共查询到20条相似文献,搜索用时 15 毫秒
1.
Castillo A Islam MT Prieto MC Majid DS 《American journal of physiology. Renal physiology》2012,302(12):F1650-F1657
Acute administration of tumor necrosis factor-α (TNF-α) resulted in decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) but induced diuretic and natriuretic responses in mice. To define the receptor subtypes involved in these renal responses, experiments were conducted to assess the responses to human recombinant TNF-α (0.3 ng·min(-1)·g body wt(-1) iv infusion for 75 min) in gene knockout (KO) mice for TNF-α receptor type 1 (TNFαR1 KO, n = 5) or type 2 (TNFαR2 KO, n = 6), and the results were compared with those obtained in corresponding wild-type [WT (C57BL/6), n = 6] mice. Basal levels of RBF (PAH clearance) and GFR (inulin clearance) were similar in TNFαR1 KO, but were lower in TNFαR2 KO, than WT mice. TNF-α infusion in WT mice decreased RBF and GFR but caused a natriuretic response, as reported previously. In TNFαR1 KO mice, TNF-α infusion failed to cause such vasoconstrictor or natriuretic responses; rather, there was an increase in RBF and a decrease in renal vascular resistance. Similar responses were also observed with infusion of murine recombinant TNF-α in TNFαR1 KO mice (n = 5). However, TNF-α infusion in TNFαR2 KO mice caused changes in renal parameters qualitatively similar to those observed in WT mice. Immunohistochemical analysis in kidney slices from WT mice demonstrated that while both receptor types were generally located in the renal vascular and tubular cells, only TNFαR1 was located in vascular smooth muscle cells. There was an increase in TNFαR1 immunoreactivity in TNFαR2 KO mice, and vice versa, compared with WT mice. Collectively, these functional and immunohistological findings in the present study demonstrate that the activation of TNFαR1, not TNFαR2, is mainly involved in mediating the acute renal vasoconstrictor and natriuretic actions of TNF-α. 相似文献
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《遗传学报》2022,49(4):269-278
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease, is featured by significantly elevated levels of various proinflammatory cytokines. Among numerous proinflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α), plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression is regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in the future. 相似文献
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Peilin Han Qingbo Cui Shulong Yang Hao Wang Peng Gao Zhaozhu Li 《Biotechnology letters》2017,39(5):711-719
Objectives
To investigate the effects of tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) on the proliferation and differentiation of tendon-derived stem cells (TDSC).Results
TNF-α inhibits the proliferation and tenogenic/osteogenic differentiation of TDSC but, after simultaneous or sequential treatment with TGF-β1 and TNF-α, the expression of tenogenic/osteogenic-related marker and proliferation of TDSC was significantly increased. During these processes, Smad2/3 and Smad1/5/8 were highly phosphorylated, meaning that the TGF-β and BMP signaling pathways were highly activated. Further study revealed that the expression of Inhibitor-Smad appeared to be negatively correlated to the proliferation and differentiation of TDSC.Conclusions
Combining the use of TNF-α and TGF-β1 could improve the proliferation and differentiation of TDSC in vitro, and the expression of I-Smad is negatively correlated with TDSC proliferation and differentiation.4.
Kim Kyoung Ah Cho Yong-Yeun Cho Jung Sik Yang Ki Hwa Lee Woon Kyu Lee Kweon-Haeng Kim Yun Shin Lim Young 《Molecular and cellular biochemistry》2002,(1):205-209
Tumor necrosis factor-alpha (TNF-) is believed to play a central role in the pathogenesis of pneumoconiosis. TNF2, a polymorphism in the TNF- gene promoter, has been associated with an increase in TNF- production and airway inflammation. To investigate the frequency of TNF2 in patients who have coal workers' pneumoconiosis (CWP) and to determine whether it is associated with development of a large opacity in CWP, we investigated the expression of the TNF2 allele in 80 patients who had CWP and in 54 healthy controls using restriction fragment length polymorphism (RFLP). Compared to controls (10.2%), the frequency of the TNF2 allele was greater in the CWP patients (20.6%). Furthermore, the TNF2 allele was very common in patients who had a large opacity (28.2%) in comparison with 13.4% in those with simple CWP. From these data, we suggest that the TNF2 allele is associated with the development of a large opacity in CWP. 相似文献
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Tumor necrosis factor-α (TNF-α) is a polypeptide cytokine that has been associated with muscle wasting and weakness in inflammatory disease. Despite its potential importance in muscle pathology, the direct effects of TNF-α on skeletal muscle have remained undefined until recently. Studies of cultured muscle cells indicate that TNF-α disrupts the differentiation process and can promote catabolism in mature cells. The latter response appears to be mediated by reactive oxygen species and nuclear factor-κB which upregulate ubiquitin/proteasome activity. This commentary outlines our current understanding of TNF-α effects on skeletal muscle and the mechanism of TNF-α action. 相似文献
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Wei Zhang Hiroshi Kudo Shiho Fujisaka Toshiro Sugiyama Naihong Chen Terumi Takahara 《Biochemical and biophysical research communications》2010,391(4):1731-1736
Non-alcoholic steatohepatitis (NASH) develops in a subset of patients with non-alcoholic fatty liver disease (NAFLD), but the exact mechanisms involved in the progression of NAFLD to NASH remain poorly understood. We investigated the role of tumor necrosis factor-α (TNF-α) in the apoptosis of hepatocytes that is related to the severity of NASH. We separated primary hepatocytes from the NAFLD liver caused by a high-fat diet. The production of intracellular reactive oxygen species was increased in steatotic hepatocytes, which were also sensitive to TNF-α. This factor induced significant apoptosis through the signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) pathway. We describe here a novel culture model of steatotic hepatocytes separated from the NAFLD liver, and demonstrate that TNF-α induces their apoptosis in vitro. 相似文献
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Atorvastatin has been shown to reduce resistin expression in macrophages after pro-inflammatory stimulation. However, the mechanism of reducing resistin expression by atorvastatin is not known. Therefore, we sought to investigate the molecular mechanisms of atorvastatin for reducing resistin expression after proinflammatory cytokine, tumor necrosis factor-α (TNF-α) stimulation in cultured macrophages. Cultured macrophages were obtained from human peripheral blood mononuclear cells. TNF-α stimulation increased resistin protein and mRNA expression and atorvastatin inhibited the induction of resistin by TNF-α. Addition of mevalonate induced resistin protein expression similar to TNF-α stimulation. However, atorvastatin did not have effect on resistin protein expression induced by mevalonate. SP600125 and JNK small interfering RNA (siRNA) completely attenuated the resistin protein expression induced by TNF-α and mevalonate. TNF-α induced phosphorylation of Rac, while atorvastatin and Rac-1 inhibitor inhibited the phosphorylation of Rac induced by TNF-α. The gel shift and promoter activity assay showed that TNF-α increased AP-1-binding activity and resistin promoter activity, while SP600125 and atorvastatin inhibited the AP-1-binding activity and resistin promoter activity induced by TNF-α. Recombinant resistin and TNF-α significantly reduced glucose uptake in cultured macrophages, while atorvastatin reversed the reduced glucose uptake by TNF-α. In conclusion, JNK and Rac pathway mediates the inhibitory effect of atorvastatin on resistin expression induced by TNF-α. 相似文献
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Arylamines and nitroarenes are very important intermediates in the industrial manufacture of dyes, pesticides and plastics, and are significant environmental pollutants. The metabolic steps of N-oxidation and nitroreduction to yield N-hydroxyarylamines are crucial for the toxic properties of arylamines and nitroarenes. Nitroarenes are reduced by microorganisms in the gut or by nitroreductases and aldehyde dehydrogenase in hepatocytes to nitrosoarenes and N-hydroxyarylamines. N-Hydroxyarylamines can be further metabolized to N-sulphonyloxyarylamines, N-acetoxyarylamines or N-hydroxyarylamine N-glucuronide. These highly reactive intermediates are responsible for the genotoxic and cytotoxic effects of this class of compounds. N-Hydroxyarylamines can form adducts with DNA, tissue proteins, and the blood proteins albumin and haemoglobin in a dose-dependent manner. DNA and protein adducts have been used to biomonitor humans exposed to such compounds. All these steps are dependent on enzymes, which are present in polymorphic forms. This article reviews the metabolism of arylamines and nitroarenes and the biomonitoring studies performed in animals and humans exposed to these substances. 相似文献
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Background
Skeletal muscle wasting is a debilitating consequence of large number of disease states and conditions. Tumor necrosis factor-α (TNF-α) is one of the most important muscle-wasting cytokine, elevated levels of which cause significant muscular abnormalities. However, the underpinning molecular mechanisms by which TNF-α causes skeletal muscle wasting are less well-understood.Methodology/Principal Findings
We have used microarray, quantitative real-time PCR (QRT-PCR), Western blot, and bioinformatics tools to study the effects of TNF-α on various molecular pathways and gene networks in C2C12 cells (a mouse myoblastic cell line). Microarray analyses of C2C12 myotubes treated with TNF-α (10 ng/ml) for 18h showed differential expression of a number of genes involved in distinct molecular pathways. The genes involved in nuclear factor-kappa B (NF-kappaB) signaling, 26s proteasome pathway, Notch1 signaling, and chemokine networks are the most important ones affected by TNF-α. The expression of some of the genes in microarray dataset showed good correlation in independent QRT-PCR and Western blot assays. Analysis of TNF-treated myotubes showed that TNF-α augments the activity of both canonical and alternative NF-κB signaling pathways in myotubes. Bioinformatics analyses of microarray dataset revealed that TNF-α affects the activity of several important pathways including those involved in oxidative stress, hepatic fibrosis, mitochondrial dysfunction, cholesterol biosynthesis, and TGF-β signaling. Furthermore, TNF-α was found to affect the gene networks related to drug metabolism, cell cycle, cancer, neurological disease, organismal injury, and abnormalities in myotubes.Conclusions
TNF-α regulates the expression of multiple genes involved in various toxic pathways which may be responsible for TNF-induced muscle loss in catabolic conditions. Our study suggests that TNF-α activates both canonical and alternative NF-κB signaling pathways in a time-dependent manner in skeletal muscle cells. The study provides novel insight into the mechanisms of action of TNF-α in skeletal muscle cells. 相似文献12.
Richard O Williams 《Arthritis research & therapy》2008,10(3):113
Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses. 相似文献
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BackgroundPsoriasis is a chronic, immune-mediated, inflammatory skin disease affecting genetically predisposed individuals and requiring long-term treatment. The etiology of psoriasis is not fully understood. This article aimed to determine association between genetic polymorphisms in tumor necrosis factor-α (TNF -α) promoter ?308 (rs1800629) and ?238 (rs 361,525) and its serum level in psoriasis patients.MethodsThe study was conducted on 70 patients with psoriasis and 70 age and sex-matched, healthy individuals. All patients were subjected to history taking and complete medical examination. The polymorphisms of TNF -α promoter gene ?308 (rs1800629) and ?238 (rs 361,525) were detected by real time PCR and Serum levels of TNF -α were measured by ELISA technique.ResultsAG polymorphism and A allele of TNF-α ?238 G/A (rs 361,525) were significantly more in patients than controls, whereas AG polymorphism and A allele of TNF-α ?308 G/A (rs1800629) were significantly more in controls than patients. There were significant high levels of TNF-α in serum of patients in comparison to controls.ConclusionsThe AG polymorphism and A allele of TNF-α ?238G/A (rs 361,525) may act as a risk factor for occurrence of psoriasis, whereas AG polymorphism and A allele of TNF-α ?308G/A (rs1800629) may have protective role. There is pivotal role of TNF-α as a pro-inflammatory mediator in pathogenesis of psoriasis. 相似文献
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Büyükakilli B Atici A Özkan A Balli E Güneş S Turhan AH Hallioglu O Kanik A 《Life sciences》2012,90(21-22):838-845
AimsPerinatal hypoxic-ischemic insult has acute and long term deleterious effects on many organs including heart. Although tumor necrosis factor alpha (TNF-α) has been reported to increase soon after hypoxia, the inhibition of this mediator has not been documented. The aim of this study was to investigate the effects of a TNF-α inhibitor (etanercept) on contractility and ultrastructure of rat heart muscles exposed to hypoxia-ischemia during neonatal period.Main methodsForty-five seven-day old rats divided into three groups were included in this study. The right carotid arteries of Saline and Etanercept groups of rats were ligated and kept in a hypoxia chamber containing 8% oxygen for 2 h. Immediately after hypoxia, while Etanercept group was administered 10 mg/kg etanercept, Saline group had only saline intraperitoneally. The carotid arteries of rats in Sham group were located without ligation and hypoxia. Mechanical activity of heart was recorded and tissue samples were examined by electron microscopy in the sixteenth week following the hypoxia-ischemia.Key findingsWhile atrial contractile force in Etanercept group was similar to Sham group, there was significant decrease in Saline group (p < 0.001). However, there was only non-significant decrease in ventricular contractility of Saline group comparing to Sham group (p > 0.05). After hypoxia-ischemia, ultrastructural degenerative changes and mitochondrial damage in atriums of Etanercept group were significantly less severe than Saline group.SignificanceThis study demonstrated that neonatal hypoxia-ischemia caused long term cardiac dysfunction and ultrastructural degenerative changes in the heart of rats. TNF-α inhibitor administration soon after hypoxia-ischemia may have heart protective effect. 相似文献
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M Bonora E De Marchi S Patergnani J M Suski F Celsi A Bononi C Giorgi S Marchi A Rimessi J Duszyński T Pozzan M R Wieckowski P Pinton 《Cell death and differentiation》2014,21(8):1198-1208
Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.Multiple sclerosis (MS) is a neurological disorder of the central nervous system that is characterized by demyelination and neurodegeneration. Although the pathogenesis of MS is not completely understood, various findings suggest that immune-mediated loss of myelin and different types of mitochondrial dysfunction are associated with this disease.1 Mitochondria are often described as cellular powerhouses that utilize oxygen to produce adenosine triphosphate (ATP), a molecule that is critical for most cellular functions.2 In addition, mitochondria are the major sites of the intracellular production of highly reactive free radicals that, if not neutralized, alter cellular metabolism and damage cellular components.3In several studies, mitochondrial dysfunction has been reported to be frequently associated with demyelination, whereas proper function is required for correct oligodendrocyte differentiation and myelination.4, 5 Furthermore, there is in vitro evidence that cytokine-induced oligodendrocyte injury involves mitochondrial dysfunction.6 One cytokine that is of particular interest in MS is tumor necrosis factor alpha (TNF-α). Evidence implicating TNF-α in the underlying pathology of MS includes: (i) reports that MS patients have elevated TNF-α levels at the sites of active MS lesions at autopsy,7 (ii) reports that TNF-α levels are elevated in the cerebrospinal fluid and serum of individuals with MS compared with unaffected individuals and that these TNF-α levels correlate with the severity of the lesions.8, 9Moreover, it has been widely reported that TNF-α is able to impair oligodendrocyte differentiation and that in leukemia cell lines, TNF-α-induced cell death requires impairments in the activity of mitochondrial respiratory chain complex I. Complex I is strategically important for regulating ATP synthesis and is one of the most important sources of reactive oxygen species (ROS) within cells.10 Despite this evidence, the relationships between mitochondrial physiology, TNF-α, and oligodendrocyte differentiation have not yet been examined. This study addressed the hypothesis that the impairment of oligodendrocyte differentiation caused by TNF-α exposure is causally linked to altered mitochondrial physiology. 相似文献
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《Cytokine & growth factor reviews》2009,20(2):165-173
Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-α (TNF-α). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-α inhibition with the use of soluble TNF-α receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-α might be an efficacious treatment for renal disease secondary to diabetes mellitus. 相似文献
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Peter A. Nickerson 《Tissue & cell》1980,12(1):117-123
Injection of diethylstilbestrol (DES) for 7 days in female gerbils significantly increased the number of vacuolar and membranous intranuclear inclusions within mammotrophs of the anterior pituitary gland. The presence of multiple inclusions adjacent to the nuclear membrane suggests that vacuolar inclusions arise from the inner nuclear membrane. DES also increased significantly the number of lipid droplets in adrenocortical parenchymal cells and in macrophages of the zona reticularis. In contrast, estradiol-17α induced only a few intranuclear inclusions in mammotrophs of castrated male gerbils after 14 days of injection. Estradiol-17α injection was totally ineffective in causing accumulation of lipid droplets in macrophages or parenchymal cells of the zona reticularis, emphasizing the importance of stereo-specificity for inducing ultrastructural changes in the anterior pituitary and adrenal cortex of the Mongolian gerbil. 相似文献