Drug Design Development and Therapy
·
2021
·
IF 4.162
Shuo Wang,Ping Zhao,Ying Zhang,Lianhua Zhu,Jianing Zhu,Yukun Luo,Qiuyang Li
Purpose Sepsis is the leading condition associated with acute kidney injury (AKI) in the hospital and intensive care unit (ICU), sepsis-induced AKI (S-AKI) is strongly associated with poor clinical outcomes. Curcumin possesses an ability to ameliorate renal injury from ischemia-reperfusion, but it is still unknown whether they have the ability to reduce S-AKI. The aim of this study was to investigate the protective effects of curcumin on S-AKI and to assess its therapeutic potential on renal function, inflammatory response, and microcirculatory perfusion.Methods Male Sprague-Dawley (SD) rats underwent cecal ligation and puncture (CLP) to induce S-AKI and immediately received vehicle (CLP group) or curcumin (CLP+Cur group) after surgery. At 12 and 24h after surgery, serum indexes, inflammatory factors, cardiac output (CO), renal blood flow and microcirculatory flow were measured.Results Serum levels of creatinine (Scr), cystatin C (CysC), IL-6 and TNF-α were significantly lower in the CLP+Cur group than those in the CLP group (P < 0.05). Treatment with curcumin improved renal microcirculation at 24h by measurement of contrast enhanced ultrasound (CEUS) quantitative parameters [peak intensity (PI); half of descending time (DT/2); area under curve (AUC); P < 0.05]. In histopathological analysis, treatment with curcumin reduced damage caused by CLP.Conclusion Curcumin can alleviate S-AKI in rats by improving renal microcirculatory perfusion and reducing inflammatory response. Curcumin may be a potential novel therapeutic agent for the prevention or reduction of S-AKI.
研究领域:
药理学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
·
2024
·
IF 3
Weike Hu
Sepsis represents an organ dysfunction resulting from the host’s maladjusted response to infection, and can give rise to acute kidney injury (AKI), which significantly increase the morbidity and mortality of septic patients. This study strived for identifying a novel therapeutic strategy for patients with sepsis-induced AKI (SI-AKI). Rat tubular epithelial NRK-52E cells were subjected to lipopolysaccharide (LPS) exposure for induction of in-vitro SI-AKI. The expressions of E1A binding protein p300 (EP300) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in NRK-52E cells were assessed by western blot and qRT-PCR, and their interaction was explored by chromatin immunoprecipitation performed with antibody for H3K27 acetylation (H3K27ac). The effect of them on SI-AKI-associated mitochondrial dysfunction of tubular epithelial cells was investigated using transfection, MTT assay, TUNEL staining, 2′,7′-Dichlorodihydrofluorescein diacetate probe assay, Mitosox assay, and JC-1 staining. MTHFD2 and EP300 were upregulated by LPS exposure in NRK-52E cells. LPS increased the acetylation of H3 histone in the MTHFD2 promoter region, and EP300 suppressed the effect of LPS. EP300 ablation inhibited the expression of MTHFD2. MTHFD2 overexpression antagonized LPS-induced viability reduction, apoptosis promotion, reactive oxygen species overproduction, and mitochondrial membrane potential collapse of NRK-52E cells. By contrast, MTHFD2 knockdown and EP300 ablation brought about opposite consequences. Furthermore, MTHFD2 overexpress and EP300 ablation counteracted each other’s effect in LPS-exposed NRK-52E cells. EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction of tubular epithelial cells in SI-AKI.
研究领域:
分子生物学
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医学
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病理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
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IF 3.831
Zuo Lihua,Zhou Lin,Xu Tanye,Li Zhuolun,Liu Liwei,Shi Yingying,Kang Jian,Gao Guanmin,Du Shuzhang,Sun Zhi,Zhang Xiaojian
Xuebijing (XBJ) injection is an ethnomedicinal formula that has been widely used in the therapy of sepsis in China. However, the underlying theraputic mechanisms remain uninvestigated. In this research, a metabolomic method based on UHPLC-Q-Orbitrap HRMS was applied to make a holistic evaluation of XBJ on septic rats which were induced by the classical cecal ligation and puncture (CLP) operation. The plasma metabolic changes were profiled and evaluated by multivariate analytical (MVA) methods. In the results, a total of 41 differential metabolites were identified between CLP-operated group and sham-operated group, which were mainly involved in amino acid metabolism and lipid metabolism. After pathway analysis, it was finally discovered that the majority of the influenced metabolic pathways caused by sepsis mainly involved in energy metabolism, oxidative stress, and inflammation metabolism. When intervened by XBJ injection, 32 of the 41 disordered metabolites had been adjusted in reverse, which suggested that XBJ could mediate the abnormal metabolic pathways synergistically. In conclusion, the present study systematically investigated the efficacy and its underlying therapeutic mechanisms of XBJ on sepsis, while offering a new insight for the subsequent relevant exploration of other Chinese medicine at the same time.
研究领域:
药理学
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代谢组学
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中医药学
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DOI
PubMed
高影响因子
JOURNAL OF BIOCHEMISTRY
·
2018
·Vol. 164
·期 6
·427-435
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IF 2.35
Xu Tanye,Zhou Lin,Shi Yingying,Liu Liwei,Zuo Lihua,Jia Qingquan,Du Shuzhang,Kang Jian,Zhang Xiaojian,Sun Zhi
Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction. Metabolomic profiling in bio-fluid or tissue is vital for elucidating the pathogenesis of sepsis and evaluating therapeutic effects of medication. In this study, an untargeted metabolomics approach was applied to study the metabolic changes in lung tissue of septic rats induced by cecal ligation and puncture (CLP) and investigate the treatment effects of Xubijing injection (XBJ). Metabolomics analyses were performed on ultra-high performance liquid chromatography-Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap-HRMS) together with multivariate statistical analysis. A total of 26 differential metabolites between CLP and sham-operated group were identified. The altered metabolic pathways included energy metabolism, amino metabolism, lipid metabolism, fatty acid metabolism and hormone metabolism. Among the 26-varied metabolites, 15 were significantly regulated after XBJ treatment. The metabolic pathway network of sepsis was drawn to interpret the pathological feature of lung damage caused by sepsis and the underlying regulating mechanism of XBJ on the molecular levels. Our findings display that LC-MS-based metabolomics is a useful tool for uncovering the underlying molecular mechanism of sepsis, and XBJ may exert therapeutic effect by regulating multiple metabolic pathways.
研究领域:
医学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Shifan Chen,Jianxu Bao,Zhen Hu,Xianda Liu,Shengjun Cheng,Weifeng Zhao,Changsheng Zhao
Sepsis is a systemic inflammatory response syndrome caused by pathogen infection, while the current antibiotics mainly utilized in clinical practice to combat infection result in the release of pathogen-associated molecular patterns (PAMPs) in the body. Herein, we provide an innovative strategy for controlling sepsis, namely, capturing active pathogens by means of extracorporeal blood purification. Carbon nanotubes (CNTs) were modified with dimethyldiallylammonium chloride (DDA) through γ-ray irradiation-induced graft polymerization to confer a positive charge. Then, CNT-DDAs are blended with polyurethane (PU) to prepare porous microspheres using the electro-spraying method. The obtained microspheres with a pore diameter of 2 μm served as pathogen traps and are termed as PU-CNT-DDA microspheres. Even at a high flow rate of 50 mL·min−1, the capture efficiencies of the PU-CNT-DDAs for Escherichia coli and Staphylococcus aureus remained 94.7% and 98.8%, respectively. This approach circumvents pathogen lysis and mortality, significantly curtails the release of PAMPs, and hampers the production of pro-inflammatory cytokines. Therefore, hemoperfusion using porous PU-CNT-DDAs as pathogen traps to capture active pathogens and alleviate inflammation opens a new route for sepsis therapy.
研究领域:
医学
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材料科学
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产品关联
DOI
PubMed
高影响因子
CLINICA CHIMICA ACTA
·
2023
·
IF 5
Yueyuan Zhang,Sha Xu,Jianxin Xu,Fuchao Xu,Geng Lu,Jiawei Zhou,Shuangshuang Gu,Jun Wang
Background Early evaluation of the severity of sepsis and estimation of its prognosis remains one of the main challenges in current therapeutic strategies. This study aimed to evaluate the prognostic value of plasma 7-ketocholesterol (7-KC) in sepsis. Methods We retrospectively measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) the plasma 7-KC concentration in 176 patients with sepsis and 90 healthy volunteers. A multivariate Cox proportional hazard model was introduced to identify independent factors, including plasma 7-KC and clinical features, for the 28-day mortality of sepsis, and a nomogram for predicting the 28-day mortality of sepsis was established. Decision curve analysis (DCA) was performed to assess the prediction model of death risk of sepsis. Results The area under the curve (AUC) of plasma 7-KC in diagnosing sepsis was 0.899 (95% CI = 0.862–0.935, P < 0.001), while it was 0.830 (95% CI = 0.764–0.894, P < 0.001) in diagnosing septic shock. The AUCs of plasma 7-KC in predicting the survival of sepsis patients in the training cohort and the test cohort were 0.770 (95% CI = 0.692–0.848, P < 0.05) and 0.869 (95% CI = 0.763–0.974, P < 0.05), respectively. In addition, high plasma 7-KC expression predicts poor prognosis in sepsis. Then, 7-KC and platelet count were identified as the two factors with significant differences by a multivariate Cox proportional hazard model, and the 28-day mortality probability ranged from 0.002 to 0.985 and was assessed using a nomogram. DCA results revealed that the combination of plasma 7-KC and platelet count showed the best prognostic efficiency of the risk threshold compared to a single factor in both the training cohort and test cohort. Conclusions Collectively, the elevated plasma 7-KC level is an indicator of sepsis and was identified as a prognostic indicator for sepsis patients, providing a landscape for predicting survival in early sepsis with potential clinical utility.
研究领域:
临床医学
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生物化学
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重症医学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Liu Li-Wei,Shi Ying-Ying,Li Zhuo-Lun,Zuo Li-Hua,Tang Meng,Jing Zi-Wei,Zhao Hong-Yu,Xue Peng,Zhou Lin,Du Qiu-Zheng,Zhang Xiao-Jian,Sun Zhi
The drug combination of biapenem (BIPM) and xuebijing injection (XBJ) is commonly applied for the treatment of sepsis in China. However, the potential synergistic mechanism is still enigmatic. There have been no studies focused on the plasma metabolome alterations in sepsis after the intervention of this combination. In this work, an untargeted metabolomics approach was performed by liquid chromatography-mass spectrometry coupled with multivariate statistical analysis to provide new insights into the synergistic effect of BIPM in combination with XBJ. We characterized the metabolic phenotype of sepsis and described metabolic footprint changes in septic rats responding to XBJ and BIPM individually and in combination, in addition to histopathological and survival evaluation. A total of 91 potential biomarkers of sepsis were identified and 32 disturbed metabolic pathways were constructed. Among these biomarkers, 36 metabolites were reversely regulated by XBJ, mainly including glycerophospholipids, sphingolipids, free fatty acids (FFAs), bile acids and acylcarnitines; 42 metabolites were regulated by BIPM, mainly including amino acids, glycerophospholipids, and acylcarnitines; 72 metabolites were regulated after XBJ-BIPM combination treatment, including most of the 91 potential biomarkers. The results showed that the interaction between XBJ and BIPM indeed exhibited a synergistic effect by affecting some key endogenous metabolites, 15 metabolites of which could not be regulated when XBJ or BIPM was used alone. Compared with Model group, 13, 22, and 27 metabolic pathways were regulated by XBJ, BIPM, and XBJ-BIPM combination, respectively. It suggested that many more endogenous metabolites and metabolic pathways were significantly regulated after combination treatment compared with XBJ or BIPM monotherapy. Metabolisms of lipids, amino acids, acylcarnitines, and bile acids were common pathways involved in the synergistic action of XBJ and BIPM. This study was the first to employ metabolomics to elucidate the synergistic effect and decipher the underlying mechanisms of BIPM in combination with XBJ against sepsis. The results provide some support for clinical application of antibiotics in combination with traditional Chinese medicines and have important implications for the treatment of sepsis in clinic.
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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
You Zhou,You Wu,Rui Zhu
Background Septic acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI), but no effective therapies exist to prevent or treat it. Although KLF6 is linked to various pathophysiological processes, its exact role in S-AKI is not yet fully understood. Methods The role of KLF was investigated using both the mouse CLP model and in vitro systems. To identify the transcriptional targets regulated by KLF6, ChIP-qPCR and luciferase reporter assays were carried out. Biochemical and cellular techniques were employed to assess cellular injury and lipid peroxidation levels. The extent of ferroptosis was evaluated through transmission electron microscopy (TEM). Results KLF6 levels were significantly increased in a renal IRI model. Knockdown of KLF6 using AAV9 reduced kidney injury in both in vitro and in vivo models, while KLF6 overexpression aggravated injury. Overexpression of KLF6 promoted ferroptosis, whereas its knockdown reduced lipid peroxidation and ferroptosis. KLF6 regulates NCOA4 expression by binding to its promoter, controlling ferroptosis. Knockdown of NCOA4 in vitro alleviated ferroptosis and cellular damage caused by KLF6 overexpression. Pharmacological inhibition of KLF6 reduced kidney injury and ferroptosis in S-AKI mice. Conclusion Our study uncovered a previously unrecognized role for KLF6 in S-AKI. By facilitating NCOA4 transcription, KLF6 intensified ferroptosis, which, in turn, aggravated septic AKI.
研究领域:
肾脏病学
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分子生物学
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病理生理学
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细胞生物学
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转录调控
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Yu Cheng,Yu Chen,Tao Song,Luojia Jiang,Yuhan He,Yupei Li,Weifeng Zhao,Baihai Su
Endotoxin and circulating histones form a pathogenic loop, driving immune dysregulation in sepsis. A multitargeted extracorporeal blood purification combining endotoxin adsorption with histone neutralization may represent a critical therapeutic approach to improve the clinical outcomes of septic patients. However, existing hemoperfusion adsorbents are often heparin-dependent and single-target and exhibit limited hemocompatibility. Herein, we developed self-anticoagulant heparin-grafted chitosan/cellulose composite microspheres (CSCEHEP) for the simultaneous adsorption of endotoxin and circulating histones. The obtained CSCEHEP microspheres significantly prolonged plasma coagulation time while maintaining excellent hemocompatibility, owing to the heparin coating. In vitro, CSCEHEP microspheres exhibited adsorption capacities of 251.0 EU/g (81.8% clearance) for endotoxin and 288.6 μg/g (62.8% clearance) for histones, respectively. Meanwhile, CSCEHEP microspheres effectively adsorbed histones in whole blood and counteracted histone-induced endothelial and kidney epithelial cytotoxicity, erythrocyte fragility, and thrombocytopenia. In conclusion, CSCEHEP microspheres are promising adsorbents for hemoperfusion to simultaneously remove endotoxins and circulating histones in septic blood.
研究领域:
免疫学
·
重症医学
·
生物材料学
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血液净化
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分子病理学
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转化医学
·
药用高分子
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Lu Geng,Zhou Jiawei,Yang Ting,Li Jin,Jiang Xinrui,Zhang Wenjun,Gu Shuangshuang,Wang Jun
Background: Sepsis and septic shock, a subset of sepsis with higher risk stratification, are hallmarked by high mortality rates and necessitated early and accurate biomarkers.Methods: Untargeted metabolomic analysis was performed to compare the metabolic features between the sepsis and control systemic inflammatory response syndrome (SIRS) groups in discovery cohort, and potential metabolic biomarkers were selected and quantified using multiple reaction monitoring based target metabolite detection method.Results: Differentially expressed metabolites including 46 metabolites in positive electrospray ionization (ESI) ion mode, 22 metabolites in negative ESI ion mode, and 4 metabolites with dual mode between sepsis and SIRS were identified and revealed. Metabolites 5-Oxoproline, L-Kynurenine and Leukotriene D4 were selected based on least absolute shrinkage and selection operator regularization logistic regression and differential expressed between sepsis and septic shock group in the training and test cohorts. Respective risk scores for sepsis and septic shock based on a 3-metabolite fingerprint classifier were established to distinguish sepsis from SIRS, septic shock from sepsis. Significant relationship between developed sepsis risk scores, septic shock risk scores and Sequential (sepsis-related) Organ Failure Assessment (SOFA), procalcitonin (PCT) and lactic acid were observed.Conclusions: Collectively, our findings demonstrated that the characteristics of plasma metabolites not only manifest phenotypic variation in sepsis onset and risk stratification of sepsis but also enable individualized treatment and improve current therapeutic strategies.
研究领域:
医学
·
代谢组学
·
重症医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Yi-ni Lu,Xiao-han Wang,Bo-cheng Xu,Yufen Zheng,Xiong Zhang,Yi Liu,Tian-yin Wang,Feng Yu
Septic cardiomyopathy (SCM) represents one of the life-threatening manifestations of sepsis, for which specific therapies are currently lacking. The mechanism of action of urinary trypsin inhibitor (UTI), widely employed in treating acute inflammatory disorders, on SCM has remained elusive. Here, we observed that UTI alleviated cardiac function, reduced myocardial injury, and improved cardiac permeability in a cecum ligation and puncture (CLP)-induced sepsis mouse model. In addition, UTI significantly decreased serum and myocardial angiopoietin 2 (ANG2) levels in CLP mice, which is a biomarker associated with sepsis prognosis. In vitro experiments utilizing mouse myocardial microvascular endothelial cells (MMVECs) were conducted to explore the molecular mechanisms underlying UTI-mediated regulation of ANG2 expression, secretion, and its impacts on endothelial permeability and neutrophil adhesion. UTI mitigated endothelial barrier dysfunction and reduced neutrophil adherence following thrombin stimulation and ANG2 overexpression. The experiments further demonstrated that UTI-induced inhibition of ANG2 expression was related to the blockade of forkhead box O1 (FOXO1) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) nuclear transcription and that UTI disrupted ANG2 exocytosis by reducing intracellular Ca 2+ concentration, a mechanism distinct from other serine protease inhibitors. In addition, UTI ameliorated barrier impairment and neutrophil adhesion in ANG2 overexpression cells by restoring tyrosine kinase receptor 2 Tie2)/protein kinase B (AKT) pathway phosphorylation. Docking predictions and surface plasmon resonance (SPR) further corroborated that UTI is strongly bound to ANG2. Altogether, our findings revealed a novel perspective wherein UTI functions as a multifaceted ANG2 inhibitor in SCM. Thus, ANG2 constitutes a promising therapeutic target for septic cardiomyopathy.
研究领域:
生物学
·
医学
·
药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Neurology
·
2022
·
IF 4.086
Liao Hongsen,Li Haojia,Bao Hongguang,Jiang Li,Du Jiayue,Guo Yaoyi,Si Yanna
Objective: This study aims to analyze the changes of fecal short chain fatty acids (SCFAs) content and gut microbiota composition in sepsis associated encephalopathy (SAE) mice, further evaluating the effect of SCFAs on cognitive function and the underlying mechanism in SAE mice.Methods: A total of 55 male adult C57BL/6 mice (2–3 months of age, 20–25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15). Seven days after surgery, fecal samples were collected for microbiota composition and SCFA analysis from 6 mice in each group randomly. Behavioral test was applied to assess cognitive impairment at the same time. After that, mice were sacrificed and brain tissue was harvested for inflammatory cytokines analysis.Results: The levels of acetic acid (.57 ± 0.09 vs 2.00 ± 0.24, p < 0.001) and propionic acid (.32 ± 0.06 vs .66 ± 0.12, p = 0.002) were significantly decreased in the CLP group compared with the sham group. The administration of SCFAs significantly increased the levels of acetic acid (1.51 ± 0.12 vs. 0.57 ± 0.09, p < 0.001) and propionic acid (0.54 ± 0.03 vs. 0.32 ± 0.06, p = 0.033) in CLP+SCFAs group compared with CLP group. Relative abundance of SCFAs-producing bacteria, including Allobaculum (0.16 ± 0.14 vs. 15.21 ± 8.12, p = 0.037), Bacteroides (1.82 ± 0.38 vs. 15.21 ± 5.95, p = 0.002) and Bifidobacterium (0.16 ± 0.06 vs. 2.24 ± 0.48, p = 0.002), significantly decreased in the CLP group compared with the sham group. The behavioral tests suggested that cognitive function was impaired in SAE mice, which could be alleviated by SCFAs pretreatment. ELISA tests indicated that the levels of IL-1β, IL-6, and TNF-α were elevated in SAE mice and SCFAs could lower them. However, the GPR43 antagonist, GLPG0974, could reverse the cognitive protective effect and anti-neuroinflammation effect of SCFAs.Conclusion: Our study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE.
研究领域:
神经科学
·
微生物学
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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
危险品化学品经营许可证（带存储）