GSTs and UGTs. Conversely, treatment with the AhR agonist β-naphthoflavone upregulated TcAhR / TcARNT expression, enhanced detoxification enzyme activities, and decreased chemical susceptibility. Transcriptome analysis following TcAhR / TcARNT knockdown identified 34 co-regulated detoxification enzyme genes, the vast majority of which were downregulated. Among these, TcFE4 and TcUGT2B7 were functionally validated to be critical for detoxification, as their individual silencing significantly heightened larval chemical susceptibility. Furthermore, bioinformatic analysis revealed that 32 co-regulated genes contained potential AhR/ARNT binding motifs in their promoters, and several were physically clustered and consistently downregulated on chromosomes. CONCLUSION These results demonstrate that the TcAhR/TcARNT pathway plays a central role in regulating a battery of detoxification genes in T. castaneum , thereby modulating its tolerance to synthetic insecticides and plant allelochemicals. This study provides fundamental insights into the molecular mechanisms of insect detoxification and resistance. © 2025 Society of Chemical Industry.
研究领域:
毒理学
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分子生物学
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昆虫学
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遗传学
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农药科学
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高影响因子
iScience
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2025
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IF 4.1
Qian Wang,Jie Chen,Huini Chen,Dongning Liang,Hong Zhou,Juanjuan Chen,Yuan Gui,Fang Yao,Yudan Chen,Xi Zeng,Yaxiang Ma,Dong Zhou,Haiyan Fu
Cisplatin is a commonly used chemotherapy agent for treating various solid tumors, but its clinical application is limited by nephrotoxicity. While the potential for cisplatin to cause chronic kidney disease (CKD) following repeated administration has been underexplored, effective therapeutic strategies for cisplatin-induced CKD are lacking. We found that cisplatin-induced CKD is characterized by renal dysfunction and inflammation, along with intestinal barrier impairment. 16S rRNA and metabolomics revealed that cisplatin disrupts the gut microbiome and raises levels of tryptophan metabolites- Indole-3-propionic acid (IPA). Notably, oral administration of IPA reproduced similar harmful effects in cisplatin-induced CKD. Integrated analyses of the microbiome, metabolomics, Raman spectroscopy and DESI-MSI indicated that IPA supplementation exacerbates the production of uremic toxins linked to tryptophan metabolism and promotes the growth of pathogenic bacteria. Our findings demonstrates that IPA exacerbates renal inflammation and fibrosis by regulating AHR/NF-κB signaling pathways, altering intestinal microbiome composition, and disrupting tryptophan metabolism.
研究领域:
肾脏病学
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肿瘤学
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毒理学
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微生物组研究
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代谢组学
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分子信号通路
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高影响因子
危险品化学品经营许可证（带存储）