Frontiers in Cell and Developmental Biology
·
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
·
分子内分泌学
·
妇产科学
·
胚胎植入
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2026
·
IF 17.1
Yuting Zhang,Ruopeng Yin,Wang Dong,Li Sun,Tao Wang,Jingzu Sun,Huanqin Dai,Yanliang Bi,Liangliang Wang,Hongwei Liu
Introduction Sepsis is a life-threatening syndrome of organ dysfunction driven by a dysregulated immune response. Effective therapeutic strategies to restore immune homeostasis remain limited. Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila have emerged as potential immunomodulatory postbiotics, yet their therapeutic potential in sepsis and the underlying mechanisms remain unexplored. Objectives This study aims to investigate whether ALOS confers protection in experimental models of sepsis induced by toxic lipopolysaccharides (LPS) or cecal ligation and puncture (CLP), and the mechanism by which ALOS exerts its anti-inflammatory and regulatory effects. Methods In LPS or CLP-induced mouse sepsis models and a porcine sepsis model, ALOS (0.2 mg/kg, i.p.) was administered once every two days before challenge or half an hour post-surgery. Survival rates, physiological and biochemical parameters were assessed. Based on 16S rRNA gene amplicon sequencing and barrier function assessment, the changes of the colonic microbiota and metabolites and anti-inflammatory capacity were analyzed. The anti-inflammatory and immunomodulatory mechanisms of ALOS were investigated through dendritic cell phenotyping, transcriptomic analysis, inhibitor assays, and conditioned medium experiments. Finally, the safety of ALOS was evaluated in C57BL/6J mice following one-week administration (0.2 mg/kg, i.p.). Results ALOS pretreatment significantly suppresses sepsis, reduces the proportion of pro-inflammatory Th17 cells, and increases regulatory T cells (Treg). Mechanistically, ALOS induced semi‑mature dendritic cells with upregulated IDO1 expression, leading to enhanced production of kynurenine (Kyn). Kyn activated the aryl hydrocarbon receptor (AhR) to drive Treg differentiation. The protective effect of ALOS was completely reversed by NLG919, whereas Kyn administration mimicked the therapeutic benefit. ALOS also produced therapeutic protection on sepsis. In a porcine sepsis model, pretreatment of ALOS exerted systemic anti‑inflammatory effects and protected multiple organs. Conclusion This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Qianwen Cao,Luyao Liu,Xiaoge Ma,Chaomin Zhong,Mengqi Tang,Mengge Liu,Ling-Bo Qu,Bo Wei,Xia Xu
1, 8-Cineole (Cin), a cyclic monoterpenoid derived from tea trees and eucalyptus species, exhibits diverse pharmacological properties. Yet, its therapeutic impact and underlying mechanism against Staphylococcus aureus (S. aureus) pneumonia remain to be elucidated. In this study, metabolomics based on UPLC-MS/MS was integrated with network pharmacology, molecular biology, and molecular docking to investigate the effects of Cin. The findings demonstrated that Cin markedly reduced mortality and lung bacterial load, lessened pulmonary damage while suppressing the levels of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the bronchoalveolar lavage fluid (BALF) of infected mice. Additionally, 19 metabolites, primarily involved in tryptophan metabolism and arginine biosynthesis, were notably modified by Cin via suppressing the enzymatic activity of indoleamine 2, 3-dioxygenase 1 (IDO1) and inducible nitric oxide synthase (iNOS), thereby attenuating the inflammatory response. Notably, knockdown of IDO1 or iNOS significantly diminished the anti-inflammation effect of Cin. In conclusion, our study validates the therapeutic potential of Cin against S. aureus pneumonia via anti-inflammation by downregulating IDO1 and iNOS. Our results provide a theoretical basis of natural substances applied in bacterial pneumonia treatment.
研究领域:
药理学
·
微生物学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Toxics
·
2024
·Vol. 12
·期 5
·374
·
IF 3.9
Huabin Liu,Yue Wu,Jiahui Cai,Yuting Chen,Cheng Zhou,Cece Qiao,Yuliang Wang,Song Wang
Auxins play crucial regulatory roles in plants coping with cadmium (Cd) stress. However, the regulatory mechanism by which auxins alleviate Cd toxicity in tomato seedlings remains unclear. Here, we demonstrate that exposure to Cd stress leads to dynamic changes in the auxin response in tomato roots, characterized by an initial increase followed by a subsequent weakening. Under Cd stress, tomato seedlings show primary root- and hypocotyl-growth inhibition, accompanied by the accumulation of Cd and reactive oxygen species (ROS) in the roots. The exogenous application of 1-naphthylacetic acid (NAA) does not mitigate the inhibitory effect of Cd toxicity on primary root growth, but it does significantly enhance lateral root development under Cd stress. Auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA) and 2,3,5-triiodobenoic acid (TIBA), aggravate the growth inhibition of primary roots caused by Cd stress. Additionally, lateral root development was inhibited by NPA. However, applying auxin synthesis inhibitors L-kynurenine (kyn) and yucasin alleviated the tomato root growth inhibition caused by Cd stress; between them, the effect of yucasin was more pronounced. Yucasin mitigates Cd toxicity in tomato seedlings by reducing Cd2+absorption and auxin accumulation, strengthening ROS scavenging, and reducing cell death in roots. These observations suggest that yucasin potentially mitigates Cd toxicity and improves the tolerance of tomato seedlings to Cd stress.
研究领域:
植物生理学
·
环境毒理学
·
植物应激反应
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Chao Zhao,Hu Zhang,Jingjing Zhou,Qiwei Liu,Qiang Lu,Ying Zhang,Xiaojin Yu,Shizhi Wang,Ran Liu,Yuepu Pu,Lihong Yin
Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD + in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.
研究领域:
肿瘤学
·
代谢组学
·
毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Junyang Li,Bingjie Mei,Lu Feng,Xiaoxin Wang,Dengfeng Wang,Jianming Huang,Guonan Zhang
Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in epithelial ovarian cancer (EOC) patients resistant to ICB therapy. Because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1 and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitor to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）