PHARMACEUTICAL BIOLOGY
·
2022
·
IF 3.889
Zhongmei He,He Yu,Hong Wu,Lili Su,Kun Shi,Yan Zhao,Ying Zong,Weijia Chen,Rui Du
Context Fibraurea recisa Pierre. (Menispermaceae) (FR) is a traditional Chinese medicine known as “Huangteng.” The total alkaloids of FR (AFR) are the main active ingredients. However, the pharmacological effects of AFR in the treatment of depression have not been reported.Objectives This study investigates the antidepressant effects of AFR by network pharmacology and verification experiments.Materials and methods Compound-Target-Pathway (C-P-T) network of FR and depression was constructed through network pharmacology. In vitro, HT-22 cells were treated with corticosterone (CORT) solution (0.35 mg/mL), then AFR (0.05 mg/mL) solution and inhibitor AZD6244 (14 μM/mL) or BAY11-7082 (10 μM/mL) were added, respectively. The cell viability was detected by CCK-8. In vivo, C57BL/6 mice were divided into 5 groups, namely the normal group, the CUMS group, the AFR (400 mg/kg) group, and the 2 groups that were simultaneously administered the inhibitory group AZD6244 (8 mg/kg) and BAY11-7082 (5 mg/kg). Western blotting was used to assess the expression level of the proteins.Results AFR could protect HT-22 cells from CORT-induced damage and increase the cell viability from 49.12 ± 3.4% to 87.26 ± 1.5%. Moreover, AFR significantly increased the levels of BDNF (1.3, 1.4-fold), p-ERK (1.4, 1.2-fold) and p-CERB (1.6, 1.3-fold), and decreased the levels of NLRP3 (11.3%, 31.6%), ASC (19.2%, 34.2%) and caspase-1 (18.0%, 27.6%) in HT-22 cells and the hippocampus, respectively.Discussion and conclusions AFR can improve depressive-like behaviours and can develop drugs for depression treatment. Further studies are needed to validate its potential in clinical medicine.
研究领域:
药理学
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神经科学
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中医药
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2021
·
IF 6.53
Baoyue Zhang,Jun Zhao,Pengfei Guo,Zhe Wang,Lvjie Xu,Ailin Liu,Guanhua Du
Naodesheng (NDS) tablets have been widely used to treat ischemic stroke clinically. NDS relieves neurological function impairment and improve learning and memory in rats with focal cerebral ischemia, suggesting that NDS has potential for Alzheimer’s disease (AD) treatment. However, there are no studies about its effective material basis and possible mechanisms. In this study, a systems pharmacology method was applied to reveal the potential molecular mechanism of NDS in the treatment of AD. First, we obtained 360 NDS candidate constituents through ADMET filter analysis. Then, 115 AD‐related targets were uncovered by pharmacophore model prediction via mapping the predicted targets against AD-related proteins. In addition, compound-target and target-function networks were established to suggest potential synergistic effects among the candidate constituents. Furthermore, potential targets regulated by NDS were integrated into AD-related pathways to demonstrate the therapeutic mechanism of NDS in AD treatment. Subsequently, a validation experiment proved the therapeutic effect of NDS on cognitive dysfunction in rats with intracerebroventricular injection of Aβ. We found that administration of NDS tablets regulates β-amyloid metabolism, improves synaptic plasticity, inhibits neuroinflammation and improves learning and memory function. In conclusion, this is the first study to provide a comprehensive systems pharmacology approach to elucidate the potential therapeutic mechanism of NDS tablets for AD treatment. We suggest that the protective effects of NDS in neurodegenerative conditions could be partly attributed to its role in improving synaptic plasticity and inhibiting neuroinflammation via NF-κB signaling pathway inhibition and cAMP/PKA/CREB signaling pathway activation.
研究领域:
药理学
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神经科学
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中医
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系统生物学
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产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2022
·Vol. 17
·期 1
·1-20
·
IF 4.546
Yu Hui,Shao Shumin,Xu Junnan,Guo Haibiao,Zhong Zhangfeng,Xu Jiangping
Background Fresh or dried Persimmon leaves (Diospyros kaki Thunb.) exhibit preventive effects on cardiovascular and cerebrovascular diseases. However, their antidepressant effects and underlying mechanisms are unclear. Thus, we investigated mechanisms responsible for Persimmon leaf extract (PLE) activity on chronic social defeat stress (CSDS)-induced depressive-like behaviors in mice.Methods CSDS was used as a mouse model of depression. We performed the sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) to identify depressive-like behavior. Spine density and dendritic morphology were assessed using Golgi staining. Neurochemicals were quantified by microdialysis, doublecortin by immunofluorescence, and cAMP using an ELISA kit. Finally, the levels of cortical proteins of phosphorylated cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), postsynaptic density synapsin-1 and protein 95 (PSD95) were quantified by western blot. 16S rRNA gene sequencing was used to detect fecal microbiota.Results Treatment of CSDS-subjected mice with PLE (30.0–60.0 mg/kg, i.g.) enhanced sucrose preference, decreased immobility times in the TST and FST but did not affect locomotor activity. Furthermore, persistent social defeat stress decreased dendritic spine density and dendritic length in the brain, as well as decreased PSD95 and synapsin-1 expression. PLE, interestingly, inhibited dendritic spine loss and increased synaptic protein levels. PLE also increased brain levels of 5-HT, cAMP, phosphorylated (p)-CREB, BDNF, PSD95, and synapsin-1 in mice subjected to CSDS. Furthermore, PLE increased their doublecortin-positive cell count in the hippocampal dentate gyrus. CSDS mice represented a distinct fecal microbiota cluster which differed compared with normal C57BL/6J mice, and the phenotype was rescued by PLE.Conclusion sPLE alleviated CSDS-induced depressive behaviors and spinal damage by suppressing serotonin reuptake and activating the cAMP/CREB/BDNF signaling pathway. Simultaneously, PLE influenced the composition of the fecal microbiota in CSDS-subjected mice.
研究领域:
药理学
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神经科学
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行为科学
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微生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2022
·Vol. 13
·期 11
·6166-6179
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IF 6.317
Hongxia Li,Xin Xu,Mengyu Cai,Yicui Qu,Zifu Ren,Chuyang Ye,Hui Shen
The aim was to investigate whether the combination of hydroxytyrosol acetate (HT-ac) and ethyl β-hydroxybutyrate (HBET) can improve the cognition of heat-stressed mice, meanwhile exploring the mechanism of action. Mice were divided into 5 groups: control, heat-stressed, HT-ac, HBET, and HT-ac + HBET. Mice were gavaged for 21 days and exposed to heat (42.5 ± 0.5 °C, RH 60 ± 10%, 1 h day-1) on days 15–21, except for the control group. Results showed that the combination of HT-ac + HBET improved the cognitive and learning abilities of heat-stressed mice, which were tested by Morris water maze, shuttle box, and jumping stage tests. The combination of HT-ac + HBET maintained the integrity of neurons and mitochondria of heat-stressed mice. Likewise, this combination increased the mitochondrial membrane potential, the ATP content, the expression of phosphorylated PKA, BDNF, phosphorylated CREB and Bcl-2, and decreased the expression of Bax, caspase-3, and intracytoplasmic Cyt C in heat-stressed mice.
研究领域:
神经科学
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药理学
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生理学
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DOI
PubMed
高影响因子
Aging-US
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2024
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IF 3.9
Yaming Yang,Zheng Yan,Qi Xie,Yong Wang,Zhiying Liu,Min Lei
Background: The purpose of this study is to observe LP45 ( Lactobacillus plantarum 45) to investigate the mechanism by which LP45 attenuates oxidative stress-induced damage and regulates the osteoblast-osteoclast balance. Materials and Methods: The oxidative stress level and osteoblast- and osteoclast-related proteins were detected by immunofluorescence staining, Western blotting, ROS fluorescent probe and ELISA. Osteoblast cell proliferation capacity was determined by the CCK-8 assay. X-ray observation and HE staining were used to detect the effect of LP45 on osteoporosis. Results: The expression level of SHP2 and Src was significantly increased, and the expression levels of NOX4, P22, P47, IL-1β, NLRP3, IRF3, RANK, β-catenin and INF-β were inhibited in LP45 group and LPS + LP45 group as compared to those in LPS group. Compared with that in LPS group, the concentration of SOD was increased and the concentration of MDA was decreased in LPS + LP45 group. The protein expressions of OPG, RANKL, RUNX3, RANK and β-catenin in LP45 group and LPS + LP45 group increased. The protein expressions of NF-κB, CREB and AP-1 in LP45 group and LPS + LP45 group decreased significantly. The results were also confirmed by immunofluorescence staining and ROS fluorescent probe. X-ray observation and HE staining showed that LP45 could inhibit the progression of osteoporosis. Conclusion: LP45 can exert its antioxidant effect by inhibiting the production of oxidative stress to activate the SHP2 signaling pathway, thus promoting osteoblast differentiation and repressing osteoclast formation to maintain bone homeostasis and improve bone metabolism.
研究领域:
微生物学
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骨骼生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Molecular Brain
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2019
·Vol. 12
·期 1
·1-12
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IF 4.051
Wang Xin-shang,Guan Shao-yu,Liu An,Yue Jiao,Hu Li-ning,Zhang Kun,Yang Liu-kun,Lu Liang,Tian Zhen,Zhao Ming-gao,Liu Shui-bing
Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover ( Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA A receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.
研究领域:
药理学
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神经科学
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疼痛研究
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传统中药
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Xinyu Fan,Jiachen Shi,Ye Liu,Mengqiu Zhang,Min Lu,Ding Qu
Background Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
研究领域:
药学
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胃肠病学
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营养科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Science of Advanced Materials
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2021
·Vol. 13
·期 5
·864-873
·
IF 1.474
Chen Ping,Yue Xinai,Dai Wei,Wang Xia,Li Yingying,Xie Hongjian,Jiang Dongmei,Jiang Yongmei
N-acetyl-L-cysteine-modified CdTe QDs (Cadmium Telluride Quantum Dots) were obtained by hydrothermal method, and DA (amino deoxyglucose), PEG (polyethylene glycol), and 9-p-D (9 polyamine acid) were obtained by ligand substitution, which were used for remodifying CdTe
QDs. Successively, a novel CdTe QDs nanoma-terial, CdTe-NALC, was obtained. This composite nanometer material was characterized by ultraviolet, fluorescence spectrum, nuclear magnetic resonance hydrogen-spectrum, and other methods to study further its biocompatibility and toxic effect on the
primary cultured mouse hippocampus neurons. PC12 cells were vitro-cultured and dissolved in the CdTe-NALC solution with different concentrations. After 24 h, the expression levels of proteins related to the cAMP (cyclic adenosine monophosphate)-CREB (cAMP response element-binding proteins)-BDNF
(brain-derived neurotrophic factor) signaling pathway in the cells were detected by ELISA (enzyme-linked immunosorbent assay) kit. In the experiment, the DA/9-p-D/PEG-modified CdTe QDs composite nanometer material was successfully manufactured by ligand replacement. The nanoparticles
had good dis-persibility with an average particle size of about 9.2 nm. DA/9-p-D/PEG modification improved the biocompatibil-ity of the QDs. CdTe composite nanomaterials could significantly reduce the cell activity of mouse hippocampal neurons and promote their apoptosis, with an evident
dose-apoptosis relationship. With the increase of CDTE-NALC solution concentration, cAMP, pCREB (phosphorylated CREB), and BDNF protein content decreased (P < 0.05).
研究领域:
纳米技术
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神经科学
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细胞生物学
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生物化学
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DOI
高影响因子
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
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2017
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IF 4.187
Shuang-Shuang Wang,Rong-Hao Mu,Cheng-Fu Li,Shu-Qi Dong,Di Geng,Qing Liu,Li-Tao Yi
Dysregulation of microRNA (miRNA) has been shown to be involved in early observations of depression. MicroRNA-124-3p (miR-124) is the most abundant microRNA in the brain . Previous studies have shown that miR-124 plays a major role in depression. Here we showed that miR-124 directly targeted glucocorticoid receptor (GR) in HEK 293 cells . In addition, inhibition of miR-124 by its antagomir (2 nmol/every two days) could reverse the decrease of sucrose preference and the increase of immobility time in mice exposed to chronic corticosterone (CORT, 40 mg/kg) injection. Moreover, these effects on behavioral improvement were coupled to the activation of brain-derived neurotrophic factor (BDNF), TrkB, ERK, and CREB, as well as the induction of synaptogenesis and neuronal proliferation. Altogether, our study suggests that miR-124 can be served as a biomarker for depression and a novel target for drug development , and demonstrates that inhibition of miR-124 may be a strategy for treating depression by activating BDNF-TrkB signaling pathway in the hippocampus .
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
EXPERIMENTAL BRAIN RESEARCH
·
2023
·Vol. 241
·期 6
·1661-1673
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IF 2
Zhang Yuhe,Chen Yan,Yuan Shushu,Yu Qingxia,Fu Jianjiong,Chen Luyun,Liu Jiaming,He Yuping
Gastrodin (Gas) has exhibited protective activity in neurological disorders. Here, we investigated the neuroprotective effect and potential mechanisms of Gas against cognitive impairment via regulating gut microbiota. APPswe/PSEN1dE9 transgenic (APP/PS1) mice were treated intragastrically with Gas for 4 weeks, and then cognitive deficits, deposits of amyloid-β (Aβ) and phosphorylation of tau were analyzed. The expression levels of insulin-like growth factor-1 (IGF-1) pathway-related proteins, such as cAMP response element-binding protein (CREB), were detected. Meanwhile, gut microbiota composition was evaluated. Our results showed that Gas treatment significantly improved cognitive deficits and Aβ deposition in APP/PS1 mice. Moreover, Gas treatment increased the level of Bcl-2 and decreased level of Bax and ultimately inhibited neuronal apoptosis. Gas treatment markedly increased the expression levels of IGF-1 and CREB in APP/PS1 mice. Moreover, Gas treatment improved abnormal composition and structure of gut microbiota in APP/PS1 mice. These findings revealed that Gas actively participated in regulating the IGF-1 pathway to inhibit neuronal apoptosis via the gut–brain axis and that it can be considered a new therapeutic strategy against Alzheimer’s disease.
研究领域:
神经科学
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药理学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 47
·期 12
·3761-3776
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IF 4.414
He Junhui,Li Dongmei,Wei Jie,Wang Sheng,Chu Shifeng,Zhang Zhao,He Fei,Wei Dongmei,Li Yi,Xie Jiaxiu,Lai Kedao,Chen Naihong,Wei Guining
Depression has become an important disease threatening human health. In recent years, the efficacy of Traditional Chinese Medicine (TCM) in treating the disease has become increasingly prominent, so it is meaningful to find new antidepressant TCM. Mahonia fortune (Lindl.) Fedde is a primary drug in traditional formulas for the treatment of depression, and alkaloids are the main components of it. However, the detailed mechanism of Mahonia alkaloids (MA) on depression remains unclear. This study aimed to investigate the effect of MA on gap junction function in depression via the miR-205/Cx43 axis. The antidepressant effects of MA were observed by a rat model of reserpine-induced depression and a model of corticosterone (CORT)-induced astrocytes. The concentrations of neurotransmitters were measured by ELISA, the expression of Connexin 43 (Cx43) protein was measured by Immunohistochemistry and western-blot, brain derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB) proteins were measured by western-blot, the pathological changes of prefrontal cortex were observed by hematoxylin–eosin (H&E) staining. Luciferase reporter assay was performed to verify the binding of miR-205 and Cx43. The regulation effect of Cx43 on CREB was verified by interference experiment. Gap junction dysfunction was detected by fluorescent yellow staining. The results confirmed that MA remarkably decreased miR-205 expression and increased Cx43, BDNF, CREB expression in depression rat and CORT-induced astrocytes. In addition, after overexpression of miR-205 in vitro, the decreased expression of Cx43, BDNF and CREB could be reversed by MA. Moreover, after interfering with Cx43, the decreased expression of CREB and BDNF could be reversed by MA. Thus, MA may ameliorate depressive behavior through CREB/BDNF pathway regulated by miR-205/Cx43 axis. Graphical Abstract
研究领域:
药理学
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神经科学
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分子生物学
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中药
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Ling Tang,Liyuan Wang,Feng Jin,Yuehan Hao,Tianming Zhao,Wenxu Zheng,Zhiyi He
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
研究领域:
神经科学
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分子生物学
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药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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