scholarly journals Non-Esterified Fatty Acids Over-Activate the TLR2/4-NF-Κb Signaling Pathway to Increase Inflammatory Cytokine Synthesis in Neutrophils from Ketotic Cows

2018 ◽  
Vol 48 (2) ◽  
pp. 827-837 ◽  
Author(s):  
Yuming Zhang ◽  
Xiaobing Li ◽  
Haolong Zhang ◽  
Zhibo Zhao ◽  
Zhicheng Peng ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Pyrrolidine Dithiocarbamate ◽  
Tlr4 Expression ◽  
Blood Concentrations ◽  
Esterified Fatty Acids ◽  
Tnf Α ◽  
High Concentrations

Background/Aims: Dairy cows with clinical ketosis display a negative energy balance and high blood concentrations of non-esterified fatty acids (NEFAs), the latter of which is an important pathological factor of ketosis in cows. The aims of this study were to investigate the inflammatory status of ketotic cows and to determine whether and through what underlying mechanism high levels of NEFAs induce an inflammatory response. Methods: Proinflammatory factors and the nuclear factor kappa B (NF-κB) signaling pathway were evaluated in neutrophils from clinical ketotic and control cows, using methods including western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. In vitro, the effects of NEFAs on the NF-κB signaling pathway in cow neutrophils were also evaluated using the above experimental techniques. Results: Ketotic cows displayed low blood concentrations of glucose and high blood NEFA and β-hydroxybutyrate concentrations. Importantly, Toll-like receptor 2 (TLR2) and TLR4 expression and IκBα and NF-κB p65 phosphorylation levels in neutrophils (PMNs) were significantly higher in ketotic cows than in control cows, indicating over-activation of the TLR2/4-induced NF-κB inflammatory pathway in PMNs in ketotic cows. The blood concentrations of the inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were also significantly increased in ketotic cows. Interestingly, we found that NEFAs were positively correlated with proinflammatory cytokines. In vitro, after pharmacological inhibition of TLR2 and TLR4 expression in cow neutrophils, TLR2 and TLR4 expression was significantly decreased, and the phosphorylation level of NF-κB p65 was also reduced. Cow neutrophils were treated with different concentrations of NEFAs and pyrrolidine dithiocarbamate (PDTC; an NF-κB inhibitor). High concentrations of NEFAs (0.5 and 1 mM) significantly increased TLR2 and TLR4 expression, IκBα and NF-κB p65 phosphorylation levels, NF-κB p65 transcriptional activity, and IL-6, IL-1β, and TNF-α synthesis in cow neutrophils. The inhibition of NF-κB by PDTC suppressed the NEFA-induced synthesis of proinflammatory cytokines. Conclusions: High concentrations of NEFAs can over-activate the TLR2/4-mediated NF-κB signaling pathway to induce the over-production of proinflammatory cytokines, thereby increasing inflammation in cows with clinical ketosis.

scholarly journals Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKβ/NF-κB signaling pathway

2018 ◽  
Vol 315 (1) ◽  
pp. C52-C61 ◽  
Author(s):  
Heng-Jun Zhou ◽  
Li-Qing Wang ◽  
Duan-Bu Wang ◽  
Jian-Bo Yu ◽  
Yu Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Tnf Α ◽  
Cord Injury

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKβ/NF-κB signaling pathway and an increase in the level of proinflammatory cytokines TNF-α and IL-1β. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-α and IL-1β production. Next, we confirmed that LPS-induced MALAT1 activated IKKβ/NF-κB signaling pathway and promoted the production of proinflammatory cytokines TNF-α and IL-1β through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-α, IL-1β levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs.

The effects of non-esterified fatty acids and β-hydroxybutyrate on the hepatic CYP2E1 in cows with clinical ketosis

2019 ◽  
Vol 86 (1) ◽  
pp. 68-72
Author(s):  
Zhicheng Peng ◽  
Xiaobing Li ◽  
Zhe Wang ◽  
Guowen Liu ◽  
Xinwei Li
Keyword(s):  
Oxidative Stress ◽  
Fatty Acids ◽  
Dairy Cows ◽  
Blood Concentrations ◽  
Cytochrome P4502e1 ◽  
Esterified Fatty Acids ◽  
Cyp2e1 Expression ◽  
Expression And Activity

AbstractDairy cows with ketosis display severe oxidative stress as well as high blood concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). Cytochrome P4502E1 (CYP2E1) plays an important role in the induction of oxidative stress. The aim of this study was to investigate CYP2E1 expression and activity in the liver of clinically ketotic cows (in vivo) and the effects of NEFA and BHB on CYP2E1 expression and activity in hepatocytes (in vitro). Dairy cows with clinical ketosis exhibited a low blood concentration of glucose but high concentrations of NEFA and BHB. Hepatic mRNA, protein expression, and activity of CYP2E1 were significantly higher in cows with clinical ketosis than in control cows. In vitro, both NEFA and BHB treatment markedly up-regulated the mRNA and protein expressions as well as activity of CYP2E1 in cow hepatocytes. Taken together, these results indicate that high levels of NEFA and BHB significantly up-regulate the expression and activity of hepatic CYP2E1, and may be influential in the induction of oxidative stress in cows with clinical ketosis.

Non-esterified fatty acids activate the ROS–p38–p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro

APOPTOSIS ◽  
2014 ◽  
Vol 19 (6) ◽  
pp. 984-997 ◽  
Author(s):  
Yuxiang Song ◽  
Xinwei Li ◽  
Yu Li ◽  
Na Li ◽  
Xiaoxia Shi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Signaling Pathway ◽  
Hepatocyte Apoptosis ◽  
Esterified Fatty Acids ◽  
Nrf2 Signaling Pathway

scholarly journals Effects of Methylprednisolone on Intracellular Bacterial Growth

2001 ◽  
Vol 8 (6) ◽  
pp. 1156-1163 ◽  
Author(s):  
G. Umberto Meduri ◽  
Siva Kanangat ◽  
Michael Bronze ◽  
David R. Patterson ◽  
Christopher U. Meduri ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Clinical Studies ◽  
Bacterial Infections ◽  
Dependent Manner ◽  
U937 Cells ◽  
Phagocytic Cells ◽  
Concentration Dependent Manner ◽  
Tnf Α ◽  
High Concentrations

ABSTRACT Clinical studies have shown positive associations among sustained and intense inflammatory responses and the incidence of bacterial infections. Patients presenting with acute respiratory distress syndrome (ARDS) and high levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and IL-6, have increased risk for developing nosocomial infections attributable to organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, andAcinetobacter spp., compared to those patients with lower levels. Our previous in vitro studies have demonstrated that these bacterial strains exhibit enhanced growth extracellularly when supplemented with high concentrations of pure recombinant TNF-α, IL-1β, or IL-6. In addition, we have shown that the intracellular milieu of phagocytic cells that are exposed to supraoptimal concentrations of TNF-α, IL-1β, and IL-6 or lipopolysaccharide (LPS) favors survival and replication of ingested bacteria. Therefore, we hypothesized that under conditions of intense inflammation the host's micromilieu favors bacterial infections by exposing phagocytic cells to protracted high levels of inflammatory cytokines. Our clinical studies have shown that methylprednisolone is capable of reducing the levels of TNF-α, IL-1β, and IL-6 in ARDS patients. Hence, we designed a series of in vitro experiments to test whether human monocytic cells (U937 cells) that are activated with high concentrations of LPS, which upregulate the release of proinflammatory cytokines from these phagocytic cells, would effectively kill or restrict bacterial survival and replication after exposure to methylprednisolone. Fresh isolates of S. aureus, P. aeruginosa, and Acinetobacter were used in our studies. Our results indicate that, compared with the control, stimulation of U937 cells with 100-ng/ml, 1.0-μg/ml, 5.0-μg/ml, or 10.0-μg/ml concentrations of LPS enhanced the intracellular survival and replication of all three species of bacteria significantly (for all, P = 0.0001). Stimulation with ≤10.0 ng of LPS generally resulted in efficient killing of the ingested bacteria. Interestingly, when exposed to graded concentrations of methylprednisolone, U937 cells that had been stimulated with 10.0 μg of LPS were able to suppress bacterial replication efficiently in a concentration-dependent manner. Significant reduction in numbers of CFU was observed at ≥150 μg of methylprednisolone per ml (Pvalues were 0.032, 0.008, and 0.009 for S. aureus, P. aeruginosa, and Acinetobacter, respectively). We have also shown that steady-state mRNA levels of TNF-α, IL-1β, and IL-6 in LPS-activated cells were reduced by treatment of such cells with methylprednisolone, in a concentration-dependent manner. The effective dose of methylprednisolone was 175 mg, a value that appeared to be independent of priming level of LPS and type of mRNA. We therefore postulate that a U-shaped relationship exists between the level of expression of TNF-α, IL-1β, and IL-6 within the phagocytic cells and their abilities to suppress active survival and replication of phagocytized bacteria.

Inhibition of binding of gonadal steroids to serum binding proteins by non-esterified fatty acids: the influence of chain length and degree of unsaturation

1989 ◽  
Vol 120 (2) ◽  
pp. 175-179 ◽  
Author(s):  
C. Street ◽  
R. J. S. Howell ◽  
L. Perry ◽  
S. Al-Othman ◽  
T. Chard
Keyword(s):  
Fatty Acids ◽  
Protein Binding ◽  
Unsaturated Fatty Acids ◽  
Late Pregnancy ◽  
Sex Hormone Binding Globulin ◽  
Partial Purification ◽  
Normal Female ◽  
Esterified Fatty Acids ◽  
Vitro Binding

Abstract. The effect of non-esterified fatty acids (NEFA) on the in vitro binding of testosterone, 5-alpha dihydrotestosterone and estradiol E2 to sex hormone binding globulin (SHBG) was examined using pooled normal female serum, and SHBG and albumin fractions obtained from the partial purification of late pregnancy serum. A range of saturated and unsaturated fatty acids were examined for their effect on steroid-protein binding. In normal female serum, NEFA added at physiological concentrations disrupted steroid-protein binding. The shorter chain (C8–C12) saturated acids and the poly-unsaturated acids proved to be more effective inhibitors than the longer chain saturated or mono-unsaturated acids. The greatest inhibition was obtained with E2 whereas the binding of dihydrotestosterone was least affected. With partially purified SHBG, the same concentrations of NEFA were less effective at inhibiting the binding of dihydrotestosterone and testosterone but elicited the same effect with E2. The binding of steroids to albumin appeared to be unaffected by these concentrations of NEFA.

Elevated non-esterified fatty acids impair survival and promote lipid accumulation and pro-inflammatory cytokine production in bovine endometrial epithelial cells

2018 ◽  
Vol 30 (12) ◽  
pp. 1770 ◽  
Author(s):  
W. Chankeaw ◽  
Y. Z. Guo ◽  
R. Båge ◽  
A. Svensson ◽  
G. Andersson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Lipid Accumulation ◽  
Negative Effects ◽  
Inflammatory Cytokine Production ◽  
Esterified Fatty Acids ◽  
Proliferation And Apoptosis ◽  
High Concentrations ◽  
Endometrial Epithelial Cells

Elevated non-esterified fatty acids (NEFAs) are associated with negative effects on bovine theca, granulosa and oviductal cells but the effects of NEFAs on bovine endometrial epithelial cells (bEECs) are not as well documented. The objective of this study was to define the effects of NEFAs on bEECs. Postprimary bEECs were treated with 150, 300 or 500 µM of either palmitic acid (PA), stearic acid (SA) or oleic acid (OA) or a mixture of NEFAs (150 µM of each FA) or 0.5% final concentration of vehicle ethanol (control). Viability and proliferation of bEECs exposed to 150 µM of each NEFA or a mixture of NEFAs were unaffected. Increased lipid accumulation was found in all treated groups (P < 0.01). In cells exposed to 500 µM of each NEFA and 300 µM PA decreased cell viability (P < 0.001), proliferation (P < 0.05) and increased apoptosis (P < 0.05) were observed. Treatment with 500 µM OA, PA and SA had the strongest effects on cell viability, proliferation and apoptosis (P < 0.05). Treatment with PA and OA increased interleukin-6 (IL-6) concentrations (P < 0.05), whereas only the highest concentration of PA, OA and SA stimulated IL-8 production (P < 0.05). These results suggest that high concentrations of NEFAs may impair endometrial function with more or less pronounced effects depending on the type of NEFA and time of exposure.

scholarly journals Ureaplasma urealyticum Modulates Endotoxin-Induced Cytokine Release by Human Monocytes Derived from Preterm and Term Newborns and Adults

2001 ◽  
Vol 69 (6) ◽  
pp. 3906-3915 ◽  
Author(s):  
Winston M. Manimtim ◽  
Jeffrey D. Hasday ◽  
Lisa Hester ◽  
Karen D. Fairchild ◽  
Judith C. Lovchik ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Ureaplasma Urealyticum ◽  
Human Monocytes ◽  
Cytokine Release ◽  
Proinflammatory Response ◽  
Pediatr Infect ◽  
High Inoculum ◽  
Tnf Α ◽  
Adult Cells

ABSTRACT We previously observed that Ureaplasma urealyticumrespiratory tract colonization in infants with a birth weight of ≤1,250 g was associated with increases in the tracheal aspirate proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) relative to the counterregulatory cytokine IL-6 during the first week of life (A. M. Patterson, V. Taciak, J. Lovchik, R. E. Fox, A. B. Campbell, and R. M. Viscardi, Pediatr. Infect. Dis. J. 17:321–328, 1998). We hypothesized thatU. urealyticum alters the host immune response in the presence of a coinflammatory stimulus (e.g., bacterial infection or hyperoxia) by shifting the balance of cytokine expression towards the proinflammatory cytokines. To test this hypothesis, we compared the release of TNF-α, IL-8, IL-6, and IL-10 in vitro by unstimulated andU. urealyticum (with or without lipopolysaccharide [LPS])-stimulated human monocytes from adult peripheral blood and from term and preterm cord blood. U. urealyticum alone and in combination with LPS induced concentration- and development-dependent changes in cytokine release. In vitro inoculation with low-inoculum U. urealyticum (103color-changing units [CCU]) (i) partially blocked the LPS-stimulated IL-6 release by all cells and reduced LPS-stimulated IL-10 release by preterm cells, (ii) stimulated TNF-α and IL-8 release by preterm cells, and (iii) augmented LPS-stimulated TNF-α release in all cells. In preterm cells, high-inoculum U. urealyticum(106 CCU) (i) stimulated TNF-α and IL-8, but not IL-6 or IL-10, release and (ii) augmented LPS-stimulated TNF-α and IL-8 release. High-inoculum U. urealyticum (i) stimulated release of all four cytokines in term cells and IL-8 release in adult cells and (ii) augmented LPS-induced TNF-α, IL-10, and IL-8 release in term cells but did not significantly affect LPS-induced cytokine release in adult cells. We speculate that U. urealyticum enhances the proinflammatory response to a second infection by blocking expression of counterregulatory cytokines (IL-6 and IL-10), predisposing the preterm infant to prolonged and dysregulated inflammation, lung injury, and impaired clearance of secondary infections.

scholarly journals Resveratrol Plays a Protective Role against Premature Ovarian Failure and Prompts Female Germline Stem Cell Survival

2019 ◽  
Vol 20 (14) ◽  
pp. 3605 ◽  
Author(s):  
Yu Jiang ◽  
Zhaoyuan Zhang ◽  
Lijun Cha ◽  
Lili Li ◽  
Dantian Zhu ◽  
...  
Keyword(s):  
Protective Effect ◽  
Signaling Pathway ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Productive Capacity ◽  
Tnf Α ◽  
Hh Signaling ◽  
Female Germline

This study was designed to investigate the protective effect of resveratrol (RES) on premature ovarian failure (POF) and the proliferation of female germline stem cells (FGSCs) at the tissue and cell levels. POF mice were lavaged with RES, and POF ovaries were co-cultured with RES and/or GANT61 in vitro. FGSCs were pretreated with Busulfan and RES and/or GANT61 and co-cultured with M1 macrophages, which were pretreated with RES. The weights of mice and their ovaries, as well as their follicle number, were measured. Ovarian function, antioxidative stress, inflammation, and FGSCs survival were evaluated. RES significantly increased the weights of POF mice and their ovaries as well as the number of follicles, while it decreased the atresia rate of follicles. Higher levels of Mvh, Oct4, SOD2, GPx, and CAT were detected after treatment with RES in vivo and in vitro. RES treatment resulted in significantly lower TNF-α and IL-6 concentrations and an obviously higher IL-10 concentration in the ovaries. In FGSCs, higher Mvh, Oct4, and SOD2 concentrations and lower TNF-α, IL-6, and MDA concentrations were measured in the RES group. Blockage of the Hh signaling pathway reversed the protective effect of RES on FGSCs. In conclusion, RES effectively improved the ovarian function of the POF model and the productive capacity of FGSCs via relieving oxidative stress and inflammation and a mechanism involving the Hh signaling pathway, suggesting that RES is a potential agent against POF and can aid in the survival of FGSCs.

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