CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Changfeng Zhong,Changmei Wang,Wei Li,Wenyuan Li,Xuemei Chen,Jieqing Guo,Yifan Feng,Xia Wu
Parkinson's disease (PD) is the fastest growing neurodegenerative disease in the world at present. Neuroinflammation plays an important role in Parkinson's disease. In our study, we initially screened magnolol/honokiol derivatives synthesized by our group for their potential anti-neuroinflammatory properties. This was done using LPS-activated BV-2 microglial cell and MPP + -induced PC-12 cell models. Most of derivatives had increased anti-inflammatory activities and decreased toxicities compared to raw materials. Then, compounds were scored with inflammatory factors IL-1β, TNF-α and IL-6 by molecular docking in silico . Our studies revealed the strongest binding compound HM568 which binds with honokiol and metformin. Furthermore, HM568 showed no acute toxicity in mice through acute toxicity. And it is stable under high temperature, high humidity and strong light irradiation. Combining cell experiments and computer results, HM568 was considered for further in vivo pharmacological validations. Intraperitoneal injection administration of MPTP into C57BL/6 mice was utilized as Parkinson's animal model. Results showed that administration of HM568 for 14 days in MPTP-PD mice led to a significant alleviation in weight loss and movement disorders. Further HM568 could significantly down-regulate the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in brain tissue of the mouse model, reduce the level of caspase-3 and the ratio of Bcl-2/Bax, and up-regulate the level of transforming factor TGF-β, thus producing anti-apoptosis and anti-neuroinflammatory effects on neuronal cells. In terms of pathological features, HM568 could reduce the infiltration of neuronal cells and alleviate the development of lesions, promote the transformation of microglia from M1 negative phenotype to M2 type, and reverse the reduction of TH-positive immune cells in mouse neurons induced by MPTP. The administration of HM568 could reduce the abnormal accumulation of α-syn, and thus produce neuroprotective effect on MPTP-PD mice. Cell experiments, molecular docking and animal experiments thus depict HM568 as a promising agent to delay neuronal degeneration in PD, and its mechanism is related to anti-neuroinflammation.
研究领域:
神经科学
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药理学
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神经退行性疾病
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炎症
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药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Zhong Zhi-feng,Han Jing,Zhang Ji-Zhou,Xiao Qing,Chen Jing-yan,Zhang Kai,Hu Juan,Chen Li-dian
Salidroside, a phenylpropanoid glycoside, is the main bioactive component of Rhodiola rosea L. Salidroside has prominent anti-stroke effects in cerebral ischemia/reperfusion models. However, the underlying mechanisms of its actions are poorly understood. This study examined the anti-stroke effects of salidroside in middle cerebral artery occlusion (MCAO)-induced rat model of stroke and its potential mechanisms involving the dopaminergic system. Salidroside administration increased the levels of dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in the ipsilateral striatum after induction of transient ischemia, which were assessed using microdialysis with high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). Furthermore, treatment with salidroside ameliorated neurobehavioral impairment, assessed with the modified neurological severity scores (mNSS), the balance beam test, and the foot fault test. Moreover, enzyme-linked immunosorbent assay (ELISA) suggested that MCAO-induced reduction in monoamine oxidase (MAO) was inhibited by salidroside. Immunohistochemical and immunofluorescence analyses revealed high level of tyrosine hydroxylase (TH) in the ipsilateral striatal caudate putamen (CPu) after cerebral ischemia/reperfusion, which could be further elevated by salidroside. In addition, salidroside could reverse the decreased immunoreactivity of TH in the substantia nigra pars compacta (SNpc). These results suggest that the anti-stroke effects of salidroside in MCAO-induced cerebral ischemia/reperfusion may involve the modulation of monoamine metabolism in the striatum and SNpc, which may be related to the function of the dopaminergic system in the rat brain.
研究领域:
神经科学
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药理学
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神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2023
·
IF 6.2
Xue-Yun Chen,Si-Ning Feng,Yin Bao,Yu-Xin Zhou,Fang Ba
Parkinson's disease (PD) is a neurodegenerative disease. Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic tool in PD. High-throughput sequencing was performed to screen potential therapeutic targets in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. The candidate gene, Clec7a, was screened out and validated. Clec7a is a pattern recognition receptor involved in neuroinflammation. The higher expression of Clec7a was observed in the substantia nigra (SN) and striatum of PD rats with dopaminergic neurons damage and was mainly localized in the microglial. Adeno-associated virus (AAV)-mediated specific knockdown of Clec7a in microglial alleviated 6-OHDA induced motor deficits and nigrostriatal dopaminergic neuron damage of rats, as evidenced by the increase of tyrosine hydroxylase (TH) -positive neurons in SN, as well as dopaminergic nerve fibers in the striatum. Clec7a knockdown restrained the neuroinflammation by suppressing inflammatory factors (IFN-γ, TNF-α, IL-1β, IL-18, and IL-6) release in SN, which might result from enhanced Arg-1 expression (M2 polarization) and defective inducible nitric oxide synthase (iNOS) expression (M1 polarization). The same phenomena were also observed in the LPS inflammatory rat model of PD. In vitro, α-synuclein fibrils induced upregulation of Clec7a expression and microglia polarization to a pro-inflammatory state of BV2 cells, leading to increased release of cytokines. However, Clec7a knockdown reversed those changes and induced a shift to an anti-inflammatory phenotype in BV2 cells. In conclusion, our study suggested that Clec7a was involved in PD pathogenesis, and its inhibition might protect rats from PD by depressing neuroinflammation through microglial polarization.
研究领域:
神经科学
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神经退行性疾病
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治疗干预
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炎症
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2024
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IF 12.4
Yan-Hang Wang,Xin Chen,Yi-Zhen Bai,Peng Gao,Zhuo Yang,Qiang Guo,Ying-Yuan Lu,Jiao Zheng,Dan Liu,Jun Yang,Peng-Fei Tu,Ke-Wu Zeng
The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.
研究领域:
神经科学
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代谢学
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药理学
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分子生物学
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内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Shanshan Jin,Rajib Mia,Md All Amin Newton,Hongju Cheng,Weihong Gao,Yuansheng Zheng,Zijian Dai,Jie Zhu
The escalating global health concern arises from chronic wounds induced by bacterial infections, posing a significant threat to individuals. Consequently, an imperative exist for the development of hydrogel dressings to facilitate prompt wound monitoring and efficacious wound management. To this end, pH-sensitive bromothymol blue (BTB) and pH-responsive drug tetracycline hydrochloride (TH) were introduced into the polysaccharide-based hydrogel to realize the integration of wound monitoring and controlled treatment. Polysaccharide-based hydrogels were formed via a Schiff base reaction by cross-linking carboxymethyl chitosan (CMCS) on an oxidized sodium alginate (OSA) skeleton. BTB was used as a pH indicator to monitor wound infection through visual color changes visually. TH could be dynamically released through the pH response of the Schiff base bond to provide effective treatment and long-term antibacterial activity for chronically infected wounds. In addition, introducing polylactic acid nanofibers (PLA) enhanced the mechanical properties of hydrogels. The multifunctional hydrogel has excellent mechanical, self-healing, injectable, antibacterial properties and biocompatibility. Furthermore, the multifaceted hydrogel dressing under consideration exhibits noteworthy capabilities in fostering the healing process of chronically infected wounds. Consequently, the research contributes novel perspectives towards the advancement of intelligent and expeditious bacterial infection monitoring and dynamic treatment platforms.
研究领域:
生物医学工程
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材料科学
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伤口护理
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药学
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组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 16
·7343-7357
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IF 5.396
Songtao Fan,Zhihong Zhang,Yadong Zhong,Chang Li,Xiaojun Huang,Fang Geng,Shaoping Nie
Fructans such as fructo-oligosaccharides (FOS) and inulin have been reported to directly regulate ileal inflammatory responses in lipopolysaccharide (LPS)-induced endotoxemic mice, without alterations in the colonic microbiota. Firstly, we replicated this model and found that a single gavage of 10 mg g−1 of fructans directly promoted caecal acetate and propionate production. Thus, the previous understanding of microbiota-independent effects of prebiotic fructans in endotoxemic mice has been challenged. In parallel, we performed a daily gavage of 160 mg kg−1 of inulin, xylan, or Dendrobium officinale polysaccharides (DOP) for two weeks prior to LPS injection. The long-term intake of prebiotic fibres reduced the bacterial load in the spleen and mesenteric lymph nodes (MLNs), and in comparison, a single gavage of fructans increased that. However, the long-term intake was unable to improve the short-chain fatty acid (SCFA) synthesis and epithelial barrier function that were impaired by LPS. Notably, the three fibre types consistently reduced the expression of mucin 2 (MUC2) and variously modulated critical mediators (IL-18, IL-22, and HIF-1α) to regulate the host–commensal microbiota interactions in the ileum. In addition, the three fibre types consistently inhibited the inflammatory T helper (Th) cell response in the ileum, while they diversely modulated the peripheral and systemic Th cell responses. Overall, the prebiotic fibres displayed microbiota-related changes in endotoxemic mice, and the potential associations with the in vivo anti-inflammatory effects of prebiotic fibres need further investigation.
研究领域:
胃肠病学
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免疫学
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微生物学
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营养学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2022
·
IF 5.307
Wenda Zhu,Yiping Fan,Yanbing Li,Lizhi Peng,Yifang Li,Fengxia Yan,Jiaqiang Zhao,Lei Zhang,Hiroshi Kurihara,Rongrong He,Heru Chen
Eight hybrids of amantadine ( ATD ) with a natural modulator gardenamide A ( GA ) via an alkylene carbonyl bridge or alkylene bridge have been designed and synthesized. Evaluated by electrophysiological assay, compound 5b was confirmed an enhanced NMDAR antagonist compared to ATD with IC 50 value of 10.2 ± 1.2 μM. 5b has been demonstrated to reverse the damages of behavioral performance, the loss of dopaminergic neurons, the reduction of TH positive, and the increase of α-synuclein in both MPTP-treated mice and zebrafish models. In both ethological and ecological experiments, the activity of 5b was confirmed better than ATD or ATD/GA combination, and was almost equal to the positive selegiline. In vivo and in vitro , 5b is shown to reverse the ascend of NR1 and i- NOS levels. This candidate was also demonstrated the activity to down-regulated MPTP-increased Ca 2+ influx in SH-SY5Y cells in a steep and sharp mode. It is displayed that 5b exerts neuroprotective effect partly by activating the PI3K/Akt signaling pathway. Taken all together, our data support that 5b is a more promising agent against PD than ATD .
研究领域:
药理学
·
神经科学
·
药物设计
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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