“Subclinical” gentamicin nephrotoxicity: a potential risk factor for exaggerated endotoxin-driven TNF-α production

2007 ◽  
Vol 293 (1) ◽  
pp. F43-F49 ◽  
Author(s):  
Richard A. Zager
Keyword(s):  
Antimicrobial Effect ◽  
Specific Response ◽  
Mrna Levels ◽  
Gram Negative ◽  
Protein Levels ◽  
Target Organs ◽  
Gentamicin Treatment ◽  
Tnf Α ◽  
Oxide Synthase ◽  
And Control

This study sought to determine whether gentamicin, a mainstay in treating Gram-negative sepsis, alters endotoxin (lipopolysaccharide; LPS)-driven TNF-α increases. CD-1 mice received 1 day of gentamicin treatment. Either 0, 24, or 72 h later, gentamicin-treated and control mice were injected with LPS. Renal cortical and plasma TNF-α, as well as MCP-1, protein levels were measured 2 or 24 h post-LPS injection. Renal cortical mRNAs for TNF-α, MCP-1, IL-10, and inducible nitric oxide synthase (iNOS) were also determined. Finally, gentamicin's potential impact(s) on TNF-α/MCP-1 mRNA levels in nontraditional “target” organs (liver, spleen) was assessed. Gentamicin, when administered alone, slightly increased renal cortical TNF-α and MCP-1 mRNAs, but without changing plasma or renal TNF-α/MCP-1 protein levels. The gentamicin protocol induced no overt renal damage (assessed by blood urea nitrogen, creatinine, and histology). Nevertheless, gentamicin augmented LPS responsiveness, as manifested, in part, by a doubling of LPS-induced plasma TNF-α increases (vs. LPS injection alone). Plasma and renal cortical MCP-1 protein levels were also selectively enhanced. Gentamicin augmented LPS-driven renal mRNA increases (TNF-α, MCP-1, IL-10, iNOS). However, this was not an entirely renal-specific response, since gentamicin also enhanced basal and LPS-stimulated hepatic TNF-α mRNA levels. Subclinical gentamicin toxicity can potentiate LPS-driven TNF-α increases. Alterations in multiple proinflammatory (TNF-α; MCP-1; iNOS) and anti-inflammatory (IL-10) genes in the kidney, and possibly in extrarenal organs, may be involved. Thus gentamicin's activity in Gram-negative sepsis may extend beyond its traditional antimicrobial effect.

scholarly journals Naphthoquinone Derivatives with Anti-Inflammatory Activity from Mangrove-Derived Endophytic Fungus Talaromyces sp. SK-S009

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 576 ◽  
Author(s):  
Hongju Liu ◽  
Chong Yan ◽  
Changqun Li ◽  
Tingting You ◽  
Zhigang She
Keyword(s):  
Nitric Oxide ◽  
Endophytic Fungus ◽  
Raw 264.7 Cells ◽  
Inflammatory Factors ◽  
No Production ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Tnf Α ◽  
Ic50 Values ◽  
Oxide Synthase

Twelve 1, 4-naphthoquinone derivatives, including two new (1 and 2) and 10 known (3–12), were obtained from endophytic fungus Talaromyces sp. SK-S009 isolated from the fruit of Kandelia obovata. All structures were identified through extensive analysis of the nuclear magnetic resonance (NMR), mass spectrometry (MS) and circular dichroism (CD), as well as by comparison with literature data. These compounds significantly inhibited the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in the murine macrophage cell line (RAW 264.7 cells). The half maximal inhibitory concentration (IC50) values, except for compound 2, were lower than that of indomethacin (26.3 μM). Compound 9 inhibited the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expressions in RAW 264.7 macrophages. Additionally, compound 9 reduced the mRNA levels of pro-inflammatory factors interleukin (IL)1β, IL-6, and tumor necrosis factor (TNF)-α. The results of this study demonstrated that these 1, 4-naphthoquinone derivatives can inhibit LPS-induced inflammation.

scholarly journals IL-33/ST2 axis promotes the inflammatory response of nasal mucosal epithelial cells through inducing the ERK1/2 pathway

2020 ◽  
Vol 26 (6) ◽  
pp. 505-513
Author(s):  
Yun-Qiu Li ◽  
Yu Zhong ◽  
Xu-Ping Xiao ◽  
Dan-Dan Li ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Ar Model ◽  
Inflammatory Factors ◽  
Mrna Levels ◽  
Model Group ◽  
Protein Levels ◽  
Tnf Α ◽  
Der P1 ◽  
The Relationship

Allergic rhinitis (AR) is a nasal mucosal inflammatory disease mediated by environmental allergens. At present, the relationship between the IL-33/ST2 axis, ERK1/2 pathway and AR progression needs further exploration. In our study, an AR model was constructed in vitro by treating HNEpC cells with Der p1. qRT-PCR was applied to assess the mRNA levels of IL-33, ST2, TNF-α, IL-6, and IL-8. Western blotting was used to measure the protein levels of IL-33, ST2, and the downstream proteins p-ERK1/2, ERK1/2, p-RSK, and RSK. IL-6, IL-8, IL-33, and TNF-α protein levels in cell supernatants were evaluated by ELISA. Flow cytometry was performed to check cell apoptosis of HNEpC in the presence or absence of Der p1. Our results indicate that the relative levels of IL-33, ST2, TNF-α, IL-6, and IL-8 were increased significantly in the AR model group. The above effects were notably reversed after transfection with shIL-33 or shST2. IL-33 stimulation further resulted in the increase in both ST2 and inflammation-associated cytokines, and these effects were restored after shST2 treatment. Also, the levels of inflammatory factors induced by IL-33 stimulation or ST2 overexpression were reversed after applying an ERK1/2 pathway blocker. In conclusion, IL-33/ST2 mediated inflammation of nasal mucosal epithelial cells by inducing the ERK1/2 pathway.

STAT3 Silencing as a Novel Therapeutic Strategy for Activated B Cell-Type Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 926-926
Author(s):  
Anna Scuto ◽  
Maciej Kujawski ◽  
Claudia Kowolik ◽  
Hua Yu ◽  
Stephen Forman ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mrna Levels ◽  
Down Regulation ◽  
Protein Levels ◽  
Stat3 Signaling ◽  
Marrow Stroma ◽  
And Control

Abstract Abstract 926 Among the non-Hodgkin's lymphomas, the diffuse large B cell lymphoma (DLBCL) represents the most frequent (30%) of the aggressive lymphomas. Persistent STAT3 signaling contributes to malignant progression in many diverse human tumors. IL-6 and IL-10 are major activators of STAT3 signaling and are important in the pathophysiology of DLBCL. STAT3 has been found to be persistently active in activated B cells (ABC), which are non-germinal center-derived DLBCL cells. We studied the consequences of STAT3 inhibition on multiple biological functions in two representative human cell lines of this group, Ly3 and Ly10 cells. For this purpose, we established stably transduced STAT3 shRNA-expressing lentivirus Ly3 cells, control lentivirus Ly3 cells, STAT3 shRNA-expressing lentivirus Ly10 cells and control lentivirus Ly10 cells. The stable expression of STAT3 shRNA results in 40-50% reduction of total STAT3 protein levels in the STAT3 shRNA lentivirus Ly3 cells compared to the control lentivirus cells. STAT3 down-regulation induced inhibition of cell proliferation (approximately 40%). Ly3 cells respond to IL-10 more than to IL-6 in terms of proliferation; both cytokines induced less proliferation in the STAT3 shRNA lentivirus Ly3 cells compared to the control lentivirus Ly3 cells. Similar results were obtained in Ly10 cells, which respond more to IL-6 than to IL-10 in terms of proliferation. We analyzed by quantitative real-time PCR the mRNA levels of different STAT3 target genes and observed significant reduction in mRNA levels of Mcl-1, Bcl-xL and Survivin in STAT3 shRNA lentivirus Ly3 cells, as well as significant reduction of Cyclin D2 and up-regulation of STAT1 in shRNA lentivirus Ly10 cells. Comparison of these gene expression profiles with data obtained from other B-cell lymphoma cell lines revealed that silencing of STAT3 resulted in down-regulation of different STAT3 target genes in a cell-dependent manner. We also observed that both STAT3 and control lentivirus Ly3 cells have the same protein levels of c-Myc; nevertheless STAT3 silencing resulted in inhibition of IL-10-inducible upregulation of c-Myc. We next investigated the effect of STAT3 inhibition on adhesion to bone marrow stroma and chemotaxis. STAT3 shRNA lentivirus Ly3 cells adhered less to the stroma layer than control cells, and the longer they were cocultured with the stroma cells in the presence of serum-free media the more they lost the ability to adhere. Moreover, STAT3 shRNA lentivirus Ly3 cells had decreased capacity to migrate toward SDF-1 alpha, an important factor that mediates proliferation, survival, chemotaxis, migration and adhesion into bone marrow stroma. Radiation, in combination with chemotherapy, is one of the therapies used for DLBCL patients. We therefore investigated whether STAT3 down-regulation sensitized Ly3 cells to radiation. Radiation induced a higher accumulation of phospho-H2A.X (first sentinel event following DNA damage such as DSBs) and apoptosis in STAT3 shRNA lentivirus cells compared to control cells. Moreover, IL-6 and IL-10 protected the STAT3 shRNA lentivirus Ly3 cells less than the control cells from the induction of phospho-H2A.X following radiation. We further investigated the effect of STAT3 silencing in animal models of Ly3 lymphoma (Nude or NOD-SCID mice). Tumors in control lentivirus Ly3-bearing mice grew robustly, whereas tumors in STAT3 shRNA lentivirus Ly3-bearing mice regressed 5 days after injection. This tumor regression was associated with Caspase-3-dependent apoptosis, significant reduction of STAT3 target genes at the protein level such as Mcl-1, c-Myc and Survivin (approximately 40% to 60% inhibition), and reduction of cytokine production such as IL-10, IL-15, Leptin and Thrombopoietin. Taken together, these results suggest that inhibition of STAT3 is a potential promising approach in the therapy of ABC-type DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals TNF‑α treatment increases DKK1 protein levels in primary osteoblasts via upregulation of DKK1 mRNA levels and downregulation of miR‑335‑5p

2020 ◽  
Vol 22 (2) ◽  
pp. 1017-1025
Author(s):  
Shanshan Li ◽  
Yixin Yin ◽  
Liping Yao ◽  
Ziyi Lin ◽  
Shengjun Sun ◽  
...  
Keyword(s):  
Mrna Levels ◽  
Protein Levels ◽  
Tnf Α ◽  
Primary Osteoblasts

Hypothalamic nitric oxide synthase is depressed in cholestatic rats

1997 ◽  
Vol 272 (5) ◽  
pp. G1034-G1040 ◽  
Author(s):  
M. G. Swain ◽  
T. Le ◽  
A. W. Tigley ◽  
P. Beck
Keyword(s):  
Nitric Oxide ◽  
Polymerase Chain Reaction ◽  
Steady State ◽  
Nitric Oxide Synthase ◽  
Mrna Levels ◽  
Chain Reaction ◽  
Bile Duct Resection ◽  
Protein Levels ◽  
Polymerase Chain ◽  
Oxide Synthase

We examined hypothalamic nitric oxide synthase (NOS) levels and release as well as steady-state mRNA levels in rats with cholestasis due to bile duct resection (BDR) and in sham-resected control rats. BDR rats had a significant reduction in hypothalamic NOS-containing neurons in the hypothalamic paraventricular nucleus as determined by NADPH-diaphorase staining, compared with sham-resected controls. In addition, NOS activity, measured indirectly by determining nitrite release from hypothalamic explants, was significantly lower in BDR rats compared with sham-resected animals. Hypothalamic steady-state NOS mRNA levels [brain constitutive NOS (bNOS)] were determined by semiquantitative reverse transcription-polymerase chain reaction and were found to be increased 1.5-fold in BDR rats compared with sham rats. In summary, BDR rats have diminished hypothalamic NOS levels and activity coupled with enhanced steady-state bNOS mRNA levels, suggesting that depressed hypothalamic NOS protein levels are due to posttranscriptional defects.

Significance of changes in TNF-α and IL-10 levels in the progression of heart failure subsequent to myocardial infarction

2006 ◽  
Vol 291 (1) ◽  
pp. H106-H113 ◽  
Author(s):  
K. Kaur ◽  
A. K. Sharma ◽  
P. K. Singal
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Cardiac Function ◽  
Interleukin 10 ◽  
Mrna Levels ◽  
Protein Ratio ◽  
Protein Levels ◽  
Tnf Α ◽  
Membrane Bound

We tested whether a decrease in the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α) correlates with the decrease in cardiac function in heart failure. It has been suggested that TNF-α plays a role in the progression of heart failure, and the effect of TNF-α in many tissues is modulated by IL-10. Any relation of these two cytokines to heart failure has never been examined. Cardiac function was assessed by echocardiographic and hemodynamic techniques in coronary artery-ligated rats at 1, 4, 8, and 16 wk after myocardial infarction (MI). Membrane-bound and soluble fractions of TNF-α and IL-10 proteins, the ratio of TNF-α to IL-10, and TNF-α and IL-10 mRNA levels were analyzed. Losartan was used to modify cardiac function in rats 4 wk after MI to further validate the relation between the IL-10-to-TNF-α ratio and cardiac function. Cardiac function deteriorated with time in all coronary artery-ligated groups, with severe failure at 16 wk after MI. Membrane-bound and soluble TNF-α protein fractions were increased 1 and 4 wk after MI, whereas TNF -α mRNA was increased 4 and 8 wk after MI. Membrane-bound IL-10 protein and mRNA levels were decreased 4, 8, and 16 wk after MI. The decrease in the IL-10-to-TNF-α protein ratio in all coronary artery-ligated groups correlated with the depressed cardiac function. Losartan improved cardiac function, membrane-bound and soluble TNF-α and IL-10 protein levels, the ratio of IL-10 to TNF-α, and IL-10 mRNA. This study suggests that a decrease in IL-10 and IL-10-to-TNF-α ratio correlates with depressed cardiac function.

scholarly journals Dihydromyricetin attenuates inflammation through TLR4/NF-kappaB pathway

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 719-725 ◽  
Author(s):  
Nianshui Jing ◽  
Xinnan Li
Keyword(s):  
Primary Response ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α ◽  
Cox 2 ◽  
Nf Kappab ◽  
Factor Α ◽  
Oxide Synthase

AbstractMicroglia plays a complex role in neuroinflammation, which has been implicated in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This study aims to explore the effect and mechanism of Dihydromyricetin (DHM) on lipopolysaccharide (LPS)-induced inflammation in microglial BV-2 cells. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide (MTT) assay. The pro-inflammatory mediators and cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α); inducible nitric oxide synthase (iNOS); and cyclooxygenase 2 (COX-2) were measured by enzyme-linked immunosorbent assay (ELISA) and/or quantitative real-time PCR (qRT-PCR). The expression of p-p65, p-IκBα, toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) were analyzed by western blot. The present study showed that DHM treatment alleviated LPS-induced viability reduction, suppressed the mRNA levels of IL-6, IL‐1β and TNF-α, inhibited the mRNA and protein expression of iNOS and COX-2, and attenuated the activation of NF-кB and TLR4 signaling in a concentration-dependent manner. In conclusion, DHM exerts an anti-inflammatory effect on LPS-induced BV-2 microglial cells, possibly through TRL4/NF-κB signaling pathway.

GRIM-19, a gene associated with retinoid-interferon-induced mortality, affects endometrial receptivity and embryo implantation

2017 ◽  
Vol 29 (7) ◽  
pp. 1447 ◽  
Author(s):  
Yang Yang ◽  
Yanyan Sun ◽  
Laiyang Cheng ◽  
Anna Li ◽  
Yanjun Shen ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Embryo Implantation ◽  
Pregnant Mouse ◽  
Endometrial Receptivity ◽  
Mrna Levels ◽  
Protein Levels ◽  
Tnf Α ◽  
Pregnant Mice ◽  
Adhesion Rate

GRIM-19 is associated with apoptosis, abnormal proliferation, immune tolerance and malignant transformation, and it also plays an important role in early embryonic development. Although the homologous deletion of GRIM-19 causes embryonic lethality in mice, the precise role of GRIM-19 in embryo implantation has not been elucidated. Here we show that GRIM-19 plays an important role in endometrial receptivity and embryo implantation. Day 1 to Day 6 pregnant mouse uteri were collected. Immunohistochemistry studies revealed the presence of GRIM-19 on the luminal epithelium and glandular epithelium throughout the implantation period in pregnant mice. The protein and mRNA levels of GRIM-19 were markedly decreased on Day 4 of pregnancy in pregnant mice, but there was no change in GRIM-19 levels in a group of pseudopregnant mice. Overexpression of GRIM-19 decreased the adhesion rate of RL95–2–BeWo co-cultured spheroids and increased apoptosis. Furthermore, STAT3 and IL-11 mRNA and protein levels were reduced by overexpressing GRIM-19, but protein and mRNA levels of TNF-α were increased. These findings indicate the involvement of GRIM-19 in the embryo implantation process by regulating adhesion, apoptosis and immune tolerance.

scholarly journals Formalin Injection Causes a Coordinated Spinal Cord CO/NO-cGMP Signaling System Response

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-33 ◽  
Author(s):  
Xiaoyou Shi ◽  
Xiangqi Li ◽  
J David Clark
Keyword(s):  
Spinal Cord ◽  
System Response ◽  
Noxious Stimulation ◽  
Formalin Injection ◽  
Specific Response ◽  
Mrna Levels ◽  
Signalling System ◽  
Time Points ◽  
Protein Levels ◽  
Cgmp Signalling

Background: The CO/NO-cGMP signalling system participates in the regulation of many physiological processes. The roles this system plays in spinal cord nociceptive signalling are particularly important. While individual components have been examined in isolation, little study has been dedicated to understanding the regulation and functioning of the system as a whole. Results: In these studies we examined the time course of expression of 13 genes coding for components of this system including isoforms of the heme oxygenase (HO), nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), cGMP dependent protein kinase (PKG) and phosphodiesterase (PDE) enzyme systems. Of the 13 genes studied, 11 had spinal cord mRNA levels elevated at one or more time points up to 48 hours after hindpaw formalin injection. Of the 11 with elevated mRNA, 8 had elevated protein levels 48 hours after formalin injection when mechanical allodynia was maximal. No component had an increased protein level which did not have an increased mRNA level at one or more time points. Injection of morphine 10 mg/kg prior to formalin completely abolished the acute nociceptive behaviours, but did not alter the degree of sensitivity which developed in the formalin treated hind paws during the subsequent 48 hours. Morphine treatment did, however, eliminate formalin induced increases in enzyme protein levels. Conclusion: Our results indicate that the expression of the components of the CO/NO-cGMP signalling system seems to be coordinated in such a way that a generalized multi-level enhancement rather than a tightly limited step specific response occurs with noxious stimulation. Furthermore, the analgesic morphine administered prior to noxious stimulation can prevent long-term changes in gene expression though not necessarily nociceptive sensitisation.

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