AQUATIC TOXICOLOGY
·
2025
·
IF 4.3
Hao Wu,Jinwei Gao,Dong Liu,Xiangrong Liu,Feiming Chen,Jiayuan Qin,Yunfei Ye,Zhenzhen Xiong,Jiayu Wu,Can Yang,Min Xie,Rui Song,Dongsheng Ou
In recent years, deltamethrin (DEL) pollution poses a significant threat to aquaculture; however, the protective role of vitamin C (VC) against acute toxicity in crucian carp has not been well understood. This study provides compelling evidence that exposure to 2.0 mg/L waterborne VC significantly mitigates DEL-induced 96-hour mortality in crucian carp ( p < 0.001). Importantly, this research represents the first documentation of the protective effects of waterborne VC in fish, which is mediated through the modulation of the aryl hydrocarbon receptor (AhR)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway—a mechanism not previously reported in crucian carp. The observed protective effect is attributed to the enhancement of antioxidant and anti-inflammatory responses via this signaling pathway. Exposure to DEL at 6.2 μg/L resulted in severe oxidative stress, characterized by significantly increased malondialdehyde (MDA) levels and depletion of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) in the liver and intestine ( p < 0.01). Histopathological damage, including hepatic vacuolation, shortened villi, and inflammation, as well as elevated reactive oxygen species (ROS), was observed. Co-exposure to VC normalized antioxidant markers, reduced MDA and ROS levels, and alleviated tissue damage ( p < 0.05). Mechanistically, VC counteracted the suppression of AhR/Nrf2 by DEL, leading to the statistically significant upregulation of antioxidant genes ( gst, sod, cat ) and suppression of pro-inflammatory cytokines ( il1β, il6, tnfα ) ( p < 0.05). VC exhibited tissue-specific regulation by enhancing hepatic Nrf2 defenses and co-activating intestinal AhR/Nrf2, as confirmed by Western blot analysis. Our study shows that waterborne VC effectively protects against acute DEL toxicity under current experimental conditions, suggesting its potential as an eco-friendly emergency intervention in aquaculture during sudden pesticide exposure. Further research is needed to confirm its effectiveness in complex pond systems and various fish species.
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高影响因子
Food Frontiers
·
2026
·Vol. 7
·期 1
·e70225
·
IF 6.9
Qiaoyu Sun,Qingqing Zhou,Sitong Ge,Danli Wu,Ping Li,Qing Gu
Impairment of intestinal barrier function is intricately linked to intestinal inflammation. Emerging evidence highlights that tryptophan-derived metabolites from the intestinal microbiota play a crucial role in maintaining the homeostasis of intestinal barrier function. In this study, a Caco-2/HT29 co-culture model was applied to evaluate the effects of indole-3-acetic acid (IAA) on the intestinal barrier and explore its underlying mechanism of action. Results demonstrated that lipopolysaccharide (LPS) caused the transepithelial resistance to drop to 387.5 ± 30.41 Ω·cm 2 , while IAA was able to increase it to 542 ± 31.11 Ω·cm 2 . At the same time, it reduced the paracellular permeability and restored the FITC-Dextran 4 (FD-4) permeability to 108.01%. This phenomenon was accompanied by an upregulation in the expression of tight junction (TJ) proteins. Concurrently, after IAA intervention, aryl hydrocarbon receptor (AHR) pathway was activated, while nuclear factor kappa-B (NF-κB) pathway was significantly inhibited. Furthermore, IAA exerted an inhibitory effect on the LPS-triggered upregulation of inflammatory factors (TNF-α, IL-6, IL-8) in RAW264.7 cells. These findings provide novel insights into the enhancement of intestinal barrier function and the in vitro anti-inflammatory properties of gut microbiota-derived metabolites.
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ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Zixu Li,Muge Xu,Yahan Zhang,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the aryl hydrocarbon receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or ferroptosis significantly attenuated these changes, highlighting the potential of AhR and ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR–NRF2/HO-1–ferroptosis–HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.
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Chinese Medicine
·
2026
·Vol. 21
·期 1
·129
·
IF 7.4
Dong Jinwang,Cao Yang,Chen Xiujin,Xie Tao,Zhang Xiaobo,Zhao Qingpeng,Shi Cunhu,Miao Qiangqiang,Xu Zhengwei,Yan Liang,Dong Liang
Background Spinal cord injury (SCI) induces gut microbiota dysbiosis, which significantly affects recovery. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine formula, has shown therapeutic effects on SCI. Although BHD is known to modulate gut microbiota, whether its benefits are mediated through the gut–spinal cord axis remains unclear. Methods A rat SCI model was established. BHD was administered orally, and fecal microbiota transplantation (FMT) from BHD-treated rats (BHD-FMT) was performed to assess neuroprotective and gut-protective effects. Behavioral testing, histology, and immunofluorescence evaluated motor recovery, inflammation, and neuroregeneration. Gut microbiota profiling was performed using 16S rDNA sequencing and metagenomics, while targeted metabolomics quantified tryptophan metabolites. Transcriptomics validated key pathways, and a microbiota–metabolite–signaling network was constructed. Results BHD significantly improved motor function, reduced spinal inflammation, and promoted neuronal survival and axonal regeneration. It restored gut function, reduced colonic inflammation, and enhanced ZO-1 and Occludin expression, which were further confirmed by FMT. BHD-FMT reshaped the gut microbiota and enriched Lactobacillus johnsonii , which correlated positively with recovery. Metabolomics showed increased tryptophan metabolites, including indole-3-lactic acid (ILA) and indole-3-propionic acid (IPA), with ILA strongly associated with functional improvement. Transcriptomic analysis and Western blot validation demonstrated that BHD-FMT activated the AhR–PI3K/Akt pathway, which was suppressed by an AhR antagonist. Conclusion BHD promotes neuroregeneration after SCI by reshaping gut microbiota and enhancing tryptophan metabolism, potentially exerting its effects through the L. johnsonii –ILA–AhR–PI3K/Akt network. These findings reveal a gut–spinal cord axis–mediated mechanism of BHD and highlight microecological targets for SCI therapy. Graphical
The alternative text for this image may have been generated using AI.
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Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
Jia Yifan,He Muchen,Wang Fan,Zhan Yaqing,Deng Qiwen,Shen Jiantong,Wang Xiwen,Ran Qi,Huang Wenqi,Ling Yihong,Wen Shihong
Background & Aims Dysfunction of the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB) contributes to the development of intestinal ischemia/reperfusion (IR) injury. Tryptophan (TRP), an essential amino acid, plays a crucial role in maintaining intestinal homeostasis, yet its regulatory effects on the GVB following IR remain unexplored. We aimed to better define the role of TRP in intestinal IR in vivo and in vitro. Methods Mice underwent intestinal ischemia/reperfusion (IR) and were fed control, TRP-recommended (TRP-r), or TRP-sufficient (TRP-s) diets. Fecal metagenomic sequencing analyzed microbial composition, and targeted metabolomics quantified tryptophan and its metabolites in intestinal and serum samples. ILA’s effects on barrier integrity were assessed via tight junction protein expression and FITC-dextran permeability assays. RNA sequencing of intestinal endothelial cells elucidated mechanisms by which ILA modulated GVB function. The STAT3-claudin 2 relationship was validated in vitro by ChIP-qPCR. Results TRP supplementation significantly reshaped the gut microbiota, mitigated tissue damage and enhanced the integrity of both the IEB and GVB. Indole-3-lactic acid (ILA), a key tryptophan metabolite, was identified as an important factor in preserving GVB function. Mechanistically, our results show that the aryl hydrocarbon receptor (AhR)/Nrf2/signal transducer and activator of transcription 3 (STAT3) pathway is essential for ILA-mediated improvement of GVB integrity and downregulation of the pore-forming protein claudin 2. Conclusions Our findings highlight the dual role of ILA in reinforcing both IEB and GVB functions and shed light on the molecular mechanisms underlying ILA’s GVB-protective effects. This study implicates that ILA or other AhR-activating metabolites may serve as promising pharmacological agents for alleviating IR-induced intestinal damage. Graphical
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IMMUNOLOGIC RESEARCH
·
2024
·
IF 3.3
Su Xiaoran,Wang Xinliu,Zhang Xin,Sun Yajie,Jia Yugai
Massive evidence shows that intestinal tryptophan metabolites affected by intestinal flora can modulate the progression of rheumatoid arthritis (RA). However, the effects and mechanisms of intestinal tryptophan metabolites on RA are not yet detailed. Herein, we investigated the protective effects of intestinal tryptophan metabolites on RA and its detailed mechanisms. In this study, the collagen-induced arthritis (CIA) rat model was established. Based on metabolomics analysis, the contents of β-indole-3-acetic acid (IAA), indolylpropionic acid, and indole-3-β-acrylic acid in the sera of CIA rats were significantly less compared with those of the normal rats. Under the condition of Treg or Th17 cell differentiation, IAA significantly promoted the differentiation and activation of Treg cells instead of Th17 cells. Intestinal tryptophan metabolites are well-known endogenic ligands of aryl hydrocarbon receptor (AhR). Not surprisingly, IAA increased the level of Foxp3 through activating the AhR pathway. Interestingly, IAA had little impact on the level of Foxp3 mRNA, but reducing the ubiquitination and degradation of Foxp3. Mechanically, IAA reduced the expression of the transcriptional coactivator TAZ, which was almost completely reversed by either AhR antagonist CH223191 or siRNA. In vitro, IAA decreased the combination of TAZ and the histone acetyltransferase Tip60, while it increased the combination of Tip60 and Foxp3. In CIA rats, oral administration of IAA increased the number of Treg cells and relieved the inflammation. A combined use with CH223191 almost abolished the effect of IAA. Taken together, IAA attenuated CIA by promoting the differentiation of Treg cells through reducing the ubiquitination of Foxp3 via the AhR-TAZ-Tip60 pathway.
研究领域:
免疫学
·
风湿病学
·
代谢组学
·
药理学
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高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2022
·Vol. 30
·期 5
·13739-13754
·
IF 5.19
Wu Hao,Bao Yuling,Yan Tongtong,Huang Hui,Jiang Ping,Zhang Zhan,Li Lei,Wu Qian
Epidemiological studies have shown that PAHs may exert adverse effects on childhood asthma. However, the underlying molecular mechanism remains to be fully elucidated. This study aimed to investigate this process in view of metabolic pathways, especially one-carbon metabolism and tryptophan metabolism. Fifty asthmatic children and 50 control subjects were recruited for this study. Serum IgE and IL-17A levels were detected by ELISA. Serum PAH concentrations were measured by GC-MS. One-carbon-related metabolites and tryptophan metabolites were determined by UPLC-Orbitrap-MS. DNA methylation was analyzed by bisulfite sequencing PCR. ChIP assays were used to examine H3K4me3 enrichment on IL-17A gene. Multivariable linear regression was performed to evaluate the association between PAHs and childhood asthma mediated by intermediators. HE staining in lung tissue, IgE and IL-17A in BALF, metabolic profiles in urine, and Ahr , Il-17a , and Cyp1a1 gene expression were determined in PAH-exposed mice. Serum Fla level was associated with childhood asthma (OR = 1.380, 95% CI: 1.063–1.792), and had a great effect on one-carbon metabolites, especially SAH, SAM, and Ser, which exerted significant mediation effects on the relationship between the Fla concentration and asthma. Moreover, we did find significant mediation effects between serum Fla and asthma by LINE-1 DNA methylation and H3K4me3 levels in the IL-17A promoter region. The differential Trp metabolites, such as Trp, tryptamine, IA, IAA, indole, IAld, and IAAld, indicated that asthmatic children had increased indole-AhR pathway. Mediation analysis failed to show a mediator effect of Trp metabolites in the association between PAHs and childhood asthma. An animal study confirmed that PAH exposure increased methylation levels, and altered Trp metabolite-AhR-IL-17A axis, which may be influenced by gender. PAHs disturbed one-carbon metabolism to influence the methyl group refilling DNA methylation and histone methylation, and disturbed tryptophan metabolism to regulate Th17-cell differentiation, which may elevate serum IL-17A concentration in asthmatic children.
研究领域:
环境卫生
·
免疫学
·
分子生物学
·
儿科
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Food Bioscience
·
2025
·
IF 5.9
Shufeng Wu,Xiang Kuang,Haizhao Song,Zhigang Liu,Ling Xiong,Bo Ren,Fang Wang,Xinchun Shen,Luanfeng Wang
Limosillactobacillus reuteri ( L. reuteri ) is known to play a beneficial role in various aspects of human health, including diabetes, inflammatory bowel disease, and neurological disorders. However, its role in regulating obesity-induced metabolic disorders remains poorly understood. We demonstrate that administering L. reuteri C501 to male mice for 10 weeks significantly alleviates high-fat diet (HFD)-induced obesity and related metabolic disorders. Treatment with L. reuteri C501 led to reduced body weight gain, improved insulin sensitivity, and attenuated inflammatory responses. Moreover, the treatment activated the aryl hydrocarbon receptor (AhR) and the circadian rhythm regulator brain and muscle ARNT-like protein 1 (Bmal1)-two key players in immune function and energy metabolism-thereby influencing lipid metabolism in HFD-fed mice. In addition, L. reuteri C501 modulated gut microbiota composition and enhanced the production of indole derivatives. Supplementation with indole-3-lactic acid (ILA), one such derivative, also improved obesity outcomes in HFD-fed mice. Notably, administering L. reuteri C501 at zeitgeber time 0 (ZT0, the beginning of the light cycle) resulted in stronger therapeutic effects, suggesting that timing of intake may critically influence its efficacy. These findings highlight L. reuteri C501 as a promising probiotic intervention for obesity, with chronobiological factors playing a key role in optimizing its metabolic benefits.
研究领域:
微生物学
·
代谢病学
·
免疫代谢
·
分子营养学
·
昼夜节律生物学
·
肠道微生物组学
·
转化医学
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Frontiers in Endocrinology
·
2024
·
IF 3.9
Chen Si-Ting,Ran Feng,Shi Wen-Wen,Liu Cheng-Kan,Wang Peng-Chao,Luo Hui-Na,Yang Zeng-Ming
Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy. Embryo implantation and decidualization were analysed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy. On day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization. Hence, Trp-free diet may impair decidualization via the IDO-KYN-AHR pathway.
研究领域:
营养学
·
生殖生物学
·
分子生物学
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ENVIRONMENT INTERNATIONAL
·
2016
·
IF 5.929
Ping Xiang,Rong-Yan Liu,Hong-Jie Sun,Yong-He Han,Rui-Wen He,Xin-Yi Cui,Lena Q. Ma
Human corneal epithelial (HCE) cells are continually exposed to dust in the air, which may cause corneal epithelium damage. Both water and organic soluble contaminants in dust may contribute to cytotoxicity in HCE cells, however, the associated toxicity mechanisms are not fully elucidated. In this study, indoor dust from residential houses and commercial offices in Nanjing, China was collected and the effects of organic and water soluble fraction of dust on primary HCE cells were examined. The concentrations of heavy metals in the dust and dust extracts were determined by ICP-MS and PAHs by GC–MS, with office dust having greater concentrations of heavy metals and PAHs than house dust. Based on LC 50 , organic extract was more toxic than water extract, and office dust was more toxic than house dust. Accordingly, the organic extracts induced more ROS , malondialdehyde, and 8-Hydroxydeoxyguanosine and higher expression of inflammatory mediators ( IL-1β , IL-6 , and IL-8 ), and AhR inducible genes ( CYP1A1 , and CYP1B1 ) than water extracts ( p < 0.05). Extracts of office dust presented greater suppression of superoxide dismutase and catalase activity than those of house dust. In addition, exposure to dust extracts activated NF-κB signal pathway except water extract of house dust. The results suggested that both water and organic soluble fractions of dust caused cytotoxicity, oxidative damage, inflammatory response, and activation of AhR inducible genes, with organic extracts having higher potential to induce adverse effects on primary HCE cells. The results based on primary HCE cells demonstrated the importance of reducing contaminants in indoor dust to reduce their adverse impacts on human eyes.
研究领域:
毒理学
·
眼科学
·
环境科学
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高影响因子
Food & Function
·
2021
·Vol. 12
·期 20
·10184-10195
·
IF 5.396
Zhenyang Gu,Wenlong Pei,Yonghua Shen,Lijuan Wang,Jun Zhu,Yi Zhang,Shengxian Fan,Qian Wu,Lei Li,Zhan Zhang
Dietary interventions, including dietary ingredients, nutrients and probiotics, exert anti-inflammatory effects in ulcerative colitis (UC). Our previous study showed that Akkermansia muciniphila (Akk), a promising probiotic, could protect against colitis via the regulation of the immune response. However, whether it can restore aberrant tryptophan (Trp) metabolism during colitis remains unclear. In this study, untargeted serum metabolomics of patients with UC and colitis mice showed that Trp metabolism was activated, which was confirmed by quantification of Trp metabolites from a validation cohort and animal study. Integrative analysis of faecal metagenomes and serum metabolomes revealed significant associations between Akk and three Trp metabolites. Live Akk, pasteurised Akk and Amuc_1100 failed to restore the reduction in Trp metabolites involved in the serotonin pathway in colitis mice. However, live Akk, pasteurised Akk and Amuc_1100 increased kynurenine (Kyn) but decreased 2-picolinic acid (PIC) levels and the PIC/Kyn ratio without regulating any of the genes involved in Trp metabolism, suggesting that they could suppress the Kyn pathway (KP) independent of colon tissue. In addition, they could significantly restore the enrichment of Trp metabolism mediated by faecal microbiota. Specifically, live Akk, pasteurised Akk and Amuc_1100 could significantly offset the reduction in indoleacetic acid (IAA) levels. Pasteurised Akk significantly elevated the serum levels of indole acrylic acid (IA). In addition, live Akk, pasteurised Akk and Amuc_1100 could upregulate aryl hydrocarbon receptor (AhR) targeted genes, including CYP1A1, IL-10 and IL-22, suggesting that Akk could activate AhR signaling by regulating Trp metabolism, thereby attenuating colonic inflammation.
研究领域:
微生物学
·
免疫学
·
胃肠病学
·
代谢组学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 30
·23495-23508
·
IF 6.7
Huang Zheng,Zhang Qing,Zhao Jianxin,Stanton Catherine,Ross R. Paul,Chen Wei,Yang Bo
Atopic dermatitis (AD) is a prevalent
early childhood inflammatory
skin disease frequently linked to gut dysbiosis. While Bifidobacterium longum subsp. infantis is a pioneer infant gut colonizer driving immune maturation, its
role in AD prevention remains unclear. Here, we investigated early
life intervention with B. longum subsp. infantis CCFM1269 using a 2,4-dinitrofluorobenzene
(DNFB)-induced murine AD model. Oral administration of CCFM1269 significantly
ameliorated AD symptoms, reducing skin/ear thickness, dermatitis scores,
and serum IgE. Mechanistically, CCFM1269 modulated the systemic Th1/Th2
balance by downregulating TSLP, IL-4, and IL-13, while upregulating
IFN-γ. Notably, CCFM1269 produced indole-3-lactic acid (ILA).
Via the gut–skin axis, ILA activated the aryl hydrocarbon receptor
(AHR) and its target CYP1A1 in skin tissues, strengthening the epidermal
barrier. Additionally, AD mitigation was associated with gut microbiota
reshaping. Ultimately, CCFM1269 alleviates AD primarily through the
ILA- AHR signaling pathway, highlighting its potential as a functional
food ingredient for early life AD prevention.
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