Mechanism of thymosin β4 in ameliorating liver fibrosis via the MAPK/NF-κB pathway

Liver fibrosis is a grievous global challenge, where hepatic stellate cells (HSCs) activation is a paramount step. This study analyzed the mechanism of Tβ4 in ameliorating liver fibrosis via the MAPK/NF-κB pathway. The liver fibrosis mouse models were established via bile duct ligation (BDL) and verified by HE and Masson staining. TGF-β1-induced activated LX-2 cells were employed in vitro experiments. Tβ4 expression was determined using RT-qPCR, HSC activation markers were examined using Western blot analysis, and ROS levels were tested via DCFH-DA kits. Cell proliferation, cycle, and migration were examined by CCK-8, flow cytometry, and Transwell assays, respectively. Effects of Tβ4 on liver fibrosis, HSC activation, ROS production, and HSC growth were analyzed after transfection of constructed Tβ4-overexpressing lentiviral vectors. MAPK/NF-κB-related protein levels were tested using Western blotting and p65 expression in the nucleus was detected through immunofluorescence. Regulation of MAPK/NF-κB pathway in TGF-β1-induced LX-2 cells was explored by adding MAPK activator U-46619 or inhibitor SB203580. Furthermore, its regulating in liver fibrosis was verified by treating BDL mice overexpressing Tβ4 with MAPK inhibitor or activator. Tβ4 was downregulated in BDL mice. Tβ4 overexpression inhibited liver fibrosis. In TGF-β1-induced fibrotic LX-2 cells, Tβ4 was reduced and cell migration and proliferation were enhanced with elevated ROS levels, while Tβ4 overexpression suppressed cell migration and proliferation. Tβ4 overexpression blocked the MAPK/NF-κB pathway activation by reducing ROS production, thus inhibiting liver fibrosis in TGF-β1 induced LX-2 cells and BDL mice. Tβ4 ameliorates liver fibrosis by impeding the MAPK/NF-κB pathway activation.     

Mindin deficiency alleviates renal fibrosis through inhibiting NF-κB and TGF-β/Smad pathways

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)-β-treated HK-2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65—the hub subunit of the NF-κB signalling pathway—translocation from the cytoplasm into the nucleus, resulting in NF-κB pathway activation in TGF-β-treated HK-2 cells. Meanwhile, mindin activated the TGF-β/Smad pathway, thereby causing fibrotic-related protein expression in vitro. Mindin^−/− mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin^−/− mice suppressed p65 translocation and deactivated NF-κB pathway. Simultaneously, mindin disruption inhibited the TGF-β/Smad pathway, alleviating the expression of ECM-related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.     

The antifibrotic effects of TGF-β1 siRNA on hepatic fibrosis in rats

Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-β1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-β1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague–Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-β1 siRNA 0.125 mg/kg treatment group, TGF-β1 siRNA 0.25 mg/kg treatment group and TGF-β1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin–Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-β1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-β1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-β1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-β1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-β1 siRNA negative control group and the TGF-β1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the mRNA expression of TGF-β1, type I collagen and type III collagen (P < 0.01). Conclusions: Using siRNA to target TGF-β1 can inhibit the expression of TGF-β1 and attenuate rat hepatic fibrosis induced by a high-fat diet and CCL4. A possible mechanism is through the down-regulation of TGF-β1 expression, which could inhibit HSC activation, as well as the proliferation and collagen production of collagen reducing, so that collagen deposition in the liver is reduced.     

Suppression by fucoidan of liver fibrogenesis via the TGF-β/Smad pathway in protecting against oxidative stress

Fucoidan, a sulfated polysaccharide extracted from various types of brown seaweed, possesses a wide range of pharmacological properties. We investigated the protective effect of fucoidan on dimethylnitrosamine-induced liver fibrogenesis in rats and its mechanism. Liver fibrosis was induced by injecting DMN (10 mg/kg, 3 times per week, I.P.) for 4 weeks, and fucoidan was simultaneously administered (100 mg/kg, 3 times per week, P.O.). The anti-oxidative and anti-inflammatory effects of fucoidan were observed by relative mediators. Fucoidan improved liver fibrosis by inhibiting the expression of transforming growth factor beta 1 (TGF-β(1))/Smad3 and the tissue inhibitor of metalloproteinase 1 (TIMP-1), and increasing the expression of metalloproteinase-9 (MMP-9). Fucoidan also significantly decreased the accumulation of the extracellular matrix (ECM) and collagen. These results suggest that fucoidan had an anti-fibrotic effect, which was exerted by inhibiting the TGF-β/Smad pathway, as well as anti-oxidative and anti-inflammatory effects.     

Roles of PPARγ/NF-κB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy

Background

Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood.

Aim

To assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP.

Methods

Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP.

Results

The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05).

Conclusions

The higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.     

NIK is involved in constitutive activation of the alternative NF-κB pathway and proliferation of pancreatic cancer cells

Pancreatic cancer has one of the poorest prognoses among human neoplasms. Constitutive activation of NF-κB is frequently observed in pancreatic cancer cells and is involved in their malignancy. However, little is known about the molecular mechanism of this constitutive NF-κB activation. Here, we show that the alternative pathway is constitutively activated and NF-κB-inducing kinase (NIK), a mediator of the alternative pathway, is significantly expressed in pancreatic cancer cells. siRNA-mediated silencing of NIK expression followed by subcellular fractionation revealed that NIK is constitutively involved in the processing of p100 and nuclear transport of p52 and RelB in pancreatic cancer cells. In addition, NIK silencing significantly suppressed proliferation of pancreatic cancer cells. These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. Therefore, NIK might be a novel target for the treatment of pancreatic cancer.     

Pirfenidone modulates macrophage polarization and ameliorates radiation-induced lung fibrosis by inhibiting the TGF-β1/Smad3 pathway

Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and radiation-induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)-approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL/6 mice received a 50 Gy dose of X-ray radiation to the whole thorax with or without the administration of PFD. Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor-β1 (TGF-β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation-induced expression of TGF-β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL-4–induced M2 macrophage polarization and IL-13–induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase-1 (ARG-1), chitinase 3-like 3 (YM-1) and TGF-β1. Notably, the PFD-induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa-B (NF-κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation-induced chemokine secretion in MLE-12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF-β1 from M2 macrophages by attenuating the activation of TGF-β1/Smad3. In conclusion, PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF-β1/Smad3.     

Acetylshikonin from Zicao ameliorates renal dysfunction and fibrosis in diabetic mice by inhibiting TGF-β1/Smad pathway

Diabetic nephropathy (DN) is the major cause of end-stage renal disease in diabetic patients. Zicao, a well-known Chinese traditional medicine, has attracted much attention due to its beneficial effects in various medical fields. In this study, we attempted to investigate the effects and mechanisms of action of acetylshikonin, the main ingredient of Zicao, on renal dysfunction in DN. Our results showed that administration with acetylshikonin not only decreased blood urea nitrogen, urine creatinine and the mean kidney-to-body weight ratio in streptozotocin-induced diabetic mice, but also restored the loss of body weight, whereas the blood glucose was not changed. Masson’s trichrome staining showed that acetylshikonin treatment resulted in a marked decrease in kidney fibrosis from diabetic mice. The increased expression of fibrosis proteins, such as plasminogen activator inhibitor type 1 (PAI-1), connective tissue growth factor, and collagen III and IV, were reduced after acetylshikonin administration. In addition, the expressions of interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, intercellular adhesion molecule 1 and infiltration of macrophages in kidney tissues were decreased in acetylshikonin-treated diabetic mice. Acetylshikonin led to a reduction of transforming growth factor-β1 (TGF-β1) expression and Smad-2/3 phosphorylation, as accompanied by increased Smad7 expression. Furthermore, in vitro treatment with acetylshikonin markedly attenuated TGF-β1-induced the PAI-1, collagen III and IV, and Smad-2/3 phosphorylation in HK2 immortalized human proximal tubule epithelial cells. Acetylshikonin also prevented epithelial-to-mesenchymal transition induced by TGF-β1. Collectively, our study provides evidences that acetylshikonin attenuates renal fibrosis though inhibiting TGF-β1/Smad signaling pathway, suggesting that acetylshikonin may be a novel therapeutic agent for the treatment of DN.     

miR-627/HMGB1/NF-κB regulatory loop modulates TGF-β1-induced pulmonary fibrosis

Pulmonary fibrosis (PF) is a fibroproliferative disease that can eventually lead to fatal lung failure. It is characterized by abnormal proliferation of fibroblasts, dysregulated fibroblast differentiation to myofibroblast, and disorganized collagen and extracellular matrix production, deposition and degradation. There is still a lack of effective treatment strategies for PF. Extracellular high-mobility group box protein 1 (HMGB1) induces PF through NF-κB-mediated TGF-β1 release. Herein, we first validate the suppressive effect of HMGB1 knockdown on TGF-β1-induced α-smooth muscle actin (α-SMA) and collagen I protein expression. In PF, miRNAs exert different effects through targeting various downstream target messenger RNAs. We searched an online database for dysregulated miRNAs in PF tissues; among them, miR-627 was predicted by online tools to target HMGB1 to inhibit its expression. miR-627 overexpression could partially reverse TGF-β1-induced normal human lung fibroblast proliferation, as well as α-SMA and collagen I protein expression. miR-627 inhibition could partially reverse the suppressive effect of HMGB1 knockdown on TGF-β1-induced α-SMA and collagen I protein expression through direct binding to the 3′-untranslated region of HMGB1. Moreover, miR-627/HMGB1 affected TGF-β1 release through RAGE/NF-κB signaling; miR-627/HMGB1 and RAGE/NF-κB signaling formed a regulatory loop to modulate TGF-β1-induced PF in vitro. In conclusion, miR-627 may be a potential agent that targets HMGB1 to inhibit its expression, thereby improving TGF-β1-induced PF in vitro.     

PKCβ/NF-κB pathway in diabetic atrial remodeling

Journal of Physiology and Biochemistry - Atrial remodeling in diabetes is partially attributed to NF-κB/TGF-β signal transduction pathway activation. We examined whether the...     

Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARγ/NF-κB pathway

Background

Docosahexaenoic acid (DHA) and DHA-derived lipid mediators have recently been shown to possess anti-inflammatory and pro-resolving properties. In fact, DHA can down-regulate lipolysaccharide (LPS)-induced activation of NF-κB via a PPARγ-dependent pathway. We sought to investigate the effects of the novel DHA-derived mediator resolvin D1 (RvD1) on LPS-induced acute lung injury and to determine whether these effects occur via a PPARγ-dependent pathway.

Methods

BALB/c mice aged 6–8 weeks were randomly divided into seven groups: two control groups receiving saline or RvD1 (600 ng) without LPS; a control group receiving LPS only; an experimental group receiving RvD1 (300 ng) or RvD1 (600 ng), followed by LPS; a group receiving the PPARγ antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 μM) and saline were administered intratracheally. RvD1 was injected intravenously 24 h and 30 min before LPS, while GW9662 was injected intravenously 30 min before RvD1. Mice were killed at 6, 12, and 24 h. Samples of bronchoalveolar lavage fluid (BALF) were analyzed for cell counts and cytokine analysis. Lung tissues were collected for histology, Western blotting and electrophoretic mobility shift assays (EMSAs).

Results

At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-α and IL-6 levels in BALF than did the group given only LPS. RvD1 markedly attenuated LPS-induced lung inflammation at 24 h, based on hematoxylin-eosin staining of histology sections. RvD1 activated PPARγ and suppressed IκBα degradation and NF-κB p65 nuclear translocation, based on Western blots and EMSAs. The PPARγ inhibitor GW9662 partially reversed RvD1-induced suppression of IκBα degradation and p65 nuclear translocation.

Conclusions

These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-κB activation through a mechanism partly dependent on PPARγ activation.     

Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men

Introduction

In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-κB cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.

Methods

Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r²≥0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40–79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre.

Results

We validated the associations between SNPs in GPR177 and BMD_a previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD_a, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD_a, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS.

Conclusion

Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-κB signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.     

The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats

Background

Our aim was to compare the effects of a Paleolithic ('Old Stone Age') diet and a diabetes diet as generally recommended on risk factors for cardiovascular disease in patients with type 2 diabetes not treated with insulin.

Methods

In a randomized cross-over study, 13 patients with type 2 diabetes, 3 women and 10 men, were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; and a Diabetes diet designed in accordance with dietary guidelines during two consecutive 3-month periods. Outcome variables included changes in weight, waist circumference, serum lipids, C-reactive protein, blood pressure, glycated haemoglobin (HbA1c), and areas under the curve for plasma glucose and plasma insulin in the 75 g oral glucose tolerance test. Dietary intake was evaluated by use of 4-day weighed food records.

Results

Study participants had on average a diabetes duration of 9 years, a mean HbA1c of 6,6% units by Mono-S standard and were usually treated with metformin alone (3 subjects) or metformin in combination with a sulfonylurea (3 subjects) or a thiazolidinedione (3 subjects). Mean average dose of metformin was 1031 mg per day. Compared to the diabetes diet, the Paleolithic diet resulted in lower mean values of HbA1c (-0.4% units, p = 0.01), triacylglycerol (-0.4 mmol/L, p = 0.003), diastolic blood pressure (-4 mmHg, p = 0.03), weight (-3 kg, p = 0.01), BMI (-1 kg/m², p = 0.04) and waist circumference (-4 cm, p = 0.02), and higher mean values of high density lipoprotein cholesterol (+0.08 mmol/L, p = 0.03). The Paleolithic diet was mainly lower in cereals and dairy products, and higher in fruits, vegetables, meat and eggs, as compared with the Diabetes diet. Further, the Paleolithic diet was lower in total energy, energy density, carbohydrate, dietary glycemic load, saturated fatty acids and calcium, and higher in unsaturated fatty acids, dietary cholesterol and several vitamins. Dietary GI was slightly lower in the Paleolithic diet (GI = 50) than in the Diabetic diet (GI = 55).

Conclusion

Over a 3-month study period, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a Diabetes diet in patients with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00435240.     

Combination of Active Components of Xiexin Decoction Ameliorates Renal Fibrosis Through the Inhibition of NF-κB and TGF-β1/Smad Pathways in db/db Diabetic Mice

Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-1β, and active nuclear factor κB (NF-κB). APF treatment also reduced type I and IV collagen, transforming growth factor-β1 (TGF-β1), and TGF-β1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-κB and TGF-β1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of α-smooth muscle actin, collagen I, TGF-β1 and NF-κB in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi-component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy.     

Influence of thrombophlebitis on TGF-β1 and its signaling pathway in the vein wall

Extensive extracellular matrix remodeling of the vein wall is involved in varicose veins pathogenesis. This process is controlled by numerous factors, including peptide growth factors. The aim of the study was to evaluate influence of thrombophlebitis on TGF-β1 and its signaling pathway in the vein wall. TGF-β1 mRNAlevels, growth factor content and its expression were evaluated by RT-PCR, ELISA, and western blot methods, respectively, in the walls of normal veins, varicose veins and varicose veins complicated by thrombophlebitis. Western blot analysis was used to assess TGF-β receptor type II (TGF-β RII) and p-Smad2/3 protein expression in the investigated material. Unchanged mRNA levels of TGF-β1, decreased TGF-β1 content, as well as decreased expression of latent and active forms of TGF-β1 were found in varicose veins. Increased expression of TGF-β RII and p-Smad2/3 were found in varicose veins. Thrombophlebitis led to increased protein expression of the TGF-β1 active form and p-Smad2/3 in the vein wall compared to varicose veins. TGF-β1 may play a role in the disease pathogenesis because of increased expression and activation of its receptor in the wall of varicose veins. Thrombophlebitis accelerates activation of TGF-β1 and activity of its receptor in the varicose vein wall.     

Intromitochondrial IκB/NF-κB signaling pathway is involved in amyloid β peptide-induced mitochondrial dysfunction

Mitochondrial dysfunction is a hallmark of amyloid β peptide (Aβ)-induced neuronal toxicity in Alzheimer’s disease (AD). However, the underlying mechanism (s) of Aβ-induced mitochondrial dysfunction is still not fully understood. There is evidence that nuclear factor-κB (NF-κB) is involved in Aβ-induced neurotoxicity and is present in mitochondria. Using HT22 murine hippocampal neuronal cells and isolated mitochondria, the present study investigated whether intramitochondrial inhibitor of NF-κB (IκB)/NF-κB signaling pathway was involved in mitochondrial dysfunction induced by Aβ. It was found that Aβ impaired mitochondrial function through a NF-κB-dependent signaling pathway. Intramitochondrial IκBα/NF-κB pathway, induced by Aβ, decreased the expression of cytochrome c oxidase subunit (COXIII) and inhibited COX activity. These results provide new insights into the mechanism underlying the neurotoxic effect of Aβ and open up new therapeutic perspectives for AD.