scholarly journals Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

2021 ◽  
pp. 1-11
Author(s):  
Yunshi Lai ◽  
Haie Tang ◽  
Xinrong Zhang ◽  
Zhanmei Zhou ◽  
Miaomiao Zhou ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Mapk Signaling ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Gut Flora ◽  
Tnf Α ◽  
Peritoneal Dialysis Fluid ◽  
Function Impairment

<b><i>Background:</i></b> Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. <b><i>Objectives:</i></b> The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. <b><i>Method:</i></b> We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. <b><i>Results:</i></b> In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. <b><i>Conclusions:</i></b> Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.

scholarly journals Icariin interferes with TDP43-induced inflammatory factor secretion and inhibits the JNK and p38 MAPK signaling pathway in vitro

2021 ◽  
Author(s):  
He Huang ◽  
Pei-Yu Wu ◽  
Zhao-Fei Zhang ◽  
Feng-Wei Qin ◽  
Wang Tang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Theoretical Basis ◽  
Mapk Signaling ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Tnf Α ◽  
Factor Secretion ◽  
Relative Factors

IntroductionTo investigate the molecular mechanism of icariin (ICA) intervention in TDP-43 mediated chondrocyte lesions of osteoarthritis.Material and methodsHC-α chondrocytes were transfected with TDP-43 lentiviruses to generate TDP-43-overexpressing chondrocytes and treated with 5 μg/mL icariin. The level of TDP-43, JNK, p38 MAPK and relative factors were detected by Western blotting assays. TNF-α and IL-1β in the supernatant were determined by ELISA.ResultsCompared with the HC-α group, TDP-43 expression was significantly increased in the TDP-43-HC-α group and was not significantly different that of the HC-α+ICA group. However, TDP-43 expression in the TDP-43-HC-α+ICA group was significantly lower than that in the TDP-43-HC-α group. ELISA showed that the secretion of TNF-α and IL-1β in the supernatant of the TDP-43-HC-α group was significantly increased (P<0.01) compared with the HC-α group, but was significantly lower in the supernatant of the TDP-43-HC-α+ICA group than that of the TDP-43-HC-α group (P<0.01). ICA treatment reduced the expression of TDP-43 in chondrocytes and inhibited the elevation of inflammatory cytokines caused by TDP-43. ICA processing can also inhibit the activation of JNK/p38 MAPK related signaling pathways caused by TDP-43. Overexpression of TDP-43 reduced the formation of stress granules (SGs)in chondrocytes, and increased receptor for activated protein kinase C1 (RACK1) level. ICA could reverse these changes.ConclusionsIcariin could interfere with TDP-43-induced secretion of inflammatory factors, inhibit JNK/p38 MAPK signaling. Our findings provided a new theoretical basis for the treatment of osteoarthritis.

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.

scholarly journals Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

2021 ◽  
Vol 14 ◽  
Author(s):  
Yating Gong ◽  
Muyao Wu ◽  
Jinchao Shen ◽  
Jiafeng Tang ◽  
Jie Li ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Edema ◽  
Nerve Cell ◽  
Cell Apoptosis ◽  
Neuronal Cell ◽  
Neurological Dysfunction ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Tnf Α ◽  
Bbb Permeability

Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl– cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1β, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.

scholarly journals The Inhibitory Impact of Schisandrin Against LPS-Induced Acute Kidney Injury in Vitro and in Vivo

2021 ◽  
Author(s):  
Weifeng Li ◽  
Qiuxia Huang ◽  
Jinjin Yu ◽  
Jiabao Yu ◽  
Yajie Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Immunohistochemical Analysis ◽  
Inflammatory Factors ◽  
Raw264.7 Macrophages ◽  
Bioactive Component

Abstract Schisandrin (Sch) is a main bioactive component of Schisandra sphenanthera Rehd.et Wils. It has been reported that Sch could regulate inflammatory disease. This study evaluated the anti-inflammatory and anti-oxidant effects effect of Sch on lipopolysaccharide (LPS)-induced macrophages activation and acute kidney injury mice. Male Kunming mice were intraperitoneally injected with LPS (15 mg/kg) after administration of Sch (12.5, 25, 50 mg/kg) seven days for developing acute kidney injury vivo model. RAW264.7 macrophages were pretreatment Sch (10, 20, 40 µM) and administrated LPS (1 µg/ml) to create an in vitro injury model. ELISA results found that Sch administration reduced the production of inflammatory factors induced by LPS in kidney tissues and RAW264.7 macrophages. It has been observed that Sch alleviated oxidative stress by reducing the levels of reactive oxygen species, myeloperoxidase and malondialdehyde, and increasing the activity of superoxide dismutase and glutathione peroxidase. Hematoxylin-eosin staining data suggested that Sch administration significantly reduced inflammatory cell infiltration and the kidney tissue damage induced by LPS. The blood urea nitrogen and creatinine levels were also reduced by Sch treatment. In addition, Western blot and immunohistochemical analysis showed that Sch up-regulated the expression of Nrf2 and HO-1, and decreased the expression of p-p38, p-JNK, p-ERK1/2, p-IκBα, p-NF-κBp65 and TLR4. The current research showed that Sch reduced LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress, and provided insights into potential ways to treat AKI.

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 Postoperative Effects of Dexmedetomidine on Serum Inflammatory Factors and Cognitive Malfunctioning in Patients with General Anesthesia

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Zitan Zhang ◽  
Wei Li ◽  
Huiqun Jia
Keyword(s):  
Elderly Patients ◽  
General Anesthesia ◽  
Postoperative Cognitive Dysfunction ◽  
Inflammatory Factors ◽  
Control Group ◽  
Inflammatory Factor ◽  
Tnf Α ◽  
Random Number Table ◽  
Factor Α ◽  
Necrosis Factor

Objective. To investigate the effects of dexmedetomidine intervention on serum inflammatory factor concentration and postoperative cognitive malfunction in elderly patients with general anesthesia. Methodology. 174 patients with general anesthesia were selected, who were categorized into a control group (HC) and a dexmedetomidine group (HS) using the random number table method, with 87 patients in individual groups. The dexmedetomidine group was pumped intravenously with dexmedetomidine at a loading dose of 1 μg/kg before induction of anesthesia for 15 min, followed by continuous intravenous pumping at a rate of 0.4 μg/kg/h, and the dosing was stopped at 30 min before concluding the surgery. The control group was administered the identical dose of saline in the same manner. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) levels and MMES scores were tested at 1 h before and 24 h after anesthesia. Results. Comparing to HC group, patients in the HS group had lower TNF-α and IL-6 levels at both scheduled points ( P  < 0.05). Conclusion. Dexmedetomidine reduced the expression of inflammatory factors in elderly patients with general anesthesia and effectively reduced the incidence of postoperative cognitive dysfunction after general anesthesia surgery.

scholarly journals Berberine Reduces Renal Cell Pyroptosis in Golden Hamsters with Diabetic Nephropathy through the Nrf2-NLRP3-Caspase-1-GSDMD Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Baozhu Ding ◽  
Songyan Geng ◽  
Xiaojie Hou ◽  
Xuelian Ma ◽  
Huazhou Xu ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Blood Lipids ◽  
Kidney Tissue ◽  
Inflammatory Factors ◽  
Control Group ◽  
Model Group ◽  
Golden Hamsters ◽  
Caspase 1 ◽  
Tnf Α ◽  
Nrf2 Expression

Objective. To observe the effect of berberine (BBR) on kidney cell pyroptosis in golden hamsters with diabetic nephropathy (DN) and to explore the molecular mechanism of its renal protection. Methods. Fifty clean-grade male golden hamsters were randomly divided into a control group (10) and a model building group (40). The DN model was established by high-sugar and high-fat feeding and injection of a small amount of STZ. After successful establishment of the model, they were randomly divided into a model group, western medicine group, and berberine high- and low-dose groups. The western medicine group was given irbesartan 13.5 mg/kg, and the berberine high- and low-dose groups were given BBR 200 mg/kg and 100 mg/kg, respectively, for 8 consecutive weeks. An automatic biochemical analyser was used to measure blood glucose, blood lipids, kidney function, MDA, and other indicators; radioimmunoassay was used to assess serum insulin; enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β, IL-6, IL-18, TNF-α; HE, PAS, and Masson staining were used to observe kidney pathological tissue morphology; western blot and real-time fluorescent quantitative PCR were used to assess protein and mRNA expression of molecules, such as Nrf2, NLRP3, Caspase-1, and GSDMD; and TUNEL staining was used to detect DNA damage. SPSS statistical software was used for the data analysis. Results. The kidney tissues of golden hamsters in the control group were normal; Nrf2 was highly expressed, serum MDA level was low, NLRP3 expression in kidney tissue was not obvious, Caspase-1 and GSDMD were weakly expressed, and only a few TUNEL-positive cells were observed. Compared with the control group, the golden hamsters in the model group had obvious renal pathological damage; blood glucose, blood lipids, renal function-related indexes, insulin, and inflammatory factors IL-1β, IL-6, IL-18, and TNF-α were increased ( P < 0.05 ); NLRP3, Caspase-1, and GSDMD expression was increased; Nrf2 expression was decreased; MDA level was increased ( P < 0.05 ); and the number of TUNEL-positive cells was increased. Compared with the model group, the pathological morphology of the kidney tissue of golden hamsters in the three treatment groups was significantly improved; blood glucose, blood lipids, renal function, and the expression of inflammatory factors IL-1β and IL-6 were reduced ( P < 0.05 ); NLRP3, Caspase-1, GSDMD, and other molecular proteins and mRNA expression were decreased; Nrf2 expression was increased; MDA level was decreased ( P < 0.05 ); and the number of TUNEL-positive cells was decreased. Conclusion. DN golden hamster kidney NLRP3-Caspase-1-GSDMD signalling was enhanced. BBR can reduce oxidative stress damage by regulating antioxidative Nrf2 and then regulating NLRP3-Caspase-1-GSDMD signalling to inhibit pyroptosis, antagonizing DN inflammation-induced damage.

scholarly journals Inhibition of BRD4 inhibits proliferation and promotes apoptosis of psoriatic keratinocytes

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaohui Sun ◽  
Pengfei Yang
Keyword(s):  
Mapk Pathway ◽  
Immunohistochemical Analysis ◽  
Severity Index ◽  
Mapk Signaling ◽  
Inflammatory Factors ◽  
Hacat Cells ◽  
Mice Model ◽  
Tnf Α ◽  
Related Proteins

Abstract Background Psoriasis is a common chronic recurrent inflammatory skin disease. The pathogenesis of psoriasis, such as other autoimmune diseases, is still unclear, which brings great difficulties to the treatment. This study aimed to investigate the role of bromine domain protein 4 (BRD4) in affecting the psoriatic keratinocytes. Methods Imiquimod-induced psoriasis mice model and TNF-α or IL-17A induced HaCAT cells, an experimental model in vitro for psoriasis, were constructed. The pathological skin changes at the back of mice were observed by hematoxylin and eosin (H&E) assay and evaluated by psoriasis area and severity index (PASI). KI67 expression and keratinocyte apoptosis at the skin tissues were, respectively, detected by Immunohistochemical analysis and TUNEL assay. The inflammatory factors in mice serum and culture supernatant were determined by ELISA assay. The related proteins expression of proliferation, apoptosis and MAPK pathway were detected by Western blot analysis. Results BRD4 expression was upregulated in injured skin on the back of imiquimod-induced mice and (+)-JQ1 relieved the skin injury by suppressing the inflammation and promoting apoptosis of keratinocytes. Consistently, BRD4 expression was also increased in TNF-α or IL-17A induced HaCAT cells. (+)-JQ1 suppressed the viability and inflammation, and promoted apoptosis of TNF-α or IL-17A induced HaCAT cells. In addition, the MAPK signaling pathway was inhibited by (+)-JQ1 whether in mice or HaCAT cells. Conclusions Inhibition of BRD4 inhibited proliferation and inflammation and promoted apoptosis of psoriatic keratinocytes.

Sign in / Sign up

Export Citation Format

Share Document