CELL BIOLOGY INTERNATIONAL
·
2018
·Vol. 42
·期 11
·1584-1593
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IF 1.936
Bo Yu,Yanan Zhao,Hongli Zhang,Di Xie,Wei Nie,Kaiyao Shi
MicroRNA-143-3p (miR-143-3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR-143-3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H 2 O 2 administration in vitro. The expression status of miR-143-3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR-143-3p inhibition on H 2 O 2 -induced changes in ERK5/PPARδ/NF-κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR-143-3p and p-ERK5. However, the up-regulated expression of miR-143-3p had no effect on the expression of ERK5, which was a direct target of miR-143-3p. The results of in vitro assays showed that H 2 O 2 administration increased the levels of miR-143-3p and p-EKR5 and induced the activation of NF-κB pathway. After the inhibition of miR-143-3p, the activation of EKR5 and NF-κB pathway was suppressed, whereas the expression of PPARδ was up-regulated. The current study demonstrated that miR-143-3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR-143-3p up-regulation appears to be a complementary response to induce the subsequent anti-inflammatory signaling transduction, which needed further exploration.
研究领域:
心血管疾病
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分子生物学
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炎症
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Xizhi Li,Tingting Zhou,Yixi Wu,Jiayi Sun,Ziyu Wang,Yuhan Huang,Ke Xu,Hongwei Ling,Na Li,Tingting Yang,Tao Wang
Exenatide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA), exerted multiple beneficial effects, including stimulating insulin secretion, slowing gastric emptying, and improving insulin resistance (IR). Our previous work demonstrated that the peroxisome proliferator-activated receptor delta (PPARδ) gene ( PPARD ) polymorphisms correlated with exenatide monotherapy efficacy, possibly due to the pivotal role of PPARδ in regulating IR. Specifically, PPARδ has been shown to modulate the nucleotide-binding domain and leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of pyroptosis, thereby participating in the regulation of this inflammatory cell death pathway. However, the underlying mechanisms by which exenatide ameliorated hepatic IR in patients with type 2 Diabetes Mellitus (T2DM) remained incompletely understood. Herein, we found that exenatide suppressed pyroptosis and ameliorated hepatic IR; furthermore, it could bind to PPARδ and upregulate PPARδ protein expression both in vitro and in vivo. Notably, PPARδ knockdown abolished the protective effects of exenatide against pyroptosis and hepatic IR, whereas pharmacological activation of PPARδ enhanced these beneficial effects. Moreover, T2DM patients carrying the AA genotype at PPARD rs3777744 and exhibiting higher baseline homeostasis model assessment of insulin resistance (HOMA-IR) showed a superior response to exenatide. Collectively, our findings revealed that exenatide ameliorated hepatic IR by suppressing pyroptosis via PPARδ, underscoring the potential of PPARD rs3777744 as a biomarker for personalized exenatide therapy in T2DM.
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Zhao Mengfei,Zhang Jichuan,Guan Meng,Li Xuanhan,Sun Huating,Mao Kuirong,Tan Huizhu,Zhang Yijia,Meng Xandi,Cong Xiuxiu,Xin Yanbao,Wang Haorui,Yu MeiLing,Chen Si,Zhou Hongxv,Wang Xinhe,Yang Yong-Guang,Sun Tianmeng,Zhang Yuning
Immune checkpoint blockade (ICB) remains limited by the immunosuppressive tumor microenvironment (TME) and by the difficulty of coordinating therapeutic agents that act in distinct tumor compartments. In particular, checkpoint antibodies must function in the tumor stroma, whereas TME-remodeling small molecules often require intracellular access, creating an extracellular–intracellular delivery mismatch that conventional carriers rarely resolve. Here, we develop an acid-gated, esterase-amplified AND-gated dendritic nanogel (DNG) for the spatiotemporally sequential codelivery of anti-PD-1 antibody (aPD-1) and the PPARδ antagonist GSK3787. The DNG comprises a PEG corona for reversible aPD-1 adsorption and a hydrophobic dendritic core for GSK3787 encapsulation. Under the combined cues of tumor acidity and esterase activity, the nanogel undergoes progressive dissociation, triggering preferential extracellular release of aPD-1 in the tumor stroma, followed by tumor-cell internalization of the GSK3787-loaded core for intracellular drug action. This AND-gated design enables spatially resolved pharmacology rather than simple codelivery. In a melanoma model, DNG@(GSK3787 + aPD-1) markedly enhances antitumor efficacy, thereby promotes CD8⁺ T cell infiltration, and elicits systemic antitumor immune responses. Mechanistically, we identify a tumor cell-centric mode of immune remodeling and further show that the dendritic core actively governs not only small-molecule encapsulation, but also antibody retention and triggered release. Together, this work establishes a materials strategy for overcoming extracellular–intracellular delivery mismatch in combination immunotherapy. Graphical AND-gated dual-responsive nanogel enables spatiotemporally sequential extracellular delivery of aPD-1 and intracellular delivery of GSK3787, thereby overcoming the extracellular–intracellular delivery mismatch and synergistically remodeling the tumor immune microenvironment for enhanced cancer immunotherapy.
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高影响因子
MICROCIRCULATION
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2020
·Vol. 28
·期 4
·e12675
·
IF 2.11
Qingbo Shao,Jing Xia,Pinwen Wu,Jiazhou Ying
Background Dexmedetomidine (Dex) exerts an effective therapeutic role in numerous diseases associated with ischemia/reperfusion (I/R) injury via its anti‑apoptosis properties. Therefore, this study explores the cardioprotective effects of Dex in cardiac microvascular endothelial cells (CMECs) in response to oxygen-glucose deprivation and re-oxygenation (OGD/R) injury and its potential mechanism. Material and methods CMECs were pretreatment with different concentration of Dex, then exposed to OGD/R. Cell viability was measured with CCK-8 assay. Apoptosis was evaluated by flow cytometry, and apoptosis-related protein was determined by Western blot. Autophagy was assessed by transmission electron microscopy and autophagy-related proteins. Besides, the role peroxisome proliferator-activated receptors (PPARδ) in Dex-mediated anti-apoptosis property was validated with agonist and antagonist. Results OGD/R significantly decreased cell viability, increased reactive oxygen species, caused disorder of autophagy, and increased apoptosis in CMECs. Dex enhanced the viability of the OGD/R-treated CMECs and effectively decreased reactive oxygen species production. Autophagy in CMECs was activated by Dex, as evidenced by the increase in the ratio of LC3B-II/I, expression level of Beclin1 and number of autophagosomes in the OGD/R-induced CMECs. The mechanistic investigation indicated that PPARδ antagonist GW501516 aggravated cell damage following OGD/R, while PPARδ agonist GW6471 partly abolished the Dex-mediated protective effects. Conclusions Dex activated the PPARδ-AMPK-PGC-1α pathway-mediated autophagy in CMECs, therefore to inhibit excessive apoptosis induced by OGD/R. Dex may potentially be a therapeutic intervention for myocardial I/R injury.
研究领域:
心脏病学
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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
NEUROTOXICITY RESEARCH
·
2016
·Vol. 31
·期 2
·259-268
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IF 3.14
Zhang Yaqiong,Gao Lingyue,Cheng Zhihua,Cai Jiayi,Niu Yixuan,Meng Weihong,Zhao Qingchun
Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30 Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20 mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1β, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.
研究领域:
神经科学
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放射生物学
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药理学
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 9
·5168-5184
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IF 4.486
Huan Nie,Yuanjun Deng,Chuiyang Zheng,Maoxing Pan,Jiqian Xie,Yupei Zhang,Qinhe Yang
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is still not fully understood, and currently, no effective pharmacotherapy is available. Nuclear receptors (NRs) are important biological participants in NAFLD that exhibit great therapeutic potential. Chaihu Shugan powder (CSP) is a traditional Chinese medicine (TCM) formula that has a wide therapeutic spectrum including NAFLD, but the effective components and functional mechanisms of CSP are unclear. We adopted a network pharmacology approach using multiple databases for Gene Ontology (GO) enrichment analysis and the molecular complex detection (MCODE) method for a protein-protein interaction (PPI) analysis, and we used molecular docking method to screen the NR targets and determine the corresponding CSP components. The screening results were validated through a NAFLD rat model that was used to explain the possible relationship between CSP and NAFLD. Finally, we screened PPARγ, FXR, PPARα, RARα and PPARδ as target genes and quercetin , kaempferol , naringenin , isorhamnetin and nobiletin as target compounds. The five components were detected through high-performance liquid chromatography-mass spectrometry (HPLC-MS), the results of which aligned with the docking experiments of PPARγ, PPARα and PPARδ. After CSP intervention, the NAFLD rat model showed ameliorated effects in terms of bodyweight, hepatic histopathology, and serum and liver lipids, and the mRNA levels of PPARγ, FXR, PPARα and RARα were significantly changed. The results from this study indicate that CSP exhibits healing effects in an NAFLD model and that the network pharmacology approach to screening NR targets and determining the corresponding CSP components is a practical strategy for explaining the mechanism by which CSP ameliorates NAFLD.
研究领域:
药理学
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中药学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
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