scholarly journals Ulinastatin improves renal microcirculation by protecting endothelial cells and inhibiting autophagy in a septic rat model

2022 ◽  
Author(s):  
Tian Li ◽  
Xiaojun Ji ◽  
Jingfeng Liu ◽  
Xinjie Guo ◽  
Ran Pang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Rat Model ◽  
Cecal Ligation ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sprague Dawley ◽  
Male Adult ◽  
Renal Microcirculation

Introduction: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. Methods: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague-Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 hours after the operation. Histological staining was used to evaluate kidney injury scores. Western blot (WB) was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors [interleukin -1β (IL-1β), interleukin -6 (IL-6), and tumor necrosis factor-α (TNF-α)] in kidney tissue, and enzyme-linked immunosorbent assay (ELISA) detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. Results: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. Conclusion: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

scholarly journals Ulinastatin improves renal microcirculation by protecting expression of VE-cadherin and inhibiting autophagy in a septic rat model

2021 ◽  
Author(s):  
Tian Li ◽  
Xiao-jun Ji ◽  
Jing-feng Liu ◽  
Xin-jie Guo ◽  
Ran Pan ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Rat Model ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Sprague Dawley ◽  
Male Adult ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Renal Microcirculation ◽  
Cell Stability

Abstract Background: Increased permeability of the renal capillary is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall, and autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the adhesion junction. Methods: We obserned the effect of Ulinastatin in the septic rat model by using contrast-enhanced ultrasonography (CEUS) to evaluate perfusion of the renal cortex and medulla. Male adult Sprague-Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50 000 U/kg) was injected into the tail vein 1 hour after the operation. At 24 hours postoperatively, CEUS was performed to evaluate the renal microcirculation blood flow and microcirculation perfusion. Histological staining was used to evaluate kidney injury scores. Western blotting was used to assess the expression of VE-cadherin and LC3II, peripheral serum cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α levels), renal function (creatinine, urea nitrogen, and S-thrombomodulin level), and the urine neutrophil gelatinase-associated lipocalin level. Results: Compared with sham group, ulinastatin reduced the inflammatory response, maintained the expression of VE-cadherin, inhibited autophagy, and meliorated cortical and medullary perfusion.Conclusions: Ulinastatin effectively protects the adhesion junction and helps to ameliorate the perfusion of kidney capillaries during sepsis by inhibiting autophagy and the expression of inflammatory factors.

scholarly journals SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Siqi Xu ◽  
Youguang Gao ◽  
Qin Zhang ◽  
Siwei Wei ◽  
Zhongqing Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Survival Time ◽  
Rat Model ◽  
Cecal Ligation ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Multiple Organ ◽  
Organ Systems

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

LncRNA NEAT1 promotes inflammatory response and induces corneal neovascularization

2018 ◽  
Vol 61 (4) ◽  
pp. 231-239 ◽  
Author(s):  
Yan-hui Bai ◽  
Yong Lv ◽  
Wei-qun Wang ◽  
Guang-li Sun ◽  
Hao-hao Zhang
Keyword(s):  
Inflammatory Response ◽  
Rat Model ◽  
Noncoding Rna ◽  
Corneal Neovascularization ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Protein Levels ◽  
Lncrna Neat1

Human corneal fibroblasts (HCFs) are implicated in corneal neovascularization (CRNV). The mechanisms underlying the inflammatory response in HCFs and the development of CRNV were explored in this study. Alkali burns were applied to the corneas of rats to establish a CRNV model. The expression of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) and mRNA and protein levels of nuclear factor kappa B (NF-κB)- activating protein (NKAP) were examined by quantitative real-time (qRT-PCR) and Western blot methods, respectively. Lipopolysaccharide (LPS) is used to stimulate HCFs for inflammatory response. The level of inflammation factors in HCF supernatant was detected using an enzyme-linked immunosorbent assay (ELISA). Binding and interactions between NEAT1 and miRNA 1246 (miR-1246) were determined by RNA immunoprecipitation (RIP) and RNA pull-down assays in HCFs. Compared with the control group (n = 6), NEAT1 was upregulated in the corneas of the CRNV rat model (n = 6). The expression of NEAT1 in HCFs was upregulated by LPS. Downregulation of NEAT1 suppressed the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). NEAT1 could bind and interact with miR-1246. LPS regulated the expression of NKAP and NF-κB signaling via the NEAT1/miR-1246 pathway. Downregulation of NEAT1in vivoinhibited CRNV progression in the CRNV rat model. The lncRNA NEAT1 induced secretion of inflammatory factors, mediated by NF-κB, by targeting miR-1246, thereby promoting CRNV progression.

scholarly journals Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation

2021 ◽  
Author(s):  
Guang Li ◽  
Bo Wang ◽  
Xiangchao Ding ◽  
Xinghua Zhang ◽  
Jian Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Recipient Cell ◽  
Cecal Ligation ◽  
Cell Permeability ◽  
Cell Counting ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vascular Density

AbstractExtracellular vesicles (EVs) can be used for intercellular communication by facilitating the transfer of miRNAs from one cell to a recipient cell. MicroRNA (miR)-210-3p is released into the blood during sepsis, inducing cytokine production and promoting leukocyte migration. Thus, the current study aimed to elucidate the role of plasma EVs in delivering miR-210-3p in sepsis-induced acute lung injury (ALI). Plasma EVs were isolated from septic patients, after which the expression of various inflammatory factors was measured using enzyme-linked immunosorbent assay. Cell viability and apoptosis were measured via cell counting kit-8 and flow cytometry. Transendothelial resistance and fluorescein isothiocyanate fluorescence were used to measure endothelial cell permeability. Matrigel was used to examine the tubulogenesis of endothelial cells. The targeting relationship between miR-210-3p and ATG7 was assessed by dual-luciferase reporter assays. The expression of ATG7 and autophagy-related genes was determined to examine autophagic activation. A sepsis mouse model was established by cecal ligation and puncture (CLP)-induced surgery. The level of miR-210-3p was highly enriched in septic EVs. MiR-210-3p enhanced THP-1 macrophage inflammation, BEAS-2B cell apoptosis, and HLMVEC permeability while inhibiting angiogenesis and cellular activity. MiR-210-3p overexpression reduced ATG7 and LC3II/LC3I expression and increased P62 expression. Improvements in vascular density and autophagosome formation, increased ATG7 expression, and changes in the ratio of LC3II/LC3I were detected, as well as reduced P62 expression, in adenovirus-anti-miR-210-3p treated mice after CLP injury. Taken together, the key findings of the current study demonstrate that plasma EVs carrying miR-210-3p target ATG7 to regulate autophagy and inflammatory activation in a sepsis-induced ALI model.

scholarly journals Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiaoxia Ye ◽  
Mingming Zhu ◽  
Xiaohang Che ◽  
Huiyang Wang ◽  
Xing-Jie Liang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Adaptor Protein ◽  
Mtor Pathway ◽  
Microglial Cells ◽  
Inflammatory Factors ◽  
Intraventricular Injection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Autophagic Flux

Abstract Background Microglial activation is a prominent feature of neuroinflammation, which is present in almost all neurodegenerative diseases. While an initial inflammatory response mediated by microglia is considered to be protective, excessive pro-inflammatory response of microglia contributes to the pathogenesis of neurodegeneration. Although autophagy is involved in the suppression of inflammation, its role and mechanism in microglia are unclear. Methods In the present study, we studied the mechanism by which lipopolysaccharide (LPS) affects microglial autophagy and the effects of autophagy on the production of pro-inflammatory factors in microglial cells by western blotting, immunocytochemistry, transfection, transmission electron microscopy (TEM), and real-time PCR. In a mouse model of neuroinflammation, generated by intraventricular injection of LPS (5 μg/animal), we induced autophagy by rapamycin injection and investigated the effects of enhanced autophagy on microglial activation by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Results We found that autophagic flux was suppressed in LPS-stimulated N9 microglial cells, as evidenced by decreased expression of the autophagy marker LC3-II (lipidated form of MAP1LC3), as well as increased levels of the autophagy adaptor protein SQSTM1. LPS significantly decreased Vps34 expression in N9 microglial cells by activating the PI3KI/AKT/MTOR pathway without affecting the levels of lysosome-associated proteins and enzymes. More importantly, overexpression of Vps34 significantly enhanced the autophagic flux and decreased the accumulation of SQSTM1 in LPS-stimulated N9 microglial cells. Moreover, our results revealed that an LPS-induced reduction in the level of Vps34 prevented the maturation of omegasomes to phagophores. Furthermore, LPS-induced neuroinflammation was significantly ameliorated by treatment with the autophagy inducer rapamycin both in vitro and in vivo. Conclusions These data reveal that LPS-induced neuroinflammation in N9 microglial cells is associated with the inhibition of autophagic flux through the activation of the PI3KI/AKT/MTOR pathway, while enhanced microglial autophagy downregulates LPS-induced neuroinflammation. Thus, this study suggests that promoting the early stages of autophagy might be a potential therapeutic approach for neuroinflammation-associated diseases.

scholarly journals NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 333-342
Author(s):  
Yawei Feng ◽  
Jun Liu ◽  
Ranliang Wu ◽  
Peng Yang ◽  
Zhiqiang Ye ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Cell Injury ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Western Blot Assay

AbstractBackground and aimAcute kidney injury (AKI) is a common complication of sepsis. Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays a vital role in various diseases, including AKI. This study aimed to investigate the function and mechanism of NEAT1 in sepsis-induced AKI.Materials and methodsA septic AKI model was established by treating HK-2 cells with lipopolysaccharide (LPS). The levels of NEAT1 and miR-22-3p were measured by quantitative real-time PCR. Cell apoptosis was assessed by flow cytometry. The levels of apoptosis-related protein and autophagy-related factors were examined by the western blot assay. An enzyme-linked immunosorbent assay was used to calculate the contents of inflammatory factors. The interaction between NEAT1 and miR-22-3p was validated by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. The levels of nuclear factor (NF)-κB pathway-related proteins were evaluated by the western blot assay.ResultsNEAT1 was upregulated, while miR-22-3p was downregulated in patients with sepsis and in LPS-stimulated HK-2 cells. LPS treatment triggered cell apoptosis, autophagy, and inflammatory response in HK-2 cells. NEAT1 knockdown attenuated LPS-induced cell injury. NEAT1 modulated LPS-triggered cell injury by targeting miR-22-3p. Furthermore, NEAT1 regulated the NF-κB pathway by modulating miR-22-3p.ConclusionDepletion of NEAT1 alleviated sepsis-induced AKI via regulating the miR-22-3p/NF-κB pathway.

scholarly journals Up-regulation of long non-coding RNA CYTOR induced by icariin promotes the viability and inhibits the apoptosis of chondrocytes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guoyou Wang ◽  
Lei Zhang ◽  
Huarui Shen ◽  
Qi Hao ◽  
Shijie Fu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Loss Of Function ◽  
Protective Function ◽  
Non Coding Rna ◽  
Effective Component ◽  
Short Hairpin Rnas ◽  
Function Models

Abstract Background Icariin (ICAR) is the main effective component extracted from epimedium, and is reported to have the potential to treat osteoarthritis (OA). However, its pharmacological function on chondrocytes has not been fully clarified. Methods Different doses of ICAR were used to treat chondrocyte cell lines, including CHON-001 and ATDC5. Then the expressions of different lncRNAs were measured by qRT-PCR. Interleukin-1β (IL-1β) was used to simulate the inflammatory response environment of chondrocytes. Overexpression plasmids and short hairpin RNAs of lncRNA CYTOR were used to construct gain-of-function and loss of function models. CCK-8 was conducted to determine the cell viability. Flow cytometry was used to detect the apoptosis of chondrocytes. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the contents of inflammatory factors (IL-6, IL-8, TNF-α) in the supernatant of the chondrocytes. Results Compared with other lncRNAs, CYTOR was changed most significantly in both CHON-001 and ATDC5 cells after treatment with ICAR. ICAR promotes the viability and inhibits the apoptosis of CHON-001 and ATDC5 cells induced by IL-1β, accompanied with reduced levels of inflammatory factors. Overexpression of CYTOR facilitated the viability of chondrocytes, while repressed their apoptosis and inflammatory response. What’s more, knockdown of CYTOR reversed the protective effects of ICAR on chondrocytes. Conclusion CYTOR was a pivotal lncRNA involved in the protective function of ICAR on chondrocytes.

scholarly journals Yiqi Wenyang Fang ameliorates allergic rhinitis through inhibiting inflammatory response and promoting the expression of Foxp3

2016 ◽  
Vol 29 (4) ◽  
pp. 696-706 ◽  
Author(s):  
Jun Shi ◽  
Yu Liu ◽  
Shihai Yan ◽  
Daonan Yan
Keyword(s):  
Allergic Rhinitis ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Pcr Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Sprague Dawley ◽  
Model Control ◽  
Tgf Β1

Allergic rhinitis (AR) is an inflammatory disease with a hypersensitivity response to environmental stimulus. The aim of this study was to evaluate the effect of Yiqi Wenyang Fang (YWF) on AR and investigate the underlying mechanism. A total of 48 female Sprague-Dawley rats were randomly divided into six groups (normal control, model control, YWF at low dose, YWF at median dose, YWF at high dose, and loratadine). Rats were injected with antigen for sensitization. Then, rats in the YWF groups were treated with different dose of YWF for 28 days. Loratadine was used as a positive control. Number of sneezes, degree of runny nose, nasal rubbing movements, and tissue damage were scored. The protein and mRNA expression of Foxp3 were determined by western blot and real time-PCR analysis, respectively. Flow cytometry was used to detect the number of CD4+CD25+Foxp3+ Treg cells. The content of interleukin (IL)-10, transforming growth factor β1 (TGF-β1), IL-13, and IL-4 in the serum were detected by enzyme-linked immunosorbent assay (ELISA). Scores of symptoms were significantly reduced and nasal mucosa damage was alleviated after YWF administration. YWF increased the expression of Foxp3, IL-10, TGF-β1, and number of CD4+CD25+Foxp3+ Treg cells which were reduced by antigen injection. The expression levels of IL-13 and IL-4 were increased after antigen administration while decreased after YWF treatment. YWF may ameliorate AR through inhibiting inflammatory response and promoting Foxp3 expression.

scholarly journals Ameliorating Effect of Pentadecapeptide Derived from Cyclina sinensis on Cyclophosphamide-Induced Nephrotoxicity

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 462
Author(s):  
Xiaoxia Jiang ◽  
Zhexin Ren ◽  
Biying Zhao ◽  
Shuyao Zhou ◽  
Xiaoguo Ying ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Antioxidant Enzymes ◽  
Glutathione Peroxidase ◽  
Anticancer Drug ◽  
Tissue Damage ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Cyclina Sinensis ◽  
Apoptotic Pathways

Cyclophosphamide (CTX) is a widely used anticancer drug with severe nephrotoxicity. The pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) has been shown to affect immunity and to protect the liver. Hence, the purpose of this study was to investigate the ameliorating effect of SCSP on CTX-induced nephrotoxicity in mice. We injected male ICR mice with CTX (80 mg/kg·day) and measured the nephrotoxicity indices, levels of antioxidant enzymes, malondialdehyde (MDA), inflammatory factors, as well as the major proteins of the NF-κB and apoptotic pathways. Cyclophosphamide induced kidney injury; the levels of kidney-injury indicators and cytokines recovered remarkably in mice after receiving SCSP. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) increased, while there was a significant decrease in MDA levels. The kidney tissue damage induced by CTX was also repaired to a certain extent. In addition, SCSP significantly inhibited inflammatory factors and apoptosis by regulating the NF-κB and apoptotic pathways. Our study shows that SCSP has the potential to ameliorate CTX-induced nephrotoxicity and may be used as a therapeutic adjuvant to ameliorate CTX-induced nephrotoxicity.

Pathophysiology of Acute Kidney Injury, Repair, and Regeneration

2014 ◽  
Author(s):  
Ching-Wei Tsai ◽  
Sanjeev Noel ◽  
Hamid Rabb
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Critical Role ◽  
Recovery Period ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Phase Cell ◽  
M2 Macrophage ◽  
Renal Stem Cells

Acute kidney injury (AKI), regardless of its aetiology, can elicit persistent or permanent kidney tissue changes that are associated with progression to end-stage renal disease and a greater risk of chronic kidney disease (CKD). In other cases, AKI may result in complete repair and restoration of normal kidney function. The pathophysiological mechanisms of renal injury and repair include vascular, tubular, and inflammatory factors. The initial injury phase is characterized by rarefaction of peritubular vessels and engagement of the immune response via Toll-like receptor binding, activation of macrophages, dendritic cells, natural killer cells, and T and B lymphocytes. During the recovery phase, cell adhesion molecules as well as cytokines and chemokines may be instrumental by directing the migration, differentiation, and proliferation of renal epithelial cells; recent data also suggest a critical role of M2 macrophage and regulatory T cell in the recovery period. Other processes contributing to renal regeneration include renal stem cells and the expression of growth hormones and trophic factors. Subtle deviations in the normal repair process can lead to maladaptive fibrotic kidney disease. Further elucidation of these mechanisms will help discover new therapeutic interventions aimed at limiting the extent of AKI and halting its progression to CKD or ESRD.

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