INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Wenyao Yang,Juanzhu Han,Liping Zhang,Yunsong Sun,Yuchen Zhu,Yiyu Liu,Jingyu Chen,Xiaoyao Liao,Hui Liao,Weizhuo Xu,Yongbo Song
Skeletal muscle inflammation associated with sepsis has been identified as a critical pathological process contributing to metabolic dysfunction and poor clinical outcomes. Voltage-gated sodium channels (VGSCs) have been implicated in immune modulation; however, their specific roles in skeletal muscle inflammation remain poorly understood. In this study, the VGSC subtype Nav1.5 was investigated as a potential regulator of inflammation, and the therapeutic efficacy of a novel recombinant scorpion peptide, DKK678, was evaluated. An in vitro model using lipopolysaccharide (LPS)-stimulated C2C12 cells and an in vivo cecal ligation and puncture (CLP) model in septic mice were established. In both models, Nav1.5 expression was significantly upregulated in response to inflammatory stimuli, while Nav1.4 expression remained unchanged. The nuclear factor kappa B (NF-κB) signaling pathway was found to be activated, contributing to increased expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adhesion molecules (VCAM-1), and gap junction proteins (Cx43). Suppression of VGSC activity using lidocaine resulted in the inhibition of NF-κB phosphorylation and downregulation of inflammatory markers, while the expression of interleukin-10 (IL-10) and interleukin-4 (IL-4) were restored. Tetrodotoxin (TTX) treatment did not replicate these effects, suggesting Nav1.5-specific involvement. DKK678 was developed through bioinformatic design and molecular docking simulations, which predicted a stronger binding affinity and structural stability with Nav1.5 compared to Nav1.4. These predictions were validated through functional experiments. In vitro, DKK678 treatment dose-dependently inhibited LPS-induced NF-κB pathway activation and reversed abnormal expression of VCAM-1 and Cx43. In vivo, DKK678 significantly ameliorated CLP-induced skeletal muscle damage, suppressed inflammatory cytokine production, and improved tissue histopathology. Furthermore, the structural integrity of immune organs such as the thymus and spleen was preserved in DKK678-treated septic mice, with partial restoration of lymphocyte populations and organ indices. Notably, Nav1.5 expression was downregulated by DKK678, while Nav1.4 expression remained unaffected. These results demonstrate that Nav1.5 serves as a critical inflammatory modulator in skeletal muscle and immune tissues. Its upregulation was shown to drive NF-κB pathway activation and inflammatory cytokine production. By targeting Nav1.5, DKK678 was able to exert dual protective effects on both skeletal muscle and immune organs under septic conditions. The therapeutic potential of DKK678 was found to be comparable to that of dexamethasone (DEX) at high doses, without altering Nav1.4 expression. In conclusion, the present study provides new mechanistic insight into the role of Nav1.5 in skeletal muscle inflammation and identifies DKK678 as a promising peptide therapeutic that targets Nav1.5 to suppress NF-κB-mediated inflammatory injury. These findings suggest that Nav1.5 inhibition represents a viable strategy for the treatment of sepsis-associated myositis and related inflammatory disorders.
研究领域:
免疫学
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药理学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2021
·Vol. 10
·期 9
·1333
·
IF 6.313
Mengyuan Fang,Tingfeng Zou,Xiaoxiao Yang,Zhen Zhang,Peichang Cao,Jihong Han,Yajun Duan,Ban-Feng Ruan,Qing-Shan Li
Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (PIF_1–PIF_16) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure–activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound,PIF_9, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover,PIF_9also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together,PIF_9was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB.Keywords:antioxidants;anti-inflammatory agents;indanone;pterostilbene;sepsis
研究领域:
药理学
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传染病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
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2013
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IF 1.206
Cheng Yang,Keng Wu,Shang-Hai Li,Qiong You
Context: The heart is one of the target organs susceptible to attack by sepsis, and protection of the cardiac function in sepsis or alleviation dysfunction caused by sepsis appears a serious and urgent problem.Objective: This study was designed to explore the effect of curcumin on myocardial injury induced by sepsis and to explore the therapeutic effect of curcumin in managing sepsis induced cardiac dysfunction.Methods: Cecal ligation and puncture surgery were used to establish the sepsis model. Curcumin was administered by peritoneal injection (200 mg/kg/d, 3 days). The effects of curcumin on the cardiac functions [Ejection Fraction (EF), Fractional Shortening (FS), Cardiac Output (CO), Heart Rate (HR)], body temperature, cTn I and superoxide dismutase levels, malondialdehyde content (an index of lipid peroxidation), and myocardial histopathological and ultrastructural studies were carried out.Results: We demonstrated that treatment of rats with curcumin significantly decreased elevated levels of cTn I and MDA (p < 0.05) in plasma, and increase the levels of SOD (p < 0.05) after CLP. Moreover, curcumin markedly enhanced the myocardial contractility by increasing the decreased EF and FS in rats with sepsis induced by CLP (p < 0.05). In addition, curcumin could alleviate the myocardial inflammation and structure damage of myocardial cells in sepsis induced by CLP.Conclusion: In conclusion, the results from the present study demonstrate that curcumin has the protective effects on cardiac function in rats with sepsis and curcumin could be considered as an effective and safe therapeutic agent for the management of sepsis induced cardiac dysfunction.
研究领域:
医学
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药理学
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病理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2023
·Vol. 28
·期 7
·145
·
IF 3.1
Cheng Chen,Xiaoxiao Meng,Yong Zhu,Jiaxiang Zhang,Ruilan Wang
Background: Early identification of sepsis improves the survival rate; however, it is one of the most challenging tasks for physicians, especially since symptoms are easily confused with those of systemic inflammatory response syndrome (SIRS). Our aim was to explore biomarkers for early identification of sepsis that would aid in its differential diagnosis. Methods: Eight patients with SIRS, eight with sepsis, and eight healthy controls were included in this study. Metabolites were screened using gas chromatography-mass spectrometry (GC-MS). Metabolism profiles were analyzed using the untargeted database of GC-MS from Lumingbio (LUG) database, and metabolic pathways were enriched based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The S-plot was used to screen the potential biomarkers distinguishing between patients with SIRS, sepsis, and healthy controls. Receiver operating characteristic (ROC) curve analysis was used to evaluate potential biomarkers between SIRS and sepsis patients. Correlation analysis was used to measure the degree of correlation between differential metabolites. Correlation analysis between 2-deoxy-d-erythro-pentofuranose-5-phosphate and clinical indicators was performed. Results: There were 51 metabolites that were distributed in the SIRS group, and they were enriched with 18 metabolic pathways compared with healthy controls. Moreover, 63 metabolites in the sepsis group were significantly distinguishable compared to the healthy controls, and were associated with 21 metabolic pathways. Methyl 3-o-acetyl-d-galactopyranoside and N-acetylputrescine were found to be candidate biomarkers for distinguishing between SIRS, sepsis, and healthy controls using the S-plot model. Only four differential metabolites, including 2-deoxy-d-erythro-pentofuranose-5-phosphate, terbutaline, allantoic acid, and homovanillic acid (HVA), were enriched in the dopaminergic synapse and tyrosine metabolism pathways when sepsis patients were compared with SIRS patients. The Area Under Curve (AUC) of 2-deoxy-d-erythro-pentofuranose-5-phosphate was 0.9297, indicating a strong diagnostic ability for sepsis. A significant negative correlation was identified between 2-deoxy-d-erythro-pentofuranose-5-phosphate and lactate (r = –0.8756, p = 0.0044). Conclusions: Methyl 3-o-acetyl-d-galactopyranoside and N-acetylputrescine may be used as candidate biomarkers to distinguish SIRS and sepsis patients from healthy controls using GC-MS. 2-deoxy-d-erythro-pentofuranose-5-phosphate may be the candidate biomarker to distinguish sepsis from SIRS. Our study explored candidate biomarkers for the early identification of sepsis, which is vital for improving its prognosis.
研究领域:
医学
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代谢组学
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临床诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Qiang Li,Linmao Ke,Dandan Yu,Han Xu,Zixuan Zhang,Rilei Yu,Tao Jiang,Yue-Wei Guo,Mingzhi Su,Xin Jin
Mitogen-activated protein kinase-interacting protein kinases (MNKs) and phosphorylate eukaryotic initiation factor 4E (p-eIF4E) play a critical role in regulating mRNA translation and protein synthesis associated with the development of cancer, metabolism, and inflammation. This study undertakes the modification of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine structure, leading to the discovery of 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (D25) as a potent and selective MNK inhibitor. D25 demonstrated inhibitory activity, with IC50 values of 120.6 nM for MNK1 and 134.7 nM for MNK2, showing exceptional selectivity. D25 inhibited the expression of pro-inflammation cytokines in RAW264.7 cells, such as inducible NO synthase, cyclooxygenase-2, and interleukin-6 (IL-6). In the lipopolysaccharide-induced sepsis mouse model, D25 significantly reduced p-eIF4E in spleen tissue and decreased the expression of tumor necrosis factor α, interleukin-1β, and IL-6, and it also reduced the production of reactive oxygen species, resulting in improved organ injury caused by inflammation. This suggests that D25 may provide a potential treatment for sepsis and sepsis-associated acute spleen injury.
研究领域:
药理学
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免疫学
·
传染病
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale
·
2025
·
IF 5.1
Bin Lu,Kun Zhang,Qingrong Dong,Lan Wei,Jia Shi,Fang Liu,Taigang Liang,Jiangfeng Du
Sepsis is a heterogeneous disease with high morbidity and mortality due to the limited therapeutic. Calycosin (CA), one of the main active ingredients of Astragalus, can potentially treat sepsis, but its therapeutic effect is limited by low blood circulation concentration and poor bioavailability. To address this challenge, we have successfully prepared BSA@Se-CA nanocomposite system （BSC） through self-assembly loading calycosin (CA) onto BSA@Se nanoparticles (BS). Compared to CA, BSC enhances the scavenging of ROS more effectively than CA alone by enhancing the activity of glutathione peroxidase (GPX). Notably, BSC reducing the expression level of inflammatory factors (NO, IL-6, IL-1β, and TNF-α) in inflammatory macrophages by synergistically inhibit the NF-κB signaling pathway. Moreover, the in vitro experiments demonstrated that BSC can also effectively alleviate RAW264.7 cells and HUVEC cells damage caused by oxidative stress, which can maintain the normal cells physiological function. In vivo, BSC exhibit significantly improve the therapeutic effect of sepsis by intraperitoneal injection, such as increase the survival rate of sepsis mice, and alleviate normal organ damage. Thus, this study provides a new strategy for improving the utilization efficiency of natural products with poor treatment effect and provides a reference for improving the therapeutic effect of sepsis.
研究领域:
药理学
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纳米医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2025
·
IF 7.5
Yunqiu Chen,Jiayun Ying,Zhiyao Li,Zhen Ning Tony He,Jiani Zhan,Heng Liang,Yuying Liu,Yijia Chen,Xuewen Li,Ting Zhu,Chunxiang Kuang,Guoping Lu,Qing Yang
Indoleamine-2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in tryptophan (Trp) catabolism along kynurenine (Kyn) pathway. Increased IDO1 activity has been noticed in patients with sepsis, while IDO1’s involvement in sepsis, especially in the initial cytokine storm phase is not yet completely understood. Using the GEO database and clinical samples of sepsis, current study revealed that IDO1-AHR-CYP1A1 axis was significantly upregulated and closely related to cytokine storm in septic patients. With cell models of cytokine storm, it was found that IDO1 promoted cytokine storm and the apoptosis of model cells via AHR-CYP1A1, and IDO1-AHR-CYP1A1 axis correlated classic cytokine storm signal pathway including STAT3, NF-κB/STAT1, JNK/p38. With mouse models of septic cytokine storm, it was shown that IDO1 inhibitors could block the upregulated IDO1-AHR-CYP1A1 axis, reduce the enhanced inflammatory cytokine levels, decrease the phosphorylation of classic cytokine storm signal pathway, rescue organ damage, and increase survival rate. It was also found that IDO1 activation occurred after the increase of inflammatory cytokine levels. Therefore, classic cytokine storm signal pathways, inflammatory cytokines and IDO1-AHR-CYP1A1 axis form a tripartite interaction loop to promote cytokine storm. IDO1 inhibitors were able to block this process.
研究领域:
免疫学
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医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 4
·468
·
IF 6.6
Xin Zhang,Shuang Han,Zhu Zeng,Jie Dai,Yi Jia
Selenium-binding protein 1 (SELENBP1) has been implicated in cancer development, neurological disorders, tissue injury, metabolic regulation, and cell differentiation. Sepsis is characterized prominently by immunological dysregulation and severe organ damage. However, whether SELENBP1 improves sepsis by regulating immune cell activity remains unknown. Here, we detected an elevation of SELENBP1 levels in the blood of sepsis patients and in the livers of septic mice. Significantly, SELENBP1 knockout (KO) prolonged survival in septic mice. This phenomenon was accompanied by decreased liver damage, reduced inflammation levels, and an increased regulatory T cell/T helper 17 cell (Treg/Th17) ratio in the spleen. Additionally, SELENBP1 deficiency induced a redox imbalance and inhibited dendritic cell (DC) maturation, resulting in a tolerogenic DC (tolDC) phenotype and an increase in the Treg/Th17 ratio. Furthermore, SELENBP1-KO mature DCs (mDCs) alleviated liver injury by increasing the Treg/Th17 ratio in the spleen, thus improving the survival of septic mice. These findings indicate that SELENBP1 is involved in sepsis by regulating DC immune activity, which might provide a potential way for sepsis treatment.
研究领域:
免疫学
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医学
✓ 已验证
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Ye Hua,Wu Lin,Liu Yan-mei,Zhang Jun-xia,Hu Huan-tao,Dong Mao-long,Ren Jun
Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg −1 , i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg −1 ·d −1 , i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.
研究领域:
药理学
·
病理学
·
心血管医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2016
·Vol. 8
·期 7
·1577-1585
·
IF 1.915
Tao Liao,Fang Yuan,Haoyang Yu,Zigang Li
Sepsis is a potentially fatal systemic body infection with a significant mortality rate worldwide. Procalcitonin (PCT) is a sensitive and specific biomarker for sepsis diagnosis, however, the traditional immune-gold labeling detection of PCT is semi-quantitative with relatively low sensitivity (>0.1 ng mL−1). Recently proposed techniques (such as electrochemical immunosensor, microarray, and total internal reflection based methods) require either a complex sensor or sophisticated equipment. Herein, we report a magnetic bead and enzyme-antibody labeled gold nanoparticle based ELISA strategy for sensitive PCT detection. This developed assay is sensitive enough to detect PCT at 20 pg mL−1, efficient for the direct human serum test. Notably, this assay specifically distinguishes PCT from other sepsis markers and the whole assay takes only 1.5 hours to finish.
研究领域:
医学诊断
·
免疫学
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Chang Liu,Quan Zou,Huixin Tang,Jia Liu,Shiqi Zhang,Caihong Fan,Junwei Zhang,Ruiqing Liu,Yashan Liu,Ruiyan Liu,Yan Zhao,Qiang Wu,Zhi Qi,Yanna Shen
Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro , MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.
研究领域:
纳米技术
·
心脏病学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SHOCK
·
2023
·
IF 3.1
Zhang Dewen,He Jian,Ding Xian,Wang Rui,Chen Wei
Background We explored the efficacy and main biological mechanism of geniposide intervention in sepsis. Methods A sepsis model was established in male BALB/c mice through cecal ligation and puncture (CLP). Different doses of geniposide (20 or 40 mg/kg) were administered intravenously at 0 and/or 24 h after CLP surgery. The survival rate of different groups was observed. Additionally, the expression levels of CD16 and MHC-II in monocytes were assessed using flow cytometry. The concentration of TNF-α, IL-1β, IL-6, and IL-10 in the serum were measured by ELISA. We also observed the biological effects of geniposide on CD16 and MHC-II expression levels in RAW264.7 cells, as well as the secretion of TNF-α, IL-1β, IL-6, and IL-10, in the LPS-induced RAW264.7 cell model. The PPARγ levels were determined using western blot analysis. Results Intravenous administration of 40 mg/kg of geniposide at 0 h after CLP significantly improved the survival outcomes in the septic mouse model, with no significant benefits from low dosing (20 mg/kg) or delayed administration (24 h). The effective dose of geniposide significantly decreased the serum cytokine TNF-α, IL-1β, IL-6, and IL-10 concentrations in septic mice ( P < 0.05). Notably, in vitro assays showed that geniposide specifically increased the IL-10 level. Geniposide significantly reduced the CD16 expression ( P < 0.05) and increased MHC-II expression in monocytes ( P < 0.05). Additionally, geniposide elevated the PPARγ level in monocytes ( P < 0.05). Conclusions High-dose early-stage geniposide administration significantly improved the survival rate in a CLP mouse sepsis model by modulating the monocyte phenotype and regulating the cytokine network (IL-6/IL-10 levels). The pharmacological mechanism of geniposide action might be exerted primarily through PPARγ upregulation.
研究领域:
免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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