JOURNAL OF CHEMICAL RESEARCH
·
2024
·
IF 1
Haodong Zhou,Yulan Zhu,Xianfeng Huang
PDE4 is a potential target for treating mental diseases including depression, Alzheimer’s disease and schizophrenia involving in the hydrolysis of cAMP. Curcumin is well-known for its potential as a neuroprotective compound against depression. It was able to inhibit PDE4 with IC50 value in the range of 10 to 20 μM with low selectivity. However, curcumin itself cannot be used clinically because of its poor drug-like properties. Herein, a series of new curcumin derivatives were designed and synthesized. Their PDE4 inhibitory activities and antidepressant effects in vivo were also evaluated. Consequently, most of these curcumin derivatives demonstrated good inhibitory activities against PDE4. Furthermore, compound 4e exhibited the most potent activity at nanomolar level (IC50 value: 23 nM). It also could improve depression-like behaviors induced by chronic stress including sugar forced swimming and water consumption tests in vivo.
研究领域:
药理学
·
神经科学
✓ 已验证
DOI
高影响因子
Frontiers in Physiology
·
2020
·
IF 3.367
Song Manyu,Wang Chaoran,Yang Haotian,Chen Yongping,Feng Xiujing,Li Bei,Fan Honggang
Chronic stress leads to immunosuppression and induces splenocyte apoptosis. STAT3 is a transcription factor that regulates immunity and apoptosis; however, it is unclear whether the increased expression of phosphorylated STAT3 (p-STAT3) observed in chronic stress is related to splenocyte apoptosis. To explore the relationship between splenocyte apoptosis and STAT3 in chronic stress, we treated rats undergoing a 21-day chronic restraint stress program with the STAT3 inhibitor S3I-201. This chronic stress model was verified by observing rats’ behavior and measuring their serum corticosterone levels. Chronic stress led to increased expression of anti-inflammatory cytokines, and p-STAT3 inhibition enhanced splenocyte apoptosis in chronic stress. We detected key proteins in three apoptotic pathways to determine which pathway mediated increasing splenocyte apoptosis and found that the death receptor pathway was the main apoptotic pathway that occurred in the spleen during chronic stress. The unfolded protein response (UPR) was also activated, but the Bcl-2 family was not involved in chronic stress. P-STAT3 inhibition had no influence on the Bcl-2 family and the death receptor pathway; however, p-STAT3 inhibition disrupted the pro-survival function of the UPR by decreasing the expression of ATF6α and p-IRE1α. Furthermore, p-STAT3 inhibition activated endoplasmic reticulum stress by promoting the expression of CHOP, p-JNK, and procaspase-12. Collectively, these findings indicate that the increased p-STAT3 expression during chronic stress may promote splenocyte survival by activating the UPR. Consequently, STAT3 and the UPR may be considered as potential therapeutic targets for chronic stress in the future.
研究领域:
免疫学
·
压力生物学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEURON
·
2023
·
IF 16.2
Xiao-Na Zhu,Jie Li,Gao-Lin Qiu,Lin Wang,Chen Lu,Yi-Ge Guo,Ke-Xin Yang,Fang Cai,Tao Xu,Ti-Fei Yuan,Ji Hu
Summary Lasker’s award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia . Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [ 18 F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
研究领域:
药理学
·
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2022
·
IF 5.273
Jingli Chen,Chang Liu,Mu Xu,Jiaxi Zhu,Zhongyuan Xia
Chronic stress is associated with impairment of synapse plasticity in hippocampus and cognitive dysfunction in rodent and human. Notably, corticosterone (CORT) is believed to take responsibility for dendritic atrophy and reduction of spine number induced by chronic stress in hippocampus. But little is known about the molecular mechanisms underlying CORT induced abnormal synapse plasticity and cognitive dysfunction. Drebrin is an F-actin binding protein that modulates memory formation and maintenance by controlling the genesis and morphology of dendritic spines . In addition, miRNAs have been reported to participate in the negative regulation of protein-coding genes. In this study, five miRNAs capable of targeting Drebrin were selected by searching miRNA databases. One of these miRNAs, miR-19b-3p, was found to be upregulated in the hippocampal neurons of mice with chronic restraint stress (CRS). Luciferase reporter assay and Fluorescence in situ hybridization (FISH) were employed to identify the interaction between miR-19b-3p and Drebrin. In addition, silencing miR-19b-3p expression in vivo using an antagomir or in vitro using an inhibitor increased Drebrin expression , ameliorated the abnormal dendritic structure and upregulated the spine density in hippocampal CA1 pyramidal neurons of CRS mice and primary hippocampal neurons cultured under CORT stimulation, respectively. Electrophysiological analysis revealed that inhibition of miR-19b-3p rescued the limited synaptic transmission and synaptic plasticity in hippocampal neurons. Moreover, blocking miR-19b-3p drastically protected against cognitive deficits in CRS mice. These in vivo and in vitro findings indicate that the upregulation of miR-19b-3p exacerbates CRS-induced abnormal synaptic plasticity and cognitive impairment by targeting Drebrin.
研究领域:
神经科学
·
分子生物学
·
认知科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2018
·Vol. 10
·期 1
·277-288
·
IF 3.289
Wanxiu Cao,Chengcheng Wang,Yaoxian Chin,Xin Chen,Yuan Gao,Shihan Yuan,Changhu Xue,Yuming Wang,Qingjuan Tang
Stress exposure can increase the appearance of intestinal dysfunction. DHA and EPA have been shown to possess significant anti-inflammatory and immuno-enhancement bioactivities. The aim of the study was to investigate whether different forms of DHA or EPA would affect intestinal barriers (including intestinal epithelium integrity and immunity responses, gut microbiota and its metabolites) in mice under chronic stress, and might therefore prevent stress induced intestinal dysfunction. Chronic stress caused a series of anomalies in the intestine, including decreased faecal water content, increased pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β and IL-6), reduced expression levels of ZO-1, occludin and E-cadherin, and aberrant microbiota composition (especially Roseburia spp., Prevotella spp., bifidobacteria and lactobacilli) and its metabolites, mainly LPS, acetic acid, propionic acid and butyric acid. Our data indicated that both DHA-PL and EPA-PL counteracted these adverse effects effectively. In conclusion, DHA-PL and EPA-PL may effectively protect mice against intestinal dysfunction under chronic stress exposure as potential ingredients for functional food.
研究领域:
营养学
·
免疫学
·
胃肠病学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yu-Qi Li,Bai-Hang Zhao,Yu-Qing Zhang,Hai-Shan Yang,Bing-Lin Zhang
Multiple nanoparticles presented in wastewater treatment plants can produce comprehensive ecotoxicity. In this study, copper oxide nanoparticles (nCuO) and zinc oxide nanoparticles (nZnO) were investigated for their co-toxicity to aerobic granular sludge (AGS) systems. The combined stress of nCuO and nZnO performed significant antagonistic effects on nitrogen removal both under acute and chronic stress. Under chronic stress, nCuO and nZnO co-existence performed significant antagonistic effects on cell membrane, adenosine triphosphate (ATP) activity and microbial community structure. PICRUSt analysis indicated that nCuO (15 mg/L) co-existence alleviated nZnO (10 mg/L) inhibition on energy production and membrane transport metabolic pathways. In addition, nCuO addition to single nZnO weakened the toxicity of nZnO to nitrogen metabolism, glucose metabolism, and electron transfer genes, contributing to an alleviation in nitrogen removal inhibition. As compared with individual stress, combined stress decreased Cu(II) release from nCuO, but increased Zn(II) release from nZnO. The combination of nCuO and nZnO increased zinc resistance gene amplification and czcC gene proportion, and promoted Zn(II) efferent from cells, also with AGS resistance.
研究领域:
环境工程
·
微生物学
·
废水处理
·
纳米技术
·
生态毒理学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）