NEUROCHEMICAL RESEARCH
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2019
·Vol. 44
·期 12
·2821-2831
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IF 2.782
Zhai Ailing,Zhang Zeng,Kong Xiangjuan
Paeoniflorin (PF) has been reported to possess neuroprotective influences on cognitive dysfunction illness. In current research, we attempted to probe into the protective influences of PF against H 2 O 2 -induced damage and the underlying regulating mechanisms on hippocampal HT-22 cells. HT-22 cells were pretreated with PF, and then induced by H 2 O 2 . Afterwards, the influences of PF pretreatment were examined using CCK-8 assay, apoptosis assay, western blot and ROS assay, respectively. In addition, the expression of microRNA-135a (miR-135a) was analyzed and altered by qRT-PCR and cell transfection, respectively. After overexpression of miR-135a, the effects of miR-135a mimic on cell functions were detected again. Moreover, influences of H 2 O 2 , PF and miR-135a overexpression on JAK2/STAT3 and ERK1/2 signal pathways were further investigated. Further experiments verified that PF pretreatment alleviated H 2 O 2 -induced oxidative stress through increasing cell viability, inhibiting cell apoptosis, reducing ROS generation and activating JAK2/STAT3 and ERK1/2 pathways. Besides, expression of miR-135a was declined by PF pretreatment. Whereas, miR-135a mimic abrogated the protective effects triggered by PF pretreatment. These results indicated that PF can alleviate H 2 O 2 -induced oxidative stress by down-regulation of miR-135a via activation of JAK2/STAT3 and ERK1/2 pathways.
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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高影响因子
TISSUE & CELL
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2025
·
IF 2.5
Minhui Wang,Daojun Chen,Daofa Zhang,Hui Han,Maowei Xie,Ying Zhang,Yun Cao,Jiali Wei
Background Renal fibrosis (RF) is a common histopathological feature of chronic kidney disease (CKD) and is closely associated with persistent inflammation and regulated cell death. However, the underlying molecular mechanisms of pyroptosis in RF are unclear. Methods Pyroptosis-related hub genes in RF were identified through bioinformatics analysis. Granzyme B ( GZMB ) was knocked down in transforming growth factor (TGF-β)-stimulated HK-2 cells and in a folic acid (FA)-induced nephropathy mouse model. Western blot and enzyme-linked immunosorbent assays were performed to detect the expression of fibrosis and pyroptosis-related markers. Cell viability was assessed by the Cell Counting Kit-8 assay. Hematoxylin and eosin (HE) and Masson's staining were used to evaluate tubular injury and collagen deposition in renal tissues. Results GZMB was identified as a pyroptosis-associated hub gene. It was significantly upregulated in RF and exhibited high diagnostic performance. In TGF-β-stimulated HK-2 cells, GZMB knockdown enhanced cell viability and reduced lactate dehydrogenase release. In vivo , GZMB silencing ameliorated tubular injury, reduced collagen deposition, and improved renal function. The expression levels of pyroptosis-related proteins, including the N-terminal fragment of gasdermin D, cleaved caspase-1, and NOD-like receptor family pyrin domain containing 3 (NLRP3), as well as fibrotic markers alpha-smooth muscle actin and collagen type I, were downregulated after GZMB knockdown. Mechanically, GZMB knockdown inhibited NLRP3 inflammasome activation and suppressed the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Conclusion GZMB deficiency inhibits pyroptosis and dampens the JAK2/STAT3 pathway, representing a potential approach for RF treatment.
研究领域:
肾脏病学
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分子生物学
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细胞信号传导
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炎症
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纤维化研究
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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
·
IF 6.5
Xueling He,Ting Zhang,Xueting Chen,Jianying Feng,Wenjie Xu,Zhiyong Li,Kunpeng Qiu,Huiqi Wang,Jianjun Zhang
Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis characterized by uncontrolled neuroinflammation. Dehydrocostus lactone (DL), a bioactive sesquiterpene lactone derived from Aucklandia lappa Decne., exhibits anti-inflammatory properties; however, its molecular targets in SAE remain unclear. Here, we investigated the protective effects and target mechanism of DL on CLP-induced septic mice and LPS-stimulated BV2 microglia. DL improved survival, attenuated brain injury, reduced inflammatory cytokine production, and restored microglial polarization homeostasis. Transcriptomic analysis revealed significant regulation of inflammatory pathways following DL treatment, while thermal proteome profiling (TPP) coupled with DIA-MS identified JAK2 as a candidate target of DL. Further validation by CETSA, SPR, molecular docking, and molecular dynamics simulations confirmed direct DL–JAK2 interaction. Mechanistically, DL suppressed JAK2 phosphorylation and downstream STAT3 activation, thereby inhibiting neuroinflammatory responses. These findings establish JAK2 as a direct pharmacological target of DL and support its potential as a candidate intervention for SAE-associated neuroinflammatory injury. Download: Download high-res image (144KB) Download: Download full-size image
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CARDIOVASCULAR RESEARCH
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2025
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IF 13.3
Zhang Huawei,Liu Jing,Sun Daqian,Liu Yuxiu,Sun Wenhao,Wang Shanshan,Xu Xiuqin
AimsVascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets.Methods and ResultsWe established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor (PDGF)-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or Nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling.ConclusionsThis study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Liu Yang,Wang Duan,Zheng Wenqian,Wang Yuxuan,Wang Peiyu,Zhao Yuping,Liu Xiaofan,Shi Yaru,Wang Yi,Zhou Na,González Fermín E.,Sun Hongchen,Zhou Ding,Xu Xiaowei
Dysregulation of the JAK2/STAT3 pathway disrupts immune balance and tissue homeostasis, leading to persistent inflammation and subsequent bone loss. Yet, commonly used JAK2 inhibitors with hydrophobicity primarily suppress inflammation but often fail to provide sustained pharmacological effects and address ongoing inflammation-induced bone destruction. Here, using computer-aided drug design, we developed hydrophilic calcium-doped carbon dots (Ca-CDs) as a multifunctional nanoinhibitor targeting JAK2. The Ca-CDs can block the excessive activation of the JAK2/STAT3 pathway by binding to JAK2, thereby reducing the secretion of pro-inflammatory cytokines and exerting anti-inflammatory effects. Furthermore, the Ca-CDs promote bone regeneration under inflammatory conditions and serve as crosslinking junctions that facilitate the formation of a Ca-CDs-based alginate hydrogel, thereby enabling prolonged drug retention and controlled release. Their application in the representative inflammatory microenvironment of periodontitis successfully validated the efficacy of the Ca-CDs-based therapeutic strategy. Overall, targeting JAK2 with Ca-CDs nanoinhibitor offers a promising treatment option for JAK2-associated inflammatory diseases.Graphical
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BIOORGANIC & MEDICINAL CHEMISTRY
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2023
·
IF 3.5
Wenbin Wang,Shiyang Zhou,Wenming Jiang,Guangying Chen
A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro , compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC 50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.
研究领域:
免疫学
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药理学
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医学
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FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
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2025
·
IF 2.2
Jianuo Li,Yuhuai Guo,Xiangxin Zeng,Hongzhao Tian,Yapeng Han,Shuo Cai,Min Sun
Introduction. The aberrant activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway is involved in spinal cord injury (SCI) progression. Electroacupuncture (EA) stimulation is effective in alleviating SCI, but the mechanism is poorly understood. Material and methods. An SCI model was constructed by cord contusion at T10, and AG490 (a JAK2 inhibitor) served as a positive control in this study. We evaluated the effects of EA on locomotor activity and spinal damage in SCI rats. The effects of EA on astrocytes and microglia and on the JAK2/STAT3 signalling pathway in the cells were investigated. Results. Behavioural tests showed that hind limb motor function of rats was improved after EA stimulation. The therapeutic effects of EA stimulation in restoring motor function, alleviating injured spinal cords, and inhibiting spinal cord neuronal apoptosis in SCI rats, were similar to those of AG490. Increased STAT3 activation was observed in astrocytes and microglia in the spinal cord of SCI rats, and this was reversed by EA stimulation. EA alleviated astrogliosis and inhibited microglia M1 polarisation in SCI rat spinal cords. In addition, RNA expression levels of pro-inflammatory factors IL-6, CXCL1, and TNF-α in rat spinal cords were suppressed by EA stimulation, while the expression level of the anti-inflammatory factor heme oxygenase 1 was increased. Meanwhile, the expression of p-JAK2, p-STAT3, and JAK2/STAT3 downstream targets SOCS3 and COX-2 in the spinal cord of SCI rats was inhibited by EA stimulation. Interestingly, the observed effects were comparable to those treated with EA. Conclusions. Our findings demonstrate that EA stimulation ameliorates SCI in rats and exerts an inhibitory effect on the JAK2/STAT3 signalling pathway.
研究领域:
神经科学
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医学
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PubMed
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Advanced Healthcare Materials
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2026
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IF 11
Jiahui Wang,Wanxin Hou,Xiuxiu Qiu,Yu Zhang,Li Tao,Yukun Chen,Beibei Hong,Lei Zhou,Hegen Li,Zhanxia Zhang
Lung cancer metastasis is the primary cause of patient mortality, underscoring an urgent need for highly effective and low-toxicity therapies. Ursolic acid (UA), a natural triterpenoid, possesses potent antitumor activity, yet its clinical translation has been hindered by poor water solubility, low bioavailability, and nonspecific distribution. To overcome these limitations, we developed a UA-loaded iron-based metal–organic framework (MOF) nanomedicine, termed Ursolic Acid-loaded Iron-MOF (UA@MOF). Harnessing the high surface area and tunable porosity of MOFs, this system enables efficient UA encapsulation and promotes tumor-targeted delivery through the enhanced permeability and retention (EPR) effect. Once internalized, UA suppresses the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway, while iron ions released from the MOF induce ferroptosis in tumor cells via Fenton reactions. Together, these dual mechanisms act synergistically to inhibit tumor growth and metastasis. This work presents a novel strategy to improve the delivery and efficacy of natural antitumor agents, offering promising potential for the treatment of metastatic lung cancer.
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Journal of Functional Foods
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2020
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IF 3.701
Liu Tang,Xiaolei Li,Liping Wan,Huiling Wang,Qianting Mai,Zixin Deng,Hong Ding
The present research was designed to evaluate the protective effects and underlying mechanisms of different ratios of linoleic acid (LA) and α-linolenic acid (ALA), two essential polyunsaturated fatty acids (PUFAs) fatty acids, on atopic dermatitis (AD)-like skin lesions induced by 2, 4-dinitrofluorobenzene (DNFB). The dorsal flank and ear pinnas of mice were sensitized and challenged with DNFB for four weeks in order to establish AD model. Simultaneously, the mice were orally administered different ratios of LA/ALA (v/v; 4:1 or 1:1), or dexamethasone (Dex; 0.1 mg/kg). Results showed that different LA/ALA ratios, especially a ratio of 4:1 treatment, could effectively ameliorate DNFB-induced skin lesions, ear edema, scratching behavior and skin inflammation, as reflected by the reduced inflammatory blood cells, IgE serum levels, and skin levels of the pro-inflammatory lipid mediators, including PGE 2 and LTB 4 . These findings were further confirmed by skin pathological examination. Moreover, LA/ALA administration markedly suppressed the proliferation and infiltration of T cells, the production of T helper cell type 1 (Th1), Th2 and Th17 cytokines in dorsal skin and serum of DNFB-treated mice. Western blotting and immunohistochemistry staining revealed that LA/ALA downregulated the protein expressions of JAK2 and STAT4, and thus reducing the synthesis of type Th1 cytokine IFN-γ. Taken together, these results suggest that optimal nutrition ratio of LA/ALA has beneficial effects on AD-like symptoms, which provide theoretical basis for its therapeutic potential in the clinical prevention and treatment of AD.
研究领域:
免疫学
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营养学
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皮肤病学
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高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
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2025
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IF 4.2
Daermu Qumu,Mu Tian,Hengxi Li,Xiujuan Yang,Binhui Han,Lanting Wei,Bo Li,Mengxue Ma,Junjie He,Xiaoni Shao
Galangin (GAL), a flavonol found in Alpinia officinarum and propolis, is a promising functional food. This study investigated the therapeutic effects and mechanisms of GAL in mice with hyperuricemic nephropathy (HN) by focusing on renal metabolomics and network pharmacology. In this study, we conducted untargeted metabolomic analysis and network pharmacology prediction. Subsequently, a compound-reaction-enzyme-gene network was constructed based on the results of metabolomics and network pharmacology to elucidate potential connections. The results demonstrated that GAL can improve renal interstitial fibrosis and inflammatory infiltration and reduce serum levels of uric acid (UA), urea nitrogen (UREA), and creatinine (CREA). Metabolome analysis indicated that GAL affected thiamine, pyrimidine, nicotinate, nicotinamide, pyruvate, glyoxylate, and dicarboxylate metabolism. Network pharmacology and experimental results showed that GAL reduced the key target expression of the tumor protein P53 (TP53), tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), heat shock protein 90 alpha family class A member 1 (HSP90aa1), albumin (ALB), and caspase-3 (CASP3). GAL also downregulated the expression of Janus kinase 2 (JAK2), phospho-JAK2 (P-JAK2), and phospho-STAT3 (P-STAT3). Furthermore, a joint analysis of the metabolome and network pharmacology showed that GAL can reverse HN through amino acid metabolism, nucleotide metabolism, energy metabolism, and endocrine system pathways. GAL can alleviate HN effectively and might play synergistic therapeutic roles through regulating metabolic profiles and the JAK2/STAT3 signaling pathway.
研究领域:
医学
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药理学
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代谢组学
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高影响因子
Indian Journal of Hematology and Blood Transfusion
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2024
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IF 0.7
Liu Xiaoyu,Yang Lin,Guan Kunping,Chen Zhen,Yang Hua
Purpose This study aims to investigate the increased toxicity of Cytarabine (Ara-c) by knockdown of chromosome segregation 1-like (CSE1L) in acute myeloid leukemia(AML) cells(Kasumi-1, U937, and THP-1 cells) and to explore its possible mechanisms. Methods Target gene silencing was achieved using the shRNA-mediated lentivirus method. Apoptosis was identified using the Annexin V PE/7-AAD double-staining assay. Cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay. Protein expression was detected by Western blotting. Results In vitro, knocking down CSE1L promoted caspase-3 and caspase-9 proteins expression and induced apoptosis in AML cells. Knockdown of CSE1L enhanced AML cells' sensitivity to Ara-c. knockdown of CSE1L reduced the expression levels of p-JKA2 and p-STAT3 proteins, while no significant difference was observed in the expression levels of total JAK2 and STAT3 proteins. Furthermore, JAK2 overexpression reversed the increase in Ara-c toxicity to AML cells caused by CSE1L knockdown. Conclusion In conclusion, our study reveals that CSE1L is a potential therapeutic target for overcoming Ara-c resistance in AML cells. Thus, we have gained new insights into the oncogenic process of CSE1L in AML cells and raised the prospect of knockdown of CSE1L in AML in combination with cytarabine-targeted therapy.
研究领域:
肿瘤学
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血液学
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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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JOURNAL OF MEDICINAL CHEMISTRY
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2026
·
IF 7.3
Qian Jianqiang,Wang Rong,Lei Weihua,Lai Jingyi,Li You,Shi Wei,Pan Mingshi,Cui Jiamin,Wang Zihao,Zhang Xiaoqi,Ye Wencai,Xiong Fei,Hu Xiaolong,Wang Hao
Chemotherapy-induced
myelosuppression (CIM) significantly impairs
hematopoiesis. Proanthocyanidin A1 ( 1 ) from peanut skin
is a JAK2 activator to alleviate CIM, but the SAR and drug-like properties
of Type-A proanthocyanidins remain unclear. Here, a series of Type-A
proanthocyanidin derivatives ( 5–35 ) were designed,
synthesized, and evaluated for JAK2 activation, leading to the identification
of compound 32 as the most potent activator (EC 50 = 64 nM). Target-binding assays demonstrated that 32 directly bound JAK2 and displayed preferential affinity for the
JH2 pseudokinase domain over the JH1 catalytic domain, indicating
a potential JH2-mediated activation mechanism. In primary BMHSCs, 32 activated the JAK2/STAT3 pathway and alleviated carboplatin-induced
damage. Consistently, oral administration of 32 at 50
mg/kg activated JAK2/STAT3 signaling in vivo and promoted hematopoietic
recovery in CIM mice, with favorable bioavailability and acceptable
preliminary safety. These findings identify 32 as a promising
orally available JAK2 activator for CIM treatment.
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