Redox Biology
·
2021
·
IF 11.799
Shan Jiang,Yongjie Shui,Yu Cui,Chun Tang,Xiaohua Wang,Xingyu Qiu,Weipeng Hu,Lingyan Fei,Yun Li,Suping Zhang,Liang Zhao,Nan Xu,Fang Dong,Xiaoqiu Ren,Ruisheng Liu,Pontus B. Persson,Andreas Patzak,En Yin Lai,Qichun Wei,Zhihua Zheng
Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l -carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg −1 min −1 ) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca 2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001 ) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001 ) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca 2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.
研究领域:
心脏病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Lei Wu,Wenqing Cheng,Haoke Xiang,Yaping Zhu,Yiran Jiang,Zixuan Wei,Mengqi Shao,Liyuan Tian,Yan Sun,Chao Lu
Chaihu Shugan San produces rapid antidepressant-like effects within 2 h in female CRS-exposed mice. • The rapid effect is comparable in onset to ketamine in female chronically stressed mice. • Hippocampal TC2N is a negative regulator of the rapid antidepressant-like action of CSS. • TC2N down-regulation is associated with hippocampal ERβ–eNOS–CaMKII–BDNF signaling. • The estrogen receptor β-linked mechanism was demonstrated in female mice and requires validation in males. Ethnopharmacological relevance Chaihu Shugan San (CSS), a classical seven-herb formula from the Ming-dynasty text Jing-Yue Quanshu, is widely prescribed for depressive disorders in China. Previous preclinical studies reported antidepressant-like effects only after weeks of repeated administration, mostly in male animals. Whether a single dose of CSS can produce rapid antidepressant-like effects in female animals, and through what mechanism, remains unclear. Aim of the study To determine whether a single administration of CSS produces rapid antidepressant-like effects in female mice exposed to chronic restraint stress (CRS), and to explore the underlying hippocampal mechanism. Methods and materials CSS quality was controlled by HPLC quantification of four index components. Female CRS mice received a single dose of CSS (1, 2 or 4 g/kg, i. g.) or ketamine (10 mg/kg, i. p.), followed by behavioral testing (tail suspension, forced swimming, sucrose preference and open field tests) within 2–24 h. Hippocampal RNA sequencing, RT-qPCR, Western blotting and ELISA were used to identify and validate candidate targets; hippocampal AAV-mediated TC2N overexpression and pretreatment with the ERβ antagonist acolbifene or the CaMKII inhibitor KN-93 were used for interventional validation. Results Batch-to-batch variation of the four index components was below 10% (RSDs 3.51–5.66%), with naringin (313.07 ± 11.16 μg/mL) and hesperidin (196.40 ± 11.11 μg/mL) as the major constituents. Acute administration of CSS (2 and 4 g/kg), like ketamine, shortened immobility time in the tail suspension test at 2 h and in the forced swimming test at 12 h, and restored sucrose preference at 24 h, without affecting locomotor activity. Hippocampal transcriptomics identified Tc2n as up-regulated by CRS and down-regulated by CSS, with Esr2, Nos3 and Camk2a showing the opposite pattern; these changes were confirmed at the mRNA and protein levels within 2 h. Hippocampal TC2N overexpression or pretreatment with acolbifene or KN-93 abolished the rapid behavioral effects of CSS and the associated changes in ERβ–eNOS–CaMKII–BDNF signaling. Conclusion CSS produces rapid, ketamine-comparable antidepressant-like behavioral effects in female CRS-exposed mice, accompanied by down-regulation of hippocampal TC2N and involvement of ERβ, eNOS, CaMKII and BDNF. Because only female mice were studied, these findings are specific to females and support an estrogen-linked mechanism that warrants confirmation in male animals and further translational study. Download: Download high-res image (318KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Yue Zhang,Lulu Hou,Tiantian Guo,Hongmin Lu,Xin Zhang,Mingwei Xing
Acetochlor, a commonly used herbicide, poses significant risks to ecosystem and organism health through contamination of the food chain. Despite its widespread use, there is a lack of comprehensive studies on its toxicological effects on avian species. This study investigates the impact of environmental acetochlor exposure on chicken liver health using metabolomics analysis and histopathological techniques. Microscopic examination revealed autophagy-like structures and endoplasmic reticulum (ER) expansion, with significant effects observed at higher exposure levels. Biochemical analysis and metabolomics also demonstrated acetochlor-induced ferroptosis, highlighting disruptions in liver function. Further, in vitro studies revealed that acetochlor stimulates autophagy, which regulates ferroptosis via ferritin degradation, mediated through the ER-CaMKII pathway. These findings emphasize the importance of understanding the molecular mechanisms involved in acetochlor toxicity, particularly the role of the Ca 2+ /CaMKII pathway, ER stress, and autophagy in ferroptosis. The study contributes to a deeper understanding of how environmental contaminants affect avian species, providing critical insights for better herbicide risk assessment, pollution control, and sustainable agricultural practices.
研究领域:
环境毒理学
·
禽类生物学
·
分子生物学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PeerJ
·
2018
·
IF 2.118
Yu Lei,Chengkun Wang,Quan Jiang,Xiaoyi Sun,Yongzhong Du,Yaofeng Zhu,Yingmei Lu
The toxicity of engineered nanoparticles remains a concern. The knowledge of biohazards associated with particular nanoparticles is crucial to make this cutting-edge technology more beneficial and safe. Here, we evaluated the toxicity of Ga 2 O 3 nanoparticles (NPs), which are frequently used to enhance the performance of metal catalysts in a variety of catalytic reactions. The potential inflammatory signaling associated with the toxicity of HA/β-Ga 2 O 3 :Cr 3+ NPs in primary cortical neurons was examined. We observed a dose-dependent decrease in cell viability and an increase in apoptosis in neurons following various concentrations (0, 1, 5, 25, 50, 100 µg/ml) of HA/β-Ga 2 O 3 :Cr 3+ NPs treatment. Consistently, constitutively active forms of calcineurin (48 kDa) were significantly elevated in cultured primary cortical neurons, which was consistent with calpain activation indicated by the breakdown products of spectrin. Moreover, HA/β-Ga 2 O 3 :Cr 3+ NPs result in the elevation of LC3-II formation, SQSTM/p62, and Cathepsin B, whereas phosphorylation of CaMKII (Thr286) and Synapsin I (Ser603) were downregulated in the same context. Taken together, these results demonstrate for the first time that calpain activation and a disturbance of autophagy signaling are evoked by exposure to HA/β-Ga 2 O 3 :Cr 3+ NPs, which may contribute to neuronal injury in vitro .
研究领域:
纳米技术
·
神经科学
·
毒理学
·
细胞生物学
✓ 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）