The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus.

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.

Indirubin mediates adverse intestinal reactions in guinea pigs by downregulating the expression of AchE through AhR.

Indirubin is the main component of the traditional Chinese medicine Indigo naturalis (IN), a potent agonist of aryl hydrocarbon receptors (AhRs). In China, IN is used to treat psoriasis and ulcerative colitis, and indirubin is used for the treatment of chronic myelogenous leukaemia. However, IN and indirubin have adverse reactions, such as abdominal pain, diarrhoea, and intussusception, and their specific mechanism is unclear.The purpose of our research was to determine the specific mechanism underlying the adverse effects of IN and indirubin. By tracking the modifications in guinea pigs after the intragastric administration of indirubin for 28 days.The results demonstrate that indirubin could accelerate bowel movements and decrease intestinal acetylcholinesterase (AchE) expression. Experiments with NCM460 cells revealed that indirubin significantly reduced the expression of AchE, and the AchE levels were increased after the silencing of AhR and re-exposure to indirubin.This study showed that the inhibition of AchE expression by indirubin plays a key role in the occurrence of adverse reactions to indirubin and that the underlying mechanism is related to AhR-mediated AchE downregulation.

Benzo[a]pyrene and a high-fat diet induce aortic injury and promote low-density lipoprotein accumulation in the endothelium.

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant which mainly exposed though diet. High-fat diet (HFD) can induce atherosclerosis, as can BaP. Unhealthy dietary habits lead to high intake of both BaP and lipids. However, the combined effect of BaP and HFD on atherosclerosis and lipid accumulation in the arterial wall, the initial stage of atherosclerosis, is unclear. In this study, C57BL/6 J mice were subchronically exposed to BaP and a HFD, and the mechanism of lipid accumulation was investigated in EA.hy926 and HEK293 cells. Results showed that BaP and HFD increased blood lipids and damaged aortic wall synergistically. Meanwhile, LDL enhanced the toxicity of BaP, and BaP promoted the production of reactive oxygen species and malonaldehyde in EA.hy926 cells, which aggravated LDL-induced cell injury. Moreover, BaP and HFD/LDL induced LDL accumulation in the aortic wall of C57BL/6 J mice/EA.hy926, and the mechanism was by activating AHR/ARNT heterodimer to combine with the scavenger receptor BⅠ (SR-BⅠ) and activin receptor-like kinase 1 (ALK1) promoter regions to transcriptional upregulate its expression, which enhanced the uptake of LDL, and promoting the production of AGEs to inhibit reverse cholesterol transport by SR-BI. BaP and lipid synergistically promoted aortic and endothelial damage, and the health risk of their combined intake should be paid attention to.

Urolithin A Alleviates Colitis in Mice by Improving Gut Microbiota Dysbiosis, Modulating Microbial Tryptophan Metabolism, and Triggering AhR Activation.

Urolithin A (UroA) is a microbial metabolite derived from ellagitannins and ellagic acid with good bioavailability. In this study, we explored the anticolitis activity of UroA and clarified the mechanism by 16S rDNA sequencing and metabonomics. UroA alleviated dextran sulfate sodium (DSS)-induced colitis in mice, characterized by a decreased disease activity index, increased colon length, and improved colonic histopathological lesions, along with inhibited phosphorylation of the mitogen-activated protein kinase signaling pathway. In addition, UroA improved gut microbiota dysbiosis and modulated the microbiota metabolome. Furthermore, targeted metabolomics focused on tryptophan catabolites showed that UroA significantly increased the production of indole-3-aldehyde (IAld) and subsequently led to increased colonic expression of aryl hydrocarbon receptor (AhR) and promoted the serum content of IL-22 in mice with colitis. Collectively, our data identified a novel anticolitis mechanism of UroA by improving gut microbiota dysbiosis, modulating microbial tryptophan metabolism, promoting IAld production, and triggering AhR/IL-22 axis activation. However, a limitation noted in this study is that these beneficial effects of UroA were found at 50 µM in vitro and 20 mg/kg in vivo, which were nonphysiological concentrations.

Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis.

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-1ß 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-1ß 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-1ß-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-1ß-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.

Hydroquinone triggers pyroptosis and endoplasmic reticulum stress via AhR-regulated oxidative stress in human lymphocytes.

Benzene is a frequent component of environmental pollution and is abundant in petrochemicals, decorative materials, motor vehicle exhaust and cigarette smoke. Benzene is a well-known carcinogen in humans and animals, but the molecular mechanism has not yet been elucidated. Our earlier research indicated that hydroquinone (HQ), one of the main reactive metabolites of benzene, could activate aryl hydrocarbon receptor (AhR), which is essential for HQ-induced toxicity, including apoptosis and DNA damage. Since AhR is an important regulator of the immune system that integrates the environmental stimulus and immune response, we examined whether and how HQ-induced AhR activity could lead to NLRP3 inflammasome-dependent pyroptosis in JHP cells. Our results showed that HQ could cause inflammation process and resultant pyroptosis. In JHP cells, HQ also induced endoplasmic reticulum stress (ERS) by releasing excessive reactive oxygen species (ROS). The activation of pyroptosis induced by HQ treatment was reversed by an antioxidant (NAC) and an ERS inhibitor (4-PBA). Interestingly, the treatment of CH223191, an AhR inhibitor, reversed HQ-induced oxidative stress, ERS and pyroptosis. These data suggested that AhR-mediated HQ-induced ERS, ROS and inflammasome activation may play vital roles in the toxic effects of benzene. This work provides insights and prospective strategies into potential mechanisms for reducing benzene-induced hematotoxicity.

Prevention of polycystic ovary syndrome and postmenopausal osteoporosis by inhibiting apoptosis with Shenling Baizhu powder compound.

Objective: Shenling Baizhu powder (SBP) has been shown to reverse the abnormal expression of the aromatic hydrocarbon receptor (AHR) mediated by air pollution. Our study aimed to understand the main ingredient of SBP and investigate its action mechanism in preventing polycystic ovary syndrome (POCS) and postmenopausal osteoporosis (PMO). Methods: The active ingredients of SBP with the highest binding affinity to AHR were screened using a Chinese medicine database, and their binding mechanism was simulated using molecular dynamics simulation (MDS). Rutin was utilized to treat ovarian granulosa cell lines and osteoblast cell lines. The cell lines were treated with a gradient of rutin concentration (0.01 mmol/L, 0.05 mmol/L and 0.1 mmol/L) to find the optimal drug dose. PCR was used to detect AHR and apoptosis-related proteins, and WB to detect the expression of AHR, caspase-3 and cleaved-caspase-3. Finally, the CCK-8 cell proliferation assay detected the proliferation of cells. Results: We obtained Rutin through the Chinese medicine database, and dynamics simulation determined its binding sites. Ovarian granulosa cell lines and osteoblast cell lines were treated with Rutin. RT-PCR and western blotting revealed that the expression of apoptosis-associated protein Bcl-2 was elevated, and the expression of AHR, Bax, caspase-3 and PARP were decreased. CCK-8 results showed accelerated proliferation in both cell types. Conclusion: Rutin, the main ingredient of SBP compound, works by binding to AHR, which can improve POCS and PMO by inhibiting cell apoptosis and by promoting cell proliferation.

Advances in multi-omics study of biomarkers of glycolipid metabolism disorder.

Glycolipid metabolism disorder are major threats to human health and life. Genetic, environmental, psychological, cellular, and molecular factors contribute to their pathogenesis. Several studies demonstrated that neuroendocrine axis dysfunction, insulin resistance, oxidative stress, chronic inflammatory response, and gut microbiota dysbiosis are core pathological links associated with it. However, the underlying molecular mechanisms and therapeutic targets of glycolipid metabolism disorder remain to be elucidated. Progress in high-throughput technologies has helped clarify the pathophysiology of glycolipid metabolism disorder. In the present review, we explored the ways and means by which genomics, transcriptomics, proteomics, metabolomics, and gut microbiomics could help identify novel candidate biomarkers for the clinical management of glycolipid metabolism disorder. We also discuss the limitations and recommended future research directions of multi-omics studies on these diseases.

Indole-3-aldehyde alleviates chondrocytes inflammation through the AhR-NF-κB signalling pathway.

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-1ß 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-1ß 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-1ß-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-1ß-induced chondrocytes, which is expected to provide a new therapeutic strategy for OA.

Multifaceted Protective Effects of Hesperidin by Aromatic Hydrocarbon Receptor in Endothelial Cell Injury Induced by Benzo[a]Pyrene.

Benzo[a]pyrene (BaP) causes atherosclerosis by activating the aromatic hydrocarbon receptor (AHR) signaling pathway to trigger lipid peroxidation and inflammation, thereby promoting the development of atherosclerosis. Hesperidin (Hsd), one of the 60 flavonoids of citrus, exhibits therapeutic effects on atherosclerosis. However, its antagonistic function for BaP remains unclear. In this study, the EA.hy926 cell model was used to systematically examine the antagonistic effect of Hsd with BaP, especially in low-density lipoprotein (LDL) oxidation and transport. Results showed that Hsd could reduce BaP-induced AHR activation in mRNA and protein expression level, and reduce LDL accumulation by decreasing the BaP-induced expression of advanced glycation end products and enhancing the BaP-inhibited Adenosine Triphosphate-binding cassette transporter A1 (ABCA1) protein and mRNA expression in EA.hy926 cells. In addition, Hsd could antagonize BaP-induced interaction of reactive oxygen species and the subsequent generation of oxidized LDL and malondialdehyde. Finally, Hsd could alleviate BaP-induced inflammatory response by decreasing IL-1ß and TNF-α expression. All these results suggest that Hsd suppresses LDL accumulation, oxidation, and inflammatory response, and thus strongly impedes the AHR pathway activated by BaP.

Endoplasmic Reticulum Stress: A New Research Direction for Polycystic Ovary Syndrome?

Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders, with sporadic ovulation, excessive androgens, and polycystic ovarian changes as the main clinical manifestations. Due to the high heterogeneity of its clinical manifestations, the discussion on its pathogenesis has not been unified. Current research has found that genetic factors, hyperandrogenism, chronic inflammation and oxidative stress, insulin resistance, and obesity are strongly associated with PCOS. Recently, when studying the specific mechanisms of the abovementioned factors in PCOS, the biological response process of endoplasmic reticulum stress (ERS) has gradually come to researchers' attention, and several studies have confirmed the involvement of ERS in the pathogenesis of PCOS and the improvement of a series of pathological manifestations of PCOS after the application of ERS inhibitors, which may be a new entry point for the treatment of PCOS. In this article, we review the relationship between ERS and various pathogenic factors of PCOS.

Ligand-independent activation of AhR by hydroquinone mediates benzene-induced hematopoietic toxicity.

Although it has been well recognized that benzene exposure can cause hematopoietic disorders such as aplastic anemia and leukemia, the underlying molecular mechanism remains to be fully understood. Emerging evidence indicated that aryl hydrocarbon receptor (AhR) plays important roles in hematopoietic and immune systems. This study investigated the activation of aryl hydrocarbon receptor (AhR) by hydroquinone (HQ) and its role in HQ-induced DNA damage and apoptosis in cultured human lymphocytes (JHP cells). We also investigated the effect of ROS on AhR activation and functions in JHP cells exposed to HQ with and without regulator including N-acetyl-l-cysteine (NAC), a potent antioxidant, and tert-butylhydroquinone (TBHQ), a Nrf2 activator. Results showed that HQ can cause oxidative stress, DNA damage and apoptosis. Pretreatment of an AhR antagonist (CH223191) can significantly increase the cell survival and mitigate HQ-induced toxicities such as DNA damage and apoptosis. We found that HQ can obviously increase expressions of total protein of AhR and prompt nuclear translocation compared to the control group. Interestingly, NAC can block HQ-induced AhR activation and DNA damage and apoptosis. Conclusively, our results indicated that HQ toxicity is mediated by AhR which is in turn regulated by ROS generated by HQ. The interaction between AhR and ROS drive and amplify the hematopoietic toxicity of HQ. This study provided new insights of mechanism and potential targets for the prevention and treatment to benzene-induced hematopoietic toxicity.

Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway.

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice.

Polycyclic aromatic hydrocarbons in bone homeostasis.

Prolonged exposure to polycyclic aromatic hydrocarbons (PAHs) may result in autoimmune diseases, such as rheumatoid arthritis (RA) and osteoporosis (OP), which are based on an imbalance in bone homeostasis. These diseases are characterized by bone erosion and even a disruption in homeostasis, including in osteoblasts and osteoclasts. Current evidence indicates that multiple factors affect the progression of bone homeostasis, such as genetic susceptibility and epigenetic modifications. However, environmental factors, especially PAHs from various sources, have been shown to play an increasingly prominent role in the progression of bone homeostasis. Hence, it is essential to investigate the effects and pathogenesis of PAHs in bone homeostasis. In this review, recent progress is summarized concerning the effects and mechanisms of PAHs and their ligands and receptors in bone homeostasis. Moreover, strategies based on the effects and mechanisms of PAHs in the regulation of the bone balance and alleviation of bone destruction are also reviewed. We further discuss the future challenges and perspectives regarding the roles of PAHs in autoimmune diseases based on bone homeostasis.

Tryptophan in the diet ameliorates motor deficits in a rotenone-induced rat Parkinson's disease model via activating the aromatic hydrocarbon receptor pathway.

BACKGROUND AND PURPOSE: Parkinson's disease (PD), a common neurodegenerative disorder with motor and nonmotor symptoms, does not have effective treatments. Dietary tryptophan (Trp) supplementation has potential benefits for the treatment of multiple disorders. However, whether additional Trp in the diet could be beneficial for PD remains to beinvestigated. In the present study, the neuroprotective role of dietary Trp on a rotenone-induced rat model of PD was determined. METHODS: The rotenone was injected to build the PD model, and then the rats were treated with Trp in the diet. And then, an open field test, western blot analysis, and enzyme linked immunosorbent assay (ELISA) were performed. RESULTS: We observed that dietary Trp significantly ameliorated impaired motor function, upregulated tyrosine hydroxylase expression, inhibited the nuclear transport of Nuclear factor-kappa B (NF-κB) in substantia nigra (SN), and downregulated the protein levels of IL-1ß, IL-6, and TNF-α in serum in rotenone-treated rats. However, these patterns were reversed in response to treatment with ampicillin, an agent that can clean intestinal Trp metabolism flora. Moreover, after using CH223191, an inhibitor of the aromatic hydrocarbon receptor (AhR) pathway, dietary Trp could not exert neuroprotective roles in the rotenone-induced rat model of PD. CONCLUSION: These results suggest that Trp in the diet can protect against rotenone-induced neurotoxicity to ameliorate motor deficits, which may be mediated through activating AhR pathway.

Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway.

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

Regulation of Nrf2 Signaling.

Regulation of antioxidant gene expression is essential for controlling oxidative stress and maintaining physiological homeostasis. In this context, the nuclear factor E2-related factor 2 (Nrf2) has been identified as the chief regulator of the transcription of diverse antioxidant genes as well as many other cytoprotective genes. Nrf2 activity is subjected to the regulation at various levels including protein stability, transcription, and post-transcription. Among the various regulatory pathways, the Keap1-Cul3-Rbx1 axis is the most prominent regulator of Nrf2 activity. Being a tightly controlled transcriptional activator of antioxidant genes, Nrf2 signaling is intimately involved in health and disease. While Nrf2 is a protector against oxidative and electrophilic tissue injury, persistent activation of Nrf2 signaling may also contribute to disease pathophysiology, such as cancer progression.

Research progression of interleukin 22 and inflammatory bowel disease / 医学研究生学报

Inflammatory bowel disease (IBD) is a type of multi-etiology-induced, abnormal immune-mediated chronic recurrent inflammation of the intestine, which includes ulcerative colitis (UC) and Crohn's disease,(CD). IL-22 is a cytokine with unique biological properties. In the intestine, IL-22 has the ability to promote the expression of antimicrobial peptides and mucins that promote mucosal barrier integrity by activating the STAT3 pathway, and may promote intestinal epithelial cell regeneration and enhance intestinal epithelial cell barrier function. IL-22 is significantly increased in the intestinal mucosa of IBD patients. IL-22 can promote the repair of intestinal inflammatory damage, but with environmental changes, such as the level of expression of IL-23, T-bet, IL-22 binding protein, IL-22displayed dural characteristic, on the one hand, it can promote the repair of inflammatory injury, on the other hand it will increase the inflammatory injury response. This article mainly explains the origin of IL-22, its mode of action, and its application prospects in clinical treatment.

Combined effects of AHR, CYP1A1, and XRCC1 genotypes and prenatal maternal smoking on infant birth size: Biomarker assessment in the Hokkaido Study.

OBJECTIVES: We investigated the individual and combined effects of maternal polymorphisms encoding the aromatic hydrocarbon receptor (AHR; rs2066853), cytochrome P450 (CYP) 1A1 (rs1048963), and the X-ray-complementing gene 1 (XRCC1; rs1799782) and prenatal smoking in relation to infant birth size. METHODS: Totally, 3263 participants (1998 non-smokers and 1265 smokers) were included in the study between 2003 and 2007. Two groups of mothers were distinguished by plasma cotinine levels by ELISA measured during the third trimester (cut-off=11.48ng/mL). We conducted data analysis using multiple linear regression models. RESULTS: Infants whose mothers smoked and had AHR-GG, CYP1A1-AG/GG, and XRCC1-CT/TT genotypes weighed, -145g less than those born of mothers who did not smoke and had the AHR-GA/AA, CYP1A1-AA, and XRCC1-CC genotypes (95% CI: -241, -50). CONCLUSIONS: We demonstrated that infants whose mothers smoked during pregnancy with the combination of AHR, CYP1A1, and XRCC1 polymorphisms had lower birth size.

Baicalin Protects Mice from Aristolochic Acid I-Induced Kidney Injury by Induction of CYP1A through the Aromatic Hydrocarbon Receptor.

Exposure to aristolochic acid I (AAI) can lead to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and urothelial cancer. The induction of hepatic CYP1A, especially CYP1A2, was considered to detoxify AAI so as to reduce its nephrotoxicity. We previously found that baicalin had the strong ability to induce CYP1A2 expression; therefore in this study, we examined the effects of baicalin on AAI toxicity, metabolism and disposition, as well as investigated the underlying mechanisms. Our toxicological studies showed that baicalin reduced the levels of blood urea nitrogen (BUN) and creatinine (CRE) in AAI-treated mice and attenuated renal injury induced by AAI. Pharmacokinetic analysis demonstrated that baicalin markedly decreased AUC of AAI in plasma and the content of AAI in liver and kidney. CYP1A induction assays showed that baicalin exposure significantly increased the hepatic expression of CYP1A1/2, which was completely abolished by inhibitors of the Aromatic hydrocarbon receptor (AhR), 3',4'-dimethoxyflavone and resveratrol, in vitro and in vivo, respectively. Moreover, the luciferase assays revealed that baicalin significantly increased the luciferase activity of the reporter gene incorporated with the Xenobiotic response elements recognized by AhR. In summary, baicalin significantly reduced the disposition of AAI and ameliorated AAI-induced kidney toxicity through AhR-dependent CYP1A1/2 induction in the liver.