Frontiers in Cell and Developmental Biology
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2025
·
IF 4.3
Hui-Na Luo,Hong-Yuan Yang,Zai-Mei Wang,Jia-Mei Luo,Tong-Tong Zhang,Zeng-Ming Yang
Progesterone (P4) is essential for pregnancy establishment and maintenance. Clinically, P4 is widely used to regulate the menstrual cycle, maintain pregnancy, and treat luteal phase deficiency. However, P4 administration protocols, particularly regarding routes, dosage, and timing remain poorly defined. Although excessive P4 impairs embryo implantation and decidualization in mice, the underlying mechanism remains unclear. Our data show that decidualization in day 8 pregnant mice and artificial decidualization in day 8 pseudopregnant mice are impaired by 4 mg or 8 mg/mouse P4. The mRNA levels of Prl8a2 and Prl3c1, markers of in vitro decidualization are significantly downregulated by 10 or 20 μM P4. The uterine fluorescent signal of indoleamine 2,3-dioxygenase 1 (IDO1) and protein levels of tryptophan 2,3-dioxygenase (TDO) are increased after ovariectomized mice are treated with excessive P4. Treatment of uterine stromal cells with excessive P4 also significantly upregulates the protein levels of IDO1 and TDO, and kynurenine (Kyn) secretion. Epacadostat (IDO1 antagonist) or RU486 (progesterone receptor antagonist) effectively block P4-induced Kyn elevation. The mRNA levels of Prl8a2 and Prl3c1 and the protein levels of BMP2 are significantly inhibited by Kyn. The high-dose of P4 activates the aryl hydrocarbon receptor (AhR) and its downstream targets CYP1A1 and CYP1B1. Under in vitro decidualization, the mRNA levels of Prl8a2 and Prl3c1 are inhibited by 2-OH-E2 and 4-OH-E2, the catalytic products of CYP1A1 and CYP1B1, respectively. CH-223191, a specific AhR antagonist, effectively counteracts the effects of Kyn on Cyp1a1, Cyp1b1, and Prl8a2 expression. Additionally, nucleolar size in stromal cells is increased both in vivo and in vitro following excessive P4 treatment. Our findings suggest that excessive P4 impairs mouse decidualization via the Kyn-AhR pathway.
研究领域:
生殖生物学
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分子内分泌学
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妇产科学
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胚胎植入
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信号转导
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2025
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IF 3.5
Yongjun Tang,Zhengning Feng,Chenlu Ma,Nian Jang,Xiaolong Chen,Yingxu He,Francis L. Martin,Hui Liu,Weiyi Pang
Breast cancer has a high global incidence, and benzo[ a ]pyrene (B[ a ]P) is considered a contributing factor that increases carcinogenic risk. This study examined B[ a ]P's oncogenic mechanisms in mammary epithelial cells. Chronic B[ a ]P exposure induced morphological changes and enhanced proliferative/clonogenic capacity in MCF-10A cells. Chronic B[ a ]P exposure altered gene expression in MCF-10A cells, revealing differential levels of circRNAs, lncRNAs, miRNAs, and mRNAs. qRT-PCR validation demonstrated strong alignment with RNA-seq results, ensuring sequencing reliability. Additionally, chronic B[ a ]P exposure upregulated the protein expression of AhR and ARNT, as well as TGF- β , pSmad2/3, and KRT14 , while increasing Vimentin expression and decreasing E-cadherin expression. Notably, treatment with the TGF- β inhibitor SB431542 reversed these protein expression changes in transformed cells. These results show that exposure to Chronic B[ a ]P induces MCF-10A cell transformation. The underlying mechanisms involve significant transcriptional alterations, AhR/ARNT expression regulation, TGF- β signaling pathway activation, KRT14 protein modulation, and EMT. Furthermore, Chronic B[ a ]P exposure may drive transformation through TGF- β modulation. Chronic B[ a ]P exposure promotes breast carcinogenesis, revealing mechanistic insights and potential preventive biomarkers.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2025
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IF 3
Shu-Mei Pan,Wen-Cai Liu,Chun-Yu Xing,Xin-Yue Pu,Qian-Qian Wang,Xuan Zhao,Qi-Chen Zhang,Dan-Dan Wang,Ya-di Zhu
Uridine-5′-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in the regulation of bilirubin metabolism and detoxification of a variety of internal and external substances, and its insufficient function can lead to hyperbilirubinemia and affect the metabolic clearance of drugs, food additives, and environmental toxicants. However, there is a lack of safe and effective UGT1A1 inducers in the clinic. This study presents Corylin, an efficient UGT1A1 inducer identified from a series of natural flavonoids and isoflavonoids. Notably, Corylin demonstrated potent induction of intracellular UGT1A1. Furthermore, nuclear receptor reporter gene assays revealed that Corylin dose-dependently activated PPARs and AhR nuclear receptors, with the most robust activation observed in the PPARβ/δ subtype. Animal experiments indicated that Corylin exhibited favorable safety profiles and significant hepatoprotective effects in mice with APAP-induced liver injury, accompanied by marked UGT1A1 expression. Collectively, this study suggests that Corylin is a potential UGT1A1 inducer and a promising candidate for the intervention of liver-related disorders.
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高影响因子
Cell Reports
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2025
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IF 6.9
Zijia Sun,Yingsheng Wang,Shaorui Liu,Hui Li,Danyang He,Heping Xu
Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.
研究领域:
神经科学
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免疫学
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胃肠病学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Juan Wang,Xiangsheng Hong,Wang Liu,Le Zhang,Saihong Yan,Zhitong Li,Jinmiao Zha
As substitutes for bisphenol A (BPA), bisphenol analogs (BPs) have raised concerns due to their frequent environmental detection and unclear safety. Here, the cytotoxicity, endocrine disruption, neurotoxicity, aryl hydrocarbon receptor (AhR) activity, and genotoxicity of nine BPs and BPA were evaluated in three types of cell lines. Over half of the tested BPs exhibited greater cytotoxicity than BPA, with IC50 values showing a linear correlation with Log Kow (R²=0.69). All tested BPs exhibited at least one endocrine-disrupting effect, notably estrogenic, which was observable even at 0.01–0.1 μM. Importantly, BPAF and BPAP exposure had widespread endocrine-suppressing effects. Moreover, all BPs (except BPP) and BPA increased SH-SY5Y cells apoptosis at 1–10 μM. Only BPF and BPP significantly increased 7-ethoxyresorufin-O-deethylase levels, highlighting their notable effects on AhR activity. BPAF significantly induced DNA damage at 1.25 μM, whereas BPA, BPF, and BPP induced damage at 20, 25, and 25 μM, respectively. Finally, ToxPi, a weighted scoring system, was used to rank the comprehensive toxicity of BPs, with 7 of 9 BPs showing higher scores than BPA. Collectively, BPs generally exhibited stronger comprehensive toxicity compared with BPA, emphasizing the urgent need for further research to confirm their potential health implications.
研究领域:
毒理学
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环境科学
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生物医学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Huangming Zhuang,Bin Li,Ting Xie,Changgeng Xu,Xunshan Ren,Fuze Jiang,Tianrun Lei,Panghu Zhou
Background Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation. Indole-3-aldehyde (3-IAld) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in multiple inflammatory diseases. However, the potential therapeutic role of 3-IAld in OA and the underlying mechanism remain to be explored. Methods IL-1β was utilized to induce chondrocytes inflammation. Then, cell counting kit-8 was carried out to assess the cytotoxicity of 3-IAld on rat chondrocytes viability. Meanwhile, RT-qPCR, Western blot, and immunofluorescence were performed to evaluate the expression of inflammatory factors, matrix-degrading enzymes and matrix synthesis protein, and the NF-κB pathway in chondrocytes treated with IL-1β alone, with 3-IAld or with siRNA-AhR. Results Our results showed that 3-IAld did not affect cellular viability at concentrations up to 50 μM. 3-IAld significantly inhibited the expression of pro-inflammatory cytokines (IL-6, iNOS and COX-2), and matrix-degrading enzymes (MMP3, MMP13 and ADAMTS5), upregulated the expression of matrix synthesis protein (aggrecan and collagen-II), and inactivated the NF-κB pathway in IL-1β-treated chondrocytes. However, AhR knockdown could totally abolish the aforementioned therapeutic capabilities and the inactivation of the NF-κB pathway induced by 3-IAld. Conclusions 3-IAld reduced inflammation through the AhR-NF-κB signalling pathway in IL-1β-induced chondrocytes, which is expected to provide a new therapeutic strategy for OA.
研究领域:
药理学
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免疫学
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骨科
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细胞生物学
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DOI
PubMed
高影响因子
Cells
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2022
·Vol. 11
·期 23
·3856
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IF 7.666
Bin Liu,Hui Chen
The aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) belong to the bHLH-PAS (basic Helix–Loop–Helix–Period/ARNT/Single-minded) family of transcription factors, which participate in the sensing and transmitting stimuli of exogenous and endogenous chemical substances, and subsequently activates genes transcription involved in various detoxification and physiological functions. However, they have not been identified inDendroctonus armandi,and their roles in the detoxification metabolism are unclear. In the present study,AhRandARNTofD. armandiwere characterized. Spatiotemporal expression profiling indicated thatDaAhRandDaARNTwere highly expressed in the adult and larval stages ofD. armandiand mainly expressed in the midgut and Malpighian tubules of adults. Additionally, the expression ofDaAhRandDaARNTsignificantly increased after exposure to (−)-?-pinene, (+)-3-carene, and (±)-limonene. SilencingDaAhRandDaARNTincreased the susceptibility ofD. armandito (−)-?-pinene, (+)-3-carene, and (±)-limonene, and the activities of detoxification enzyme were also remarkably reduced. Moreover,DaCYP6DF1andDaGSTs2were significantly down-regulated after injections ofdsAhRanddsARNTin the male and female adults, with the expression ofDaCYP6DF1decreasing by higher than 70%. The present study revealed that the transcription factorsAhRandARNTofD. armandiwere induced by terpenoids and participated in the regulation ofDaCYP6DF1 expression, which was associated withD. armandi’s susceptibility to (−)-?-pinene and (±)-limonene. These results may provide a theoretical basis for the integrated control ofD. armandiand improve our comprehension of insect toxicology.Keywords:Dendroctonus armandi;AhR;ARNT;detoxification metabolism;transcriptional regulation
研究领域:
昆虫学
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分子生物学
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毒理学
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-22
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IF 12.6
Yang Chuan,Xie Langlang,Deng Zihan,Ai Hongbo,Xiang Tingwen,Yan Xiaojing,Ling Zhiguo,Xiao Shiyu,Tang Yong,Huang Gang,Luo Fei,Chen Yueqi
Dysbiosis of gut microbiota significantly exacerbates the progression of rheumatoid arthritis (RA). Targeting gut microbiota may present a promising therapeutic strategy for RA. Gold nanospheres (GNS), known for excellent biocompatibility, stability and minimal toxicity, have emerged as precise modulators of gut microbiota, reshaping intestinal environments to treat various inflammatory diseases. Our study found that oral administration of 60-nm GNS effectively ameliorated collagen-induced arthritis (CIA) in mice, with a marked reduction in disease severity and synovial inflammation. Specifically, GNS notably enriched the probiotic genus Ligilactobacillus while restoring intestinal barrier function by upregulating tight junction proteins Claudin-1 and ZO-1. Targeted metabolomics analysis revealed GNS substantially increased the production of indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in gut, which were shown to activate the aryl hydrocarbon receptor (AhR) pathway. Mechanistic studies demonstrated that the IPA/IAA mixture inhibited PTEN ubiquitination, stabilizing PTEN protein levels and suppressing NF-κB activation in synovial tissues. These changes correlated with reduced synovial hyperplasia and inflammatory infiltration. Our findings established GNS as an effective nanomodulator of the gut-joint axis, providing novel insights into microbiota-targeted therapies for RA and other inflammatory diseases. Graphical abstract
研究领域:
医学
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免疫学
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微生物学
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纳米技术
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PubMed
高影响因子
Microbiome
·
2023
·Vol. 11
·期 1
·1-23
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IF 15.5
Hu Jun,Chen Jianwei,Xu Xiaojian,Hou Qiliang,Ren Jing,Yan Xianghua
Background The intestinal epithelial barrier confers protection against the intestinal invasion by pathogens and exposure to food antigens and toxins. Growing studies have linked the gut microbiota to the intestinal epithelial barrier function. The mining of the gut microbes that facilitate the function of intestinal epithelial barrier is urgently needed.Results Here, we studied a landscape of the gut microbiome of seven pig breeds using metagenomics and 16S rDNA gene amplicon sequencing. The results indicated an obvious difference in the gut microbiome between Congjiang miniature (CM) pigs (a native Chinese breed) and commercial Duroc × [Landrace × Yorkshire] (DLY) pigs. CM finishing pigs had stronger intestinal epithelial barrier function than the DLY finishing pigs. Fecal microbiota transplantation from CM and DLY finishing pigs to germ-free (GF) mice transferred the intestinal epithelial barrier characteristics. By comparing the gut microbiome of the recipient GF mice, we identified and validated Bacteroides fragilis as a microbial species that contributes to the intestinal epithelial barrier. B. fragilis-derived 3-phenylpropionic acid metabolite had an important function on the enhancement of intestinal epithelial barrier. Furthermore, 3-phenylpropionic acid facilitated the intestinal epithelial barrier by activating aryl hydrocarbon receptor (AhR) signaling.Conclusion sThese findings suggest that manipulation of B. fragilis and 3-phenylpropionic acid is a promising strategy for improving intestinal epithelial barrier.
Video Abstract
研究领域:
微生物学
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免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Lidong Chao,Ruoning Wu,Yudi Zhang,Jilong Luo,Xue-jiao Gao
Sodium pentachlorophenol (PCP-Na) is a persistent halogenated aromatic compound with poorly understood cardiotoxicity. This study investigated the underlying mechanisms using mouse models and HL-1 cardiomyocytes, integrating network toxicology, molecular docking, and targeted interventions with the AHR inhibitor CH223191, the antioxidant N-acetylcysteine (NAC), and the CYP1A1 inhibitor α-naphthoflavone (ANF). Findings demonstrate that PCP-Na promotes AHR nuclear translocation and dose-dependently activates the downstream target gene CYP1A1. This AHR/CYP1A1/ROS signaling axis triggers excessive oxidative stress, subsequently leading to mitochondrial dynamic imbalance, impaired ATP production, and cardiomyocyte apoptosis. By systematically elucidating these molecular pathways, this study highlights AHR as a direct target of PCP-Na and provides a critical theoretical basis for the safety assessment of agricultural and environmental matrices contaminated with persistent organic pollutants. These results offer novel insights into the protective potential of AHR/CYP1A1 inhibitors against halogenated contaminant-induced cardiac injury.
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高影响因子
CURRENT MOLECULAR MEDICINE
·
2025
·Vol. 25
·期 9
·1191-1201
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IF 2.5
Yongkang Wu,Jing Xie,Qing Tao,Lina Tan,Xiangyu Zhu,Jin Yong
ObjectiveNonalcoholic fatty liver disease (NAFLD) is a prevalent liver condition worldwide, and the statistics show that men have a higher incidence and prevalence than women, but its toxicological mechanism is not completely clear. This research is intended to explore the role of BaP in NAFLD and to study how the environmental pollutant BaP influences the AHR/ERα axis to mediate the progression of NAFLD.MethodsIn this study, we established NAFLD models in vivo and in vitro by treating HepG2 cells with a high-fat diet and Oleic acid (OA) in C57BL/6J mice. Liver injury indexes ALT, AST, and lipid metabolism indexes TG and TC were evaluated to verify the success of modeling. Then, the model was treated with BaP, and the mRNA and protein expressions of CYP1A1, ERα, and SREBP-1c were evaluated by RT-PCR and WB, and the changes of liver fat were evaluated by HE and oil red O staining. Next, BaP was added into the cells treated with or without estradiol (E2), and the lipid metabolism in the cells was evaluated by oil red O staining, and whether the above levels of CYP1A1, ERα and SREBP-1c were changed.ResultsOur results show that after exposure to BaP, ERα protein levels in mice and cells are inhibited, mRNA and protein levels of SREBP-1c are reduced, and lipid metabolism processes are obstructed. The addition of E2 can reduce the increase of SREBP-1c mRNA and protein expression induced by OA, and reduce the deposition of lipids in cells. However, BaP treatment can weaken the action of E2 and destroy the protection of E2 in cells.ConclusionThe results showed that E2 could reduce SREBP-1c mRNA and protein levels. BaP can stimulate AHR, leading to the degradation of ERα protein, reducing the binding of E2 to ERα, and aggravating the progression of NAFLD. This reveals the toxicological mechanism by which environmental pollutant BaP influences E2 to mediate NAFLD, and provides strong evidence for differences in NAFLD between the sexes.
研究领域:
毒理学
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环境健康
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分子生物学
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内分泌学
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肝脏病学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Caihong Wang,Qihao Xu,Chaozhi Wei,Qinglian Hu,Yingping Xiao,Yuanxiang Jin
The higher prevalence of ulcerative colitis (UC) and the side effects of its therapeutic agents contribute to finding novel treatments. This study aimed to investigate whether kynurenine (KYN), a tryptophan metabolite, has the possibility of alleviating UC and further clarifying the underlying mechanism. The effect of KYN on treating UC was evaluated by intestinal pathology, inflammatory cytokines, and tight-junction proteins in colitis mice and LPS-stimulated Caco-2 cells. Our results revealed that KYN relieved pathological symptoms of UC, improved intestinal barrier function, enhanced AhR expression, and inhibited NF-κB signaling pathway activation in the colon of colitis mice. Moreover, the improved intestinal barrier function, the decreased inflammasome production, and the inhibited activation of the NF-κB signaling pathway by KYN were dependent on AhR in Caco-2 cells. KYN could trigger AhR activation, inactivate the NF-κB signaling pathway, and inhibit NLRP3 inflammasome production, thus alleviating intestinal epithelial barrier dysfunction and reducing intestinal inflammation. In conclusion, the present study reveals that KYN ameliorates UC by improving the intestinal epithelial barrier and activating the AhR-NF-κB-NLRP3 signaling pathway, and it can be a promising therapeutic agent and dietary supplement for alleviating UC.
研究领域:
胃肠病学
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免疫学
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药理学
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PubMed
高影响因子
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