Frontiers in Pharmacology
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2024
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IF 4.4
Xin Qiao,Xiaojuan Cao,Shuang Xu,Cunlin Wang,Rui Guo,Xiaojuan Yao,Qiong Zhang
Background: Dysregulated and excessive inflammatory reactions can lead to tissue damage, which is the underlying cause of most human diseases. Menisoxoisoaporphine A (MA), a novel oxoisoaporphine alkaloid, was obtained from Menispermi Rhizoma, a traditional Chinese medicinal herb used in the treatment of inflammatory conditions in clinical practice. This suggests that MA has very promising potential for the development of anti-inflammatory therapeutics. Hence, this study aims to investigate the anti-inflammatory effects and underlying mechanisms of MA.Method: The anti-inflammatory effects of MA were evaluated in lipopolysaccharide (LPS)-induced mouse macrophage RAW264.7 cells. Its underlying mechanisms were explored through RNA sequencing and Western blotting. The binding modes and interactions sites between MA and phosphodiesterase 4B (PDE4B) were predicted using molecular docking and validated by molecular dynamics simulation.Results: MA treatment significantly reduced LPS-induced morphological changes, inflammatory cytokine relesae, and proinflammatory genes expression in RAW264.7 cells compared to the LPS-induced controls. Transcriptome sequencing analysis suggested that PDE4B might be a key target for MA to exert its therapeutic effect. Mechanismly, MA directly acted on Tyr405 site of PDE4B, thus leading to a sustained elevation of the cyclic adenosine monophosphate (cAMP) levels, which subsequently inactivated NF-κB signaling pathway by phosphorylating protein kinase A (PKA). MA inhibited the NF-κB-mediated inflammatory response depending on PDE4B.Conclusion: MA, a natural and novel compound, exerted anti-inflammatory effects in LPS-induced RAW264.7 macrophage cells. It demonstrated a strong binding ability to the Tyr405 sites of PDE4B, thereby inhibiting NF-κB signaling pathway by regulating the cAMP-PKA axis. Elucidating the interaction between MA and PDE4B holds significant potential for the advancement of innovative therapeutic strategies aimed at inflammatory diseases. By strategically modulating this interaction, it may be feasible to achieve more precise regulation of inflammatory responses, thereby offering promising therapeutic benefits for conditions such as rheumatoid arthritis, asthma, and inflammatory bowel disease.
研究领域:
药理学
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免疫学
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分子生物学
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炎症性疾病
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Yi Feng,Xiaoyu Liu,Xinyi Zhang,Yongzhi Sun,Kexin Ren,Xuemei Qian,Wenjing Sun,Ji Li,Bo Yu
This is the first report of geraniin alleviating visceral adipose tissue expansion. • Geraniin promotes lipid metabolic remodeling in visceral adipose tissue. • This is the first in vivo study of geraniin activating cAMP-LKB1-AMPK signaling. • β-adrenergic receptors contributes to geraniin-induced lipid metabolic remodeling. • This study provides a new insight on the anti-obesity potential of natural tannin. Ethnopharmacological relevance Geranium ( Geranium wilfordii Maxim.) has traditionally been used as a folk medicine in East Asia and Europe. Geraniin, the major bioactive constituent of geranium, has been reported to ameliorate dyslipidemia and insulin resistance, but its effects against adipose metabolic dysfunction remain unclear. Aim of the study To investigate the protective effects of geraniin against pathological visceral adipose tissue (VAT) expansion in high-fat diet-fed (HFD-fed) mice and to elucidate the underlying mechanisms. Methods Adipose tissue content was detected using micro-CT. Adipocyte morphology and macrophage infiltration in VAT were evaluated by HE staining and immunohistochemistry. Target gene and protein expression were analyzed by qPCR, Western blot, and immunofluorescence staining. Circulating free fatty acid (FFA) profiles were quantified using GC-MS. Results Geraniin markedly attenuated body weight gain and pathological VAT expansion in HFD-fed mice without affecting food intake. Geraniin reduced adipocyte hypertrophy and inflammatory responses in VAT. Mechanistically, geraniin suppressed the SREBP-1/FAS-associated lipogenic program while enhancing PGC-1α/ATGL-associated lipolytic program. These metabolic changes were accompanied by increased cAMP level and enhanced LKB1 and AMPK phosphorylation. Importantly, propranolol reversed geraniin-induced cAMP accumulation and LKB1-AMPK activation, as well as lipid metabolic remodeling in VAT. Consistent findings were observed in 3T3-L1 adipocytes. In addition, geraniin partially normalized circulating FFA profiles, particularly by reducing palmitic acid levels. Conclusion Geraniin alleviated pathological VAT expansion in HFD-fed mice through lipid metabolic remodeling. Our findings suggest that β-adrenergic receptor (ADRB)-associated signaling and downstream cAMP-LKB1-AMPK activation may contribute to the protective effects of geraniin, supporting its therapeutic potential for abdominal obesity and related metabolic disorders. Download: Download high-res image (280KB) Download: Download full-size image
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EUROPEAN JOURNAL OF NEUROSCIENCE
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2023
·Vol. 58
·期 10
·4123-4136
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IF 3.4
Hong Ni,Zhongzhao Guo,Yue Wu,Jie Wang,Yang Yang,Zilu Zhu,Deheng Wang
It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signalling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. We found COX-2 gene knockout (KO) could significantly impact the learning and memory ability, cause neuronal structure disorder and influence gamma oscillations. These might be mediated by the inhibition of prostaglandin (PG) E2/cAMP pathway and phosphorylated protein kinase A (p-PKA)-phosphorylated cAMP response element binding protein (p-CREB)-brain derived neurotrophic factor (BDNF) axis. It suggested COX-2 might play a critical role in learning, regulating neuronal structure and gamma oscillations in the hippocampus CA1 by regulating COX-2/BDNF signalling pathway.
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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Journal of Animal Science and Biotechnology
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2024
·Vol. 15
·期 1
·1-18
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IF 6.3
Shang Lijun,Yang Fengjuan,Chen Qingyun,Dai Ziqi,Yang Guangxin,Zeng Xiangfang,Qiao Shiyan,Yu Haitao
Background The antibacterial and immunomodulatory activities of bacteriocins make them attractive targets for development as anti-infective drugs. Although the importance of the enteric nervous system (ENS) in the struggle against infections of the intestine has been demonstrated, whether it is involved in bacteriocins anti-infective mechanisms is poorly defined. Results Here, we demonstrated that the bacteriocin Microcin J25 (J25) significantly alleviated diarrhea and intestinal inflammation in piglets caused by enterotoxigenic Escherichia coli (ETEC) infection. Mechanistically, macrophage levels were significantly downregulated after J25 treatment, and this was replicated in a mouse model. Omics analysis and validation screening revealed that J25 treatment induced significant changes in the dopaminergic neuron pathway, but little change in microbial structure. The alleviation of inflammation may occur by down-regulating dopamine receptor (DR) D1 and the downstream DAG-PKC pathway, thus inhibiting arachidonic acid decomposition, and the inhibition of macrophages may occur through the up-regulation of DRD5 and the downstream cAMP-PKA pathway, thus inhibiting NF-κB. Conclusions Our studies’ findings provide insight into the changes and possible roles of the ENS in J25 treatment of ETEC infection, providing a more sophisticated foundational understanding for developing the application potential of J25.
研究领域:
微生物学
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免疫学
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神经科学
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药理学
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Comparative Biochemistry and Physiology D-Genomics & Proteomics
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2025
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IF 2.4
Sumbul Mureed Mastoi,Yang Hua,Waqar Ali Chandio,Paras Mureed Mastoi,Yang Wei
The female parasitoid wasp Scleroderma sichuanensis (Hymenoptera: Bethylidae) utilizes various intricate behavior strategies, including host detection, learning, and memory, to enhance its survival and reproductive success. RNA-Seq analysis conducted under sublethal insecticide stress identified three differentially expressed genes, SsOR5, SsGRIN2B, and SsPDE8A, selected for functional validation due to their likely roles in host searching behavior. The SsOR5, an odorant receptor, is believed to interact with other olfactory receptors and downstream signaling molecules to improve host detection. In contrast, SsGRIN2B, an NMDA-type glutamate receptor, may influence synaptic plasticity and neural transmission, thereby affecting leering behavior. Additionally, SsPDE8A modulates cAMP-dependent signaling pathways, which are crucial for memory consolidation and behavioral response. This research investigates these genes in S. sichuanensis using RNA interference (RNAi) to assess changes in host finding efficiency. Adult female wasp received dsRNA treatments at doses of (0.5 μL, 1 μL, and 3 μL) and time durations (12, 24, 48, and 72 h), with the most significant gene silencing observed at 3 μL for 48–72 h. Behavioral assays conducted with a Y-tube olfactometer revealed that knockdown of SsOR5 significantly reduced host attraction, while knockdown of SsGRIN2B and SsPDE8A led to moderate reeducations, highlighting the varying contributions of these genes to olfactory drive behavior. This study demonstrates that insecticides induced changes in gene expression can disrupt neural and olfactory pathways essential for host location, and emphasizes the potential of RNAi-based approaches to target behaviorally significant genes, offering new strategies for parasitoid-mediated pest management.
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Virulence
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2024
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IF 5.5
Fen Wang,Jinping Zhang,Qian Zhang,Zhangyong Song,Caiyan Xin
Candida albicans is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of C. albicans. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of C. albicans. In the present study, the antifungal activities of equol against C. albicans were investigated. In vitro, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against C. albicans. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of C. albicans. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors RFG1 and TUP1. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.
研究领域:
微生物学
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药理学
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分子生物学
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传染病学
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Nature Communications
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2024
·Vol. 15
·期 1
·1-16
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IF 14.7
Wu Xin,Yu Yuanhuan,Wang Meiyan,Dai Di,Yin Jianli,Liu Wenjing,Kong Deqiang,Tang Shasha,Meng Meiyao,Gao Tian,Zhang Yuanjin,Zhou Yang,Guan Ningzi,Zhao Shangang,Ye Haifeng
Gene therapies provide treatment options for many diseases, but the safe and long-term control of therapeutic transgene expression remains a primary issue for clinical applications. Here, we develop a muscone-induced transgene system packaged into adeno-associated virus (AAV) vectors (AAV MUSE ) based on a G protein-coupled murine olfactory receptor (MOR215-1) and a synthetic cAMP-responsive promoter (P CRE ). Upon exposure to the trigger, muscone binds to MOR215-1 and activates the cAMP signaling pathway to initiate transgene expression. AAV MUSE enables remote, muscone dose- and exposure-time-dependent control of luciferase expression in the livers or lungs of mice for at least 20 weeks. Moreover, we apply this AAV MUSE to treat two chronic inflammatory diseases: nonalcoholic fatty liver disease (NAFLD) and allergic asthma, showing that inhalation of muscone—after only one injection of AAV MUSE —can achieve long-term controllable expression of therapeutic proteins (ΔhFGF21 or ΔmIL-4). Our odorant-molecule-controlled system can advance gene-based precision therapies for human diseases.
研究领域:
基因治疗
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药理学
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分子生物学
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慢性病管理
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Xiaoping Xie,Kexin Wang,Xiaoyan Shen,Xu li,Su Wang,Shun Yuan,Bowen Li,Zhiwei Wang
Microplastics (MPs) have attracted widespread attention because they can lead to combined toxicity by adsorbing heavy metals from the environment. Exposure to lead (Pb), a frequently adsorbed heavy metal by MPs, is common. In the current study, the coexistence of MPs and Pb was assessed in human samples. Then, mice were used as models to examine how co-exposure to MPs and Pb promotes aortic medial degeneration. The results showed that MPs and Pb co-exposure were detected in patients with aortic disease. In mice, MPs and Pb co-exposure promoted the damage of elastic fibers, loss of vascular smooth muscle cells (VSMCs), and release of inflammatory factors. In vitro cell models revealed that co-exposure to MPs and Pb induced excessive reactive oxygen species generation, impaired mitochondrial function, and triggered PANoptosome assembly in VSMCs. These events led to PANoptosis and inflammation through the cAMP/PKA-ROS signaling pathway. However, the use of the PKA activator 8-Br-cAMP or mitochondrial ROS scavenger Mito-TEMPO improved, mitochondrial function in VSMCs, reduced cell death, and inhibited inflammatory factor release. Taken together, the present study provided novel insights into the combined toxicity of MPs and Pb co-exposure on the aorta. Environmental Implication Microplastics (MPs) and Lead (Pb) are pervasive in the environment, yet studies on the cardiovascular toxicity of MPs and Pb co-exposure remain scarce. This research investigates the effects of MPs and Pb co-exposure on aortic medial degeneration (AMD). The findings reveal the presence of MPs and Pb exposure in patients. Co-exposure to MPs and Pb accelerates AMD in the mice. Further experiments confirm that co-exposure to MPs and Pb affects vascular smooth muscle cell activity and inflammation by regulating the cAMP/PKA pathway and mitochondrial function. Our study offers new insights into the synergistic toxic mechanisms of MPs and Pb.
研究领域:
环境科学
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毒理学
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心血管疾病
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FITOTERAPIA
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2026
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IF 2.9
Wei Xiao,Shuting Zhai,Kuangyi Liu,Zhijian Lu,Xizi Yongbo,Yi Liu,Ruiyin Ye,Mingzhen He,Zhiqiang Li
This study aimed to elucidate the sedative–hypnotic effects of a stem–derived bioactive fraction from Syringa oblata Lindl. (ZDX) and to reveal its underlying mechanisms, thereby providing a theoretical and practical basis for the development of new sleep aid drugs. ZDX was prepared by optimizing the extraction and purification procedures. Using UPLC–Q–TOF–MS, the prototype compounds absorbed into the brain of insomnia mice were analyzed, and 15 bioactive compounds were identified or predicted, including Dihydrocubebin, (−)-Cubebin, Isoguamarol, and others. Its efficacy and mechanisms were investigated using network pharmacology, transcriptomics, metabolomics, and molecular docking, complemented by in vivo pharmacodynamic and molecular analyses. In an insomnia mouse model, ZDX significantly increased body weight, reduced sleep latency, and prolonged total sleep duration, while alleviating anxiety and depression–like behaviors and improving histopathological damage in the hippocampus and hypothalamus, showing significant sedative–hypnotic effects. Mechanistically, ZDX modulated key genes and proteins involved in the cAMP signaling pathway, enhanced superoxide dismutase activity, reduced malondialdehyde levels, decreased inflammatory cytokines (IL–6, IL–1β, and TNF–α), and restored neurotransmitter homeostasis in the brain. Collectively, ZDX exerts sedative–hypnotic effects, at least in part, by activating the cAMP/PKA–CREB–BDNF axis and coordinately regulating neurotransmission, oxidative stress, and inflammation.
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BIOMEDICINE & PHARMACOTHERAPY
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2021
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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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Chinese Medicine
·
2022
·Vol. 17
·期 1
·1-20
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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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Nature Communications
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2024
·Vol. 15
·期 1
·1-18
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IF 14.7
Weng Haobo,Zou Weijuan,Tian Fangyan,Xie Huilin,Liu Ao,Liu Wen,Liu Yu,Zhou Nianwei,Cai Xiaojun,Wu Jianrong,Zheng Yuanyi,Shu Xianhong
Heart failure causes considerable morbidity and mortality worldwide. Clinically applied drugs for the treatment of heart failure are still severely limited by poor delivery efficiency to the heart and off-target consumption. Inspired by the high heart delivery efficiency of inhaled drugs, we present an inhalable cardiac-targeting peptide (CTP)-modified calcium phosphate (CaP) nanoparticle for the delivery of TP-10, a selective inhibitor of PDE10A. The CTP modification significantly promotes cardiomyocyte and fibroblast targeting during the pathological state of heart failure in male mice. TP-10 is subsequently released from TP-10@CaP-CTP and effectively attenuates cardiac remodelling and improved cardiac function. In view of these results, a low dosage (2.5 mg/kg/2 days) of inhaled medication exerted good therapeutic effects without causing severe lung injury after long-term treatment. In addition, the mechanism underlying the amelioration of heart failure is investigated, and the results reveal that the therapeutic effects of this system on cardiomyocytes and cardiac fibroblasts are mainly mediated through the cAMP/AMPK and cGMP/PKG signalling pathways. By demonstrating the targeting capacity of CTP and verifying the biosafety of inhalable CaP nanoparticles in the lung, this work provides a perspective for exploring myocardium-targeted therapy and presents a promising clinical strategy for the long-term management of heart failure.
研究领域:
心脏病学
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纳米医学
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药理学
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分子生物学
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