BIOMEDICINE & PHARMACOTHERAPY
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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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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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PubMed
高影响因子
EMBO Molecular Medicine
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2025
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IF 8.3
FengShengyong,MaEnhao,NaXiaona,WangZongmei,TaiWanbo,BaoXinhui,WangMao,ChangHan,WuBaolei,LiuMiaoxi,LiJuzhen,ShiHuicheng,YangCeli,XiMenglu,YangHaibing,LiYuhan,ZhuYibin,WangPenghua,ZhaoLing,ZhaoAi,ChengGong
Vaccination offers the most effective protection against contagious infectious diseases primarily by inducing humoral immunity. Vaccination efficacy is influenced by various factors. We report that dietary administration of arachidonic acid (ARA) significantly boosts rabies vaccine-induced production of neutralizing antibodies and protection against lethal rabies virus (RABV) infection in mice. In human volunteers, oral supplementation of ARA accelerates the expression of neutralizing antibodies to the levels sufficient for protection against RABV as early as one week after primary immunization. Mechanistically, ARA is enriched in lymph nodes and metabolized into immune modulators there. One of the ARA metabolites, prostaglandin I2 (PGI2), via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis, upregulates the expression of costimulatory molecule CD86, and activates activation-induced cytidine deaminase (AID) in B cells. These results suggest that ARA can be a potent dietary adjuvant to foster germinal center (GC) B cell response and humoral immunity.
研究领域:
免疫学
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营养科学
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病毒学
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疫苗研究
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2016
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IF 4.191
Wenjun Zhao,Aiyun Li,Xin Feng,Ting Hou,Kang Liu,Baolin Liu,Ning Zhang
This study aims to investigate the effects of metformin and resveratrol on muscle insulin resistance with emphasis on the regulation of lipolysis in hypoxic adipose tissue. ICR mice were fed with high fat diet (HFD) for 10 days with administration of metformin, resveratrol, or intraperitoneal injection of digoxin . Adipose hypoxia, inflammation and cAMP/PKA-dependent lipolysis were investigated. Moreover, lipid deposition and insulin resistance were examined in the muscle. Metformin and resveratrol attenuated adipose hypoxia, inhibited HIF-1α expression and inflammation in the adipose tissue of HFD-fed mice. Metformin and resveratrol inhibited lipolysis through prevention of PKA/HSL activation by decreasing the accumulation of cAMP via preserving PDE3B . Metformin and resveratrol reduced FFAs influx and DAG accumulation, and thus improved insulin signaling in the muscle by inhibiting PKCθ translocation. This study presents a new view of regulating lipid metabolism to ameliorate insulin resistance and provides the clinical guiding significance for obesity and type 2 diabetes with metformin and resveratrol treatment.
研究领域:
药理学
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内分泌学
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代谢学
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PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
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2021
·Vol. 42
·期 9
·435-443
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IF 1.627
Hui Qiu,Zhengbing Guo,Qian Xu,Shengfang Mao,Wenming Wu
The present study was aimed to systemically assess the absorption risks of amentoflavone (AMF). Physicochemical properties of AMF were evaluated using in vitro assays including water solubility and stability in both simulated gastric and intestinal fluids, as well as logD, pka and permeability studies in a monolayer Caco-2 model. The results together suggested that AMF was a compound with moderate intestinal absorption and the poor solubility was the key rate-limiting step for the oral absorption of AMF, and PVP-K30 were thus used as a solubilizer to improve its solubility and oral bioavailability. Furthermore, studies on pharmacokinetics and biliary excretion of AMF with tween 80 or PVP-K30 were performed after oral administration, and the results showed that the percentage of AMF conjugates in bile was determined up to be 96.73% and no AMF conjugates were detected in rat plasma. The above results revealed that the poor oral absorption of AMF may probably be attributed to the low solubility, high level of metabolism and hepatic first-pass effects. The relative bioavailability of AMF solubilized by PVP-K30 was about 2-fold than that of AMF suspended in 1% tween 80. The present study may help provide scientific insights to guide the rational design of AMF into more efficient formulation systems.
研究领域:
药理学
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药物递送系统
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药剂学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Xin Yan,Jun Huang,Youjie Zeng,Xuefeng Zhong,Yangxia Fu,Haiyan Xiao,Xia Wang,Huilin Lian,Hui Luo,Dai Li,Ren Guo
Background Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. Methods The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. Results Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. Conclusion This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.
研究领域:
心脏病学
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肺医学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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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
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细胞生物学
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DOI
PubMed
高影响因子
Redox Biology
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2025
·
IF 11.9
Jing Fu,Congping Su,Yin Ge,Zhou Ao,Li Xia,Yingxiang Chen,Yizheng Yang,Shiwei Chen,Rui Xu,Xiaoyan Yang,Kai Huang,Qin Fu
Cyclic adenosine monophosphate (cAMP) plays a major role in normal and pathologic signaling in the heart. Phosphodiesterase 4 (PDE4) is a major PDE degrading cAMP in the heart. There are inconsistencies concerning the roles of the PDE4 isoforms 4B and 4D in regulation of cardiac function. Cardiac PDE4B overexpression is beneficial in remodeling and heart failure (HF), however, the effect of PDE4D and PDE4 inhibitor in HF remains unclear. We generated global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression to determine the role of PDE4D in cardiac hypertrophy and HF. PDE4D upregulation was observed in failing hearts from human and isoproterenol injection and TAC mice. In vitro , isoproterenol stimulation increased PDE4D expression via PKA but had no effect on PDE4B expression in cardiomyocytes. PDE4D overexpression per se induced oxidative stress, mitochondrial damage and cardiomyocyte hypertrophy by decreasing PINK1/Parkin-mediated mitophagy through inhibiting cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while PDE4B overexpression did not affect CREB-SIRT1 pathway and mitophagy but exhibited a protective effect on isoproterenol-induced oxidative stress and hypertrophy in cardiomyocytes. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo , ISO injection or TAC inhibited cardiac mitophagy and caused cardiac hypertrophy and HF, which were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency. Conversely, cardiac PDE4D overexpression suppressed cardiac mitophagy and abolished the protective effects of global PDE4D haploinsufficiency on TAC-induced cardiac hypertrophy and HF. In conclusion, these studies elucidate a novel mechanism by which sustained adrenergic stimulation contributes to cardiac hypertrophy and HF by increasing PDE4D via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy . PDE4D inhibition may represent a novel therapeutic strategy for HF.
研究领域:
心血管研究
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Shi Dingfang,Bai Yunhao,Long Ruiling,Xia Jing,Xu Wenxuan,Qin Dongshen,Yang Xuejun,Ding Ming,Hou Xiao-Yu
Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY–cAMP–PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY–PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.
研究领域:
神经科学
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细胞生物学
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分子生物学
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药理学
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神经病学
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产品关联
DOI
PubMed
高影响因子
TALANTA
·
2019
·
IF 4.916
Yang Xing,Ying Zhou,Li Fan,Yajuan Yang,Yuan Zhang,Xu Deng,Chuan Dong,Shaomin Shuang
Herein, we figured out a novel ratiometric fluorescent probe based on Janus silica nanoparticles (SiO 2 NPs) where fluorescein isothiocyanate (FITC) and rhodamine B (RB) were asymmetrically functionalized for intracellular pH detection. With this unique strategy, the probe exhibited dual emission bands at 530 and 580 nm upon excitation at a single wavelength of 488 nm. The pH titrations of the probe showed a remarkable increase in ratiometric intensities ratio (I 530nm /I 580nm ) when the pH was switched from 3.0 to 8.0 with a acid dissociation constant (pKa) value of 6.64. The probe was successfully applied to imaging and detection of pH in living cells without noticeable cytotoxicity, indicating that it is a promising candidate for bioanalysis and bioimaging.
研究领域:
纳米技术
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生物化学
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生物医学工程
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Jie Weng,Songlian Liu,Yajun Tong,Kewei Tang,Leilan Yin,Site Bai,Ludi Ou,Qinghua Yin,Qiang Zhou
Introduction Cervical cancer ranks as the fourth most common malignancy among women worldwide. It is closely associated with the dysregulation of numerous genes and signaling pathways. Conventional treatments for cervical cancer often lead to adverse side effects and the development of drug resistance. Methods In this study, network pharmacology was employed to identify the active components and potential targets of Crocus sativus L. Molecular docking and surface plasmon resonance analyses were used to validate the interaction between lauric acid and a key target. Lauric acid‐modified gold nanoparticles (Au@LA) were synthesized and characterized. Results Twenty‐three active components and 819 potential targets of Crocus sativus L. were identified, with PTGS2 being the main target. Au@LA selectively inhibited HeLa cell proliferation, induced apoptosis, downregulated SLC7A11 and GPX4, and modulated oxidative stress markers. In macrophages, Au@LA shifted M2 polarization to the pro‐inflammatory M1 phenotype and modulated the PGE2/EP2/cAMP‐PKA signaling axis. Conclusion Our findings indicate that Au@LA has dual anti‐cervical cancer properties through inducing ferroptosis in HeLa cells and reprogramming macrophage polarization. It shows promise as a candidate for natural product‐based nanomedicine in cervical cancer therapy, potentially opening new avenues for more effective and targeted treatments in the future.
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PubMed
高影响因子
TALANTA
·
2021
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IF 6.057
Ning Xia,Ting Sun,Lin Liu,Linxu Tian,Zhifang Sun
Heterogeneous analysis has great application prospects in the detection of post-translational modification (PTM) enzymes with the advantages of signal enhancement, less sample demand, and high sensitivity and selectivity . Nevertheless, once the substrate was fixed on a solid interface, the steric hindrance might limit the approaching of catalytic center to the substrate, thus reducing the efficiency of PTM. Herein, we suggested that the avidin-modified interface could be used to develop heterogeneous sensing platforms with biotin-labeled substrates as the probes, in which the enzymatic PTM was performed in solution and the heterogeneous assay was conducted on a solid surface. The sensing strategy integrates the advantages but overcomes the defects of both homogeneous and heterogeneous assays. Protein kinase A (PKA) and histone acetyltransferase (HAT) were determined as the examples by using sequence-specific peptide substrates. The signal changes were monitored by HRP-based colorimetric assay and antibody-amplified surface plasmon resonance (SPR). The methods were used for analysis of cell lysates and evaluation of inhibition efficiency with satisfactory results. The strategy can be used for the detection of a variety of biological enzymes and provide a new idea for the design of various heterogeneous biosensors. Thus, this work should be of great significance to the popularization and practical application of biosensors.
研究领域:
生物化学
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分子生物学
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分析化学
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生物技术
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DOI
PubMed
高影响因子
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