Nutrients
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2023
·Vol. 15
·期 19
·4282
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IF 5.9
Ying Chen,Ruili Pan,Liya Mei,Peijun Tian,Linlin Wang,Jianxin Zhao,Wei Chen,Gang Wang
Intestinal peristalsis is vital for gastrointestinal physiology and host homeostasis and is frequently dysregulated in intestinal disorders. Gut microbiota can regulate gut motility, especially through the tryptophan metabolism pathway. However, the role of indoles as microbial tryptophan metabolites in colonic function requires further exploration. Here, we show that the delivery of indole acetic acid (IAA) targeting the colon can improve gut motility by activating the aryl hydrocarbon receptor (AHR). To achieve colon-targeted delivery, Eudragit S-100 (ES) and chitosan (CS) were used as drug carriers. After optimisation, IAA-loaded ES-coated CS nanoparticles exhibited an encapsulation efficiency of 83% and a drug-loading capacity of 16%. These nanoparticles exhibited pH-dependent characteristics and remained stable in acidic conditions and the upper intestine. In simulated intestinal fluid (pH 7.4) and colonic lumen, considerable amounts of IAA were released after approximately 4 h. Compared with free IAA, the nanoparticles exerted enhanced therapeutic effects on gut movement disorders induced by loperamide. The efficacy of IAA treatment was attributable to the activation of the AHR signalling pathway and increased levels of AHR agonists. Furthermore, the oral administration of IAA-loaded nanoparticles promoted serotonin secretion and maintained the intestinal barrier function. The experimental outcomes demonstrate the efficiency of the proposed colon-specific delivery system and highlight the role of IAA, produced by gut microbiota metabolism, in regulating gut peristalsis through AHR activation.Keywords:chitosan;Eudragit S-100;drug delivery;indole acetic acid;gut motility;aryl hydrocarbon receptor
研究领域:
生物医学工程
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消化系统研究
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微生物学
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PubMed
高影响因子
PeerJ
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2020
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IF 2.379
Xiaoyan Li,Yiyan Lu,Xiaojun Ou,Sijing Zeng,Ying Wang,Xiaoxiao Qi,Lijun Zhu,Zhongqiu Liu
Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 ( p = 0.015 and 0.017, respectively) and 26 weeks ( p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 ( r 2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.
研究领域:
药理学
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肿瘤学
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分子生物学
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PubMed
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BRITISH JOURNAL OF PHARMACOLOGY
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2024
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IF 6.8
Qian-Wen Zhang,Meng-Jiao Yang,Chun-Yu Liao,Reham Taha,Qing-Yu Li,Mohammed Ismail Abdelmotalab,Si-Yu Zhao,Yan Xu,Zhen-Zhou Jiang,Cheng-Han Chu,Xin Huang,Chun-Hua Jiao,Li-Xin Sun
Background and Purpose Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease, and the range of current clinical treatments is not ideal. We previously found that polysaccharide of Atractylodes macrocephala Koidz (PAMK) is beneficial in DSS-induced colitis, and we aimed to investigate the underlying mechanisms in this study. Experimental Approach PAMK was used to treat DSS-induced colitis in mice, 16S rRNA sequencing analysis was used to detect changes in the intestinal microbiota, targeted metabolomics analysis was used to determine the content of tryptophan-metabolizing bacteria, and western blotting was used to determine aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) levels. Furthermore, antibiotic-mediated depletion of gut microbiota and faecal microbiota transplantation were performed to assess the role of the gut microbiota in PAMK alleviation of colitis. Key Results PAMK treatment relieved intestinal microbiota dysbiosis in mice with colitis, contributed to the proliferation of tryptophan-metabolizing bacteria, and increased the levels of tryptophan metabolites, resulting in a significant increase in the nuclear translocation of PXR and expression of PXR and its target genes, but not AhR. The gut microbiota is important in PAMK treatment of colitis, including in the alleviation of symptoms, inhibition of inflammation, maintenance of the integrity of the intestinal barrier, and the regulation of the Th17/Treg cell balance. Conclusion and Implications Based on our findings, we elucidate a novel mechanism by which PAMK alleviates DSS-induced colitis and thus provides evidence to support the potential development of PAMK as a new clinical drug against UC.
研究领域:
免疫学
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微生物学
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药理学
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胃肠病学
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PubMed
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Frontiers in Microbiology
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2026
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IF 5.8
Yong Liang,Yang Zhang,Yu Shi,Qimeng Zhang,Hongxi Zhang
ObjectiveConstipation is a prevalent functional gastrointestinal disorder characterized by impaired intestinal barrier function, often driven by gut microbiota dysbiosis and metabolic disturbances. Shouhui Tongbian Capsules (SHTB), a traditional Chinese medicine formulation, has demonstrated clinical efficacy in constipation management. This study aimed to elucidate the molecular mechanisms underlying SHTB's anti-constipation effects through modulation of the gut microbiota–tryptophan metabolism–aryl hydrocarbon receptor (AhR) signaling axis.MethodsA loperamide-induced murine constipation model was established to evaluate the therapeutic efficacy of SHTB, as assessed by time to first black stool defecation, fecal pellet count, fecal water content, and small intestinal propulsion rate. Colonic histopathology was examined by hematoxylin and eosin (H&E) and Alcian blue–periodic acid–Schiff (AB-PAS) staining. 16S rRNA gene sequencing and metabolomic profiling were used to characterize gut microbiota composition and metabolite alterations in SHTB-treated constipated mice. Key findings were subsequently validated through fecal microbiota transplantation (FMT) and pharmacological AhR inhibition.ResultsSHTB significantly improved defecation parameters in constipated mice (P < 0.001). Mechanistically, SHTB may promote tryptophan metabolic flux through gut microbiota remodeling, particularly through enrichment of Bifidobacterium (P < 0.05) and Alistipes (P < 0.01), leading to activation of colonic AhR signaling (P < 0.05) and reinforced intestinal barrier integrity. FMT with SHTB-conditioned microbiota restored key bacterial populations and reactivated AhR expression (P < 0.05) in recipient mice. Critically, pharmacological blockade of AhR with CH223191 abolished all SHTB-mediated therapeutic benefits, with no significant differences observed between the CH223191 + Lop and CH223191 + Lop + SHTB groups (P > 0.05), thereby identifying AhR as an indispensable mediator of SHTB's anti-constipation mechanism.ConclusionSHTB alleviates constipation in a murine model by enhancing intestinal barrier integrity through modulation of the gut microbiota–tryptophan metabolism–AhR signaling axis, thereby providing mechanistic support for its clinical application in managing constipation.
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PHYTOMEDICINE
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2026
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IF 11.3
Xiaoya Li,Xingyu Liu,Qinbin Ye,Shengchen Wang,Xiaoyu Xi,Jingyi Jiang,Xiaoshuang Mao,Meirong Fang,Wen Jin,Cheng Xiao
EZP enhances bone protection of MTX in RA by bidirectionally regulating OC and OB. • EZP augments the osteoprotective effect of MTX by IDO1-KYN-AhR pathway. • Salidroside and ferulic acid from EZP are responsible for synergizing with MTX. • We provide a promising integrative strategy for managing bone disorders in RA. Progressive joint destruction and systemic bone loss are key factors contributing to disability and secondary osteoporosis in rheumatoid arthritis (RA). However, current clinical drugs, including first-line methotrexate (MTX), provide limited bone protection. Enhancing the regulatory effect of MTX on RA bone homeostasis through combination with traditional Chinese medicine (TCM) may offer a new perspective for RA treatment. This study investigated whether Erzhi Pill (EZP), a kidney-tonifying TCM formula, enhances MTX efficacy in regulating bone homeostasis in RA via the IDO1-KYN-AhR signaling pathway. Using primary osteoblast/osteoclast models and a kidney deficiency collagen-induced arthritis (KD-CIA) rat model, we demonstrated that the MTX+EZP combination was superior to MTX monotherapy in promoting osteoblast differentiation/function, suppressing osteoclastogenesis, and mitigating bone destruction and loss in KD-CIA rats. These effects were associated with the restoration of suppressed IDO1-KYN-AhR signaling activity. Furthermore, siRNA-mediated knockdown or pharmacological inhibition of IDO1 or AhR reversed the regulatory effects of MTX+EZP on osteoblast-osteoclast differentiation/function and its bone-protective actions in KD-CIA rats. Finally, salidroside and ferulic acid were identified as the potential active compounds in EZP responsible for synergizing with MTX. In summary, our findings demonstrate that EZP enhances the efficacy of MTX in regulating RA bone homeostasis by activating the IDO1-KYN-AhR signaling pathway, representing a promising integrative strategy for managing RA-induced bone metabolism disorders.
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Redox Biology
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2026
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IF 16.2
Yuetong Liu,Ge Hong,Tianjun Liu,Hong Liu
Photodynamic therapy (PDT) has emerged as a promising local treatment for breast cancer, with emerging evidence highlighting its potential to modulate the immune response. However, its effects on tumor microenvironment (TME) metabolism remain poorly understood. In this study, we introduce a novel photosensitizer, DTP, which efficiently generates reactive oxygen species and induces apoptosis in breast cancer cells in vitro. In vivo, DTP preferentially accumulates in tumors, significantly inhibiting tumor growth and reducing Ki-67 expression upon 650 nm irradiation. Untargeted metabolomics revealed significant alterations in the tryptophan metabolism pathway following DTP-PDT. Further targeted metabolomic analysis identified a specific reduction in kynurenine (Kyn), an immunosuppressive metabolite, within the tumor. Mechanistically, DTP-PDT reduced indoleamine 2,3-dioxygenase 1 (IDO1)-dependent Kyn production, diminished AhR nuclear localization and decreased AhR transcriptional activity in tumor-infiltrating T cells. This metabolic reprogramming alleviated the immunosuppressive TME, as evidenced by increased infiltration of CD8 + T cells and a reduction in regulatory T cells. Notably, exogenous Kyn partially restored the Kyn–AhR axis and attenuated the immune remodeling induced by DTP-PDT. Building on these immune-activating effects, we combined DTP-PDT with PD-L1 blockade, which significantly suppressed pulmonary metastasis and enhanced central memory T-cell generation, resulting in durable systemic antitumor immunity.
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Engineering
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2025
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IF 11.6
Huanyu Li,Ziwei Yang,Chuanyu Zhang,Xueyong Wei,Wenjing Wang,Ting Bai,Zhichao Deng,Bowen Gao,Manli Cui,Weixuan Jing,Mingzhen Zhang,Zhaoxiang Yu,Mingxin Zhang
Ulcerative colitis (UC) is a chronic, non-specific inflammatory disorder of the intestines whose etiology is influenced by various factors. Intestinal barrier impairment due to disturbances in the intestinal microenvironment is a key feature of UC. Current therapeutic strategies are constrained in their capacity to fully restore the intestinal barrier and achieve comprehensive resolution of inflammation in a coordinated manner. In this study, we constructed a pterostilbene (PSB)-loaded prebiotic microcapsule (PSB@MC) using a microfluidic electrospray method and characterized it using various means. Its safety, biodistribution, protective, and therapeutic effects on colitis were evaluated in various animal models. The potential mechanisms by which PSB@MC exerts its therapeutic effects were subsequently explored. The results indicated that PSB@MC exhibited favorable biocompatibility and facilitated targeted delivery of PSB to the colon. Moreover, the wrinkled morphology of PSB@MC contributed to prolonged drug retention in the colon. Oral PSB@MC administration restored intestinal microenvironment homeostasis by scavenging reactive oxygen species (ROS), decreasing pro-inflammatory cytokines, modulating gut microbiota and metabolism, and providing protective and therapeutic benefits against dextran sulfate sodium-induced colitis. Additionally, our research demonstrated that PSB@MC could activate the aryl hydrocarbon receptor/interleukin-22 (AHR/IL-22) pathway to enhance the integrity of the intestinal barrier. These results suggest that PSB@MC could be a new, secure, and efficient UC therapy option.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Simiao Qiao,Fanshu Li,Jia Huang,Xiaoqian Wu,Xiaoying Cao,Xifeng Zhang,Zhifeng Wei
This study was designed to clarify the reason for PM 2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM 2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM 2.5 via controlling “aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)” axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM 2.5 -induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM 2.5 activated “AHR-HSP90” axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM 2.5 , and was suggested as a potential compound to combat the exacerbation of asthma.
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iMeta
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2024
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IF 23.7
Shi Zhong,Yu-Qing Sun,Jin-Xi Huo,Wen-Yi Xu,Ya-Nan Yang,Jun-Bo Yang,Wei-Jie Wu,Yong-Xin Liu,Chong-Ming Wu,You-Gui Li
Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes , especially Alistipes onderdonkii , and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota. Graphical Sanghuangporus is a medical mushroom with potent anticolitic effects. It modulates the gut microbiota and specifically enriches Alistipes onderdonkii , which can produce 5-hydroxyindole-3-acetic acid, thus activating the aryl hydrocarbon receptor pathway and ameliorating colitis. Highlights Sanghuangporus (SH) polyphenol extract potently alleviated symptoms of colon colitis in dextran sodium sulfate-induced colitis mice. The gut microbiota especially Alistipes onderdonkii mediates the anticolitic effect of SH. The SH-enriched microbial metabolite 5-hydroxyindole-3-acetic acid exhibited an anticolitic effect via the activation of the aryl hydrocarbon receptor. The “gut microbiota-metabolites-signaling pathway” provides an effective perspective for the study of complex Chinese medicine systems.
研究领域:
微生物学
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免疫学
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药理学
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胃肠病学
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Acta Pharmaceutica Sinica B
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2020
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IF 7.097
Di Wang,Danting Li,Yuxin Zhang,Jie Chen,Ying Zhang,Chuyao Liao,Siyuan Qin,Yuan Tian,Zunjian Zhang,Fengguo Xu
Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)−kynurenine (KYN)−kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)−indoleamine 2,3-dioxygenase 1 (IDO1)−aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.
研究领域:
药理学
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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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PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Mei Wang,Na Luo,Yanpeng Gao,Guiying Li,Taicheng An
Derivatives of polycyclic aromatic hydrocarbons (PAHs) pose significant threat to environment and human health due to their widespread and potential hazards. However, adverse effects and action mechanisms of PAH derivatives on human health have not been attempted yet. Herein, we chose pyrene and its derivatives (1-hydroxypyrene, 1-nitropyrene, and 1-methylpyrene) to investigate adverse effect mechanism to human lungs using in vitro and in vivo methods. Results showed that pyrene derivatives have higher lung health risks than original pyrene. They can activate AhR, subsequently affecting expression of downstream target genes CYP1A1 and CYP1B1. The binding energies of pyrene and its derivatives ranged from −16.07 to −27.25 kcal/mol by molecular dynamics simulations, implying that pyrene and its derivatives acted as agonists of AhR and increased adverse effects on lungs. Specifically, 1-nitropyrene exhibited stabler binding conformation and stronger AhR expression. In addition, sensitivity of pyrene and its derivatives to AhR activation was attributed to type and number of key amino acids in AhR, that is, pyrene (Leu293), 1-nitropyrene (Cys333, Met348, and Val381), 1-hydroxypyrene (Leu293 and Phe287), and 1-methylpyrene (Met348). In summary, we provide a universal approach for understanding action mechanisms of PAH derivatives on human health, and their adverse effects should be taken seriously.
研究领域:
环境健康
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毒理学
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分子生物学
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药理学
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AQUATIC TOXICOLOGY
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2025
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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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