Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: Involvement of NF-κB signaling pathway

Background

Our previous studies demonstrated that berberine could improve the renal function in rats and mice with diabetic nephropathy (DN) and inhibit extracellular matrix (ECM) component, fibronectin (FN) expression in rat mesangial cells (MCs) cultured under high glucose. However, the molecular mechanisms have not been fully elucidated.

Objective

To explore the potential mechanisms of berberine in the treatment of DN, we investigated the effects of berberine on lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-κB) activation and its downstream inflammatory mediators, such as intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta 1 (TGF-β1), inducible nitric oxide synthase (iNOS) and fibronectin (FN) protein expression in rat MCs.

Method

Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The activation of NF-κB was detected by Western blot and confocal microscopy. The protein levels of ICAM-1, TGF-β1, iNOS and FN in rat MCs were detected by Western blot.

Results

Our results revealed that berberine significantly suppressed LPS-induced cell proliferation and inhibited LPS-induced NF-κB nuclear translocation in MCs, as well as protein expression of ICAM-1, TGF-β1, iNOS and FN.

Conclusion

Berberine significantly repressed LPS-induced cell proliferation and FN expression in rat MCs through inhibiting the activation of NF-κB signaling pathway and protein expression of its downstream inflammatory mediators. The ameliorative effects of berberine on DN might be associated with this inhibition effect on NF-κB signaling pathway which was independent of its hypoglycemic effect.     

Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-κB pathway

Age-related inflammation is the predominant factor for neurodegenerative diseases like Alzheimer’s disease (AD). In the present study, we examined memory performance and neuroinflammation in D-galactose (D-gal)-induced sub-acute aging model of rats. Our results demonstrated that chronic administration of D-gal (120 mg/kg) produced cognitive impairment as determined by Morris water maze (MWM) test and step-down passive avoidance test. D-gal also activated nuclear factor kappa B (NF-κB) p65/RelA by down-regulating the expression level of sirtuins 1 (SIRT1) in the hippocampus. Treatment with Salidroside (Sal, 20, 40 mg/kg) for 28 days ameliorated D-gal-induced memory deficits and inflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, D-gal-induced activation of NF-κB signaling pathway in the brain was also inhibited by Sal via up-regulating SIRT1. These results suggest that D-gal-triggered memory impairment and inflammatory response may be associated with SIRT1/NF-κB signaling pathway, whereas treatment with Sal could positively affect these changes in hippocampus.     

Iron-induced oxidative stress stimulates osteoclast differentiation via NF-κB signaling pathway in mouse model

BackgroundWomen transitioned to postmenopausal status experience a corresponding gain in iron stores. Recently clinical researches have observed increased serum ferritin level in postmenopausal women, and ferritin level was negatively correlated with bone mineral density.PurposeTo explore the mechanism of iron-induced osteopenia in mouse model.MethodsBriefly, in this study, we established an iron accumulation mouse model with ovariectomy. Primary osteoclasts and osteoblasts were extracted for this research. Biomarkers of bone metabolism and cell signaling pathways were measured.ResultsWe found that bone mass changed later than ferritin and decreased gradually following overiectomy. We also observed higher levels of bone resorption and oxidative stress when iron was administered. When stimulated with iron, primary osteoclasts derived from bone marrow-derived macrophages (BMMs) underwent differentiation and numerous reactive oxygen species (ROS) were generated. Further, we found that iron activated the JNK, ERK and NF-κB signaling pathways in vivo. In vitro, we found that only NF-κB signaling was stimulated by iron and that suppression of this pathway blocked osteoclast differentiation. To determine whether these effects were related to ROS, osteoclasts were treated with H₂O₂. We found that ROS stimulated osteoclast activity, and that this effect was reversed upon NF-κB suppression.ConclusionsThese data suggest that ROS might be a downstream factor of iron and regulated NF-κB signaling in osteoclasts in mouse model.     

Modulation of the airway smooth muscle phenotype in a murine asthma model and effects of nuclear factor-κB inhibition

Objective: Phenotype modulation of airway smooth muscle (ASM) is a unique characteristic of asthma and is considered to regulate airway remodeling, airway hyperresponsiveness (AHR) and inflammation. The nuclear factor-κB (NF-κB) signaling pathway plays a crucial role in phenotypic modulation. Thus, models of acute and chronic asthma were established and pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor was delivered by intraperitoneal injection. Methods: The Penh value was measured using the BUXCO WBP system. Lung tissues were subjected to histologic analysis. Phenotypic markers of ASM and COL1A1 mRNA levels were measured by RT-PCR. Expression levels of phosphorylated p65 (pP65) and α-SMA were detected by Western blot. Serum cytokine levels were quantified by RayBiotech ELISA array. Results: PDTC intervention decreased the Penh values in both the acute and chronic models. The ASM area and the airway collagen area were decreased in the PDTC intervention group. A decrease in phenotypic markers were detected in both the acute and chronic models in time-dependent manner, and PDTC intervention partially reversed the phenotypic modulation. The effect of PDTC intervention on systemic inflammation was also verified. Conclusion: These results revealed the existence of a dynamic ASM phenotype modulation procedure in asthma development and that targeting NF-κB by PDTC was effective to mitigate ASM phenotype modulation and major asthmatic pathological features.     

Polydatin ameliorates experimental diabetes-induced fibronectin through inhibiting the activation of NF-κB signaling pathway in rat glomerular mesangial cells

A number of studies have recently demonstrated the involvement of nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses in the pathogenesis of diabetic nephropathy (DN). Polydatin has been shown to have the ability of anti-adhesive inflammation. However, the possible protective and beneficial effects of polydatin on DN via suppressing inflammatory damage and extracellular matrix (ECM) accumulation are not fully elucidated. We found that the polydatin could inhibit the induction and activity of NF-κB, and meanwhile ameliorating ECM accumulation in streptozotocin-diabetic rats. We aimed to investigate the effect of polydatin on fibronectin (FN) protein expression, and to elucidate its potential mechanism involving the NF-κB inflammatory signaling pathway in rat glomerular mesangial cells (GMCs) cultured under high glucose. The results revealed that polydatin significantly suppressed high glucose-induced FN production, inhibited NF-κB nuclear translocation, reduced the DNA-binding activity of NF-κB, as well as decreased the protein expression of ICAM-1 and TGF-β in GMCs. These findings suggested that polydatin significantly represses high glucose-induced FN expression in rat GMCs, which may be closely related to its inhibition of the NF-κB signaling pathway. Hence, we elucidated the potential mechanisms of the anti-inflammatory effects and ECM accumulation alleviation of polydatin in GMCs of DN in vitro.     

Yunpi Xiefei Huatan decoction alleviates airway inflammation and mucus hypersecretion in young asthmatic rats via inhibiting PI3K/AKT/NF-κB signaling pathway

<正>Objective To explore the effect of Yunpi Xiefei Huatan Decoction (YXHD) on airway inflammation and mucus hypersecretion in young asthmatic rats based on the correlation of interleukin (IL)-23/T helper cell(Th17) inflammation axis and phosphatidylinositol 3kinase (PI3K)/protein kinase B(AKT)/nuclear factor kappa-B(NF-κB) signal axis.Methods Fifty-six young SD rats were randomly divided into 7 groups:normal group,model group,low-dose group of YXHD(LTCM),     

Curcumin reduces lung inflammation via Wnt/β-catenin signaling in mouse model of asthma

Objectives: Asthma is a chronic inflammatory, heterogeneous airway disease affecting millions of people around the world. Curcumin has been found to have anti-inflammatory and antifibrosis effects. Researchers reported that curcumin regulated Wnt/β-catenin signaling in lots of cells. However, whether curcumin regulates the levels of Wnt/β-Catenin signaling in lung tissues and DCs (dendritic cells) remains unclear. In this study, we assessed the effects of curcumin on DCs and asthma. Methods: C57BL/6 mice immunized with OVA (ovalbumin) were challenged thrice with an aerosol of OVA every second day for 8 days. Dexamethasone or curcumin was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 24 once a day for 9 days. Mice were analyzed for effects of curcumin on asthma, inflammatory cell infiltration and cytokine levels in lung tissue. DCs were isolated from mouse bone morrow. The surface markers CD40, CD86 and CD11c of DCs was detected by FACS (fluorescence activated cell sorting) and the function of DCs was detected by mixed lymphocyte reaction. The expression of GSK-3β and β-catenin was detected by Western Blot. Results: Results showed that OVA increased the number of inflammatory factors in BALF (bronchoalveolar lavage fluid), elevated lung inflammation scores in mice. Curcumin dose-dependently reversed the alterations induced by OVA in the asthmatic mice. Curcumin activated Wnt/β-catenin signaling pathway in DCs and asthmatic mouse lungs. Conclusions: Curcumin could influence the morphology and function of DCs, ease asthma symptom and inflammatory reaction through the activation of Wnt/β-catenin signaling. These results provide new evidence new evidence for application of curcumin on asthma.     

Melatonin attenuates hepatic ischemia-reperfusion injury in rats by inhibiting NF-κB signaling pathway

BackgroundThe sterile inflammatory response is one of the key mechanisms leading to hepatic ischemia-reperfusion injury. Melatonin has been shown to prevent organ injuries, but its roles in the inflammatory response after hepatic ischemia-reperfusion injury have not been fully explored, especially in late ischemia-reperfusion injury. The present study aimed to investigate the roles and possible mechanisms of melatonin in the inflammatory response after hepatic ischemia-reperfusion injury.MethodsSixty Sprague-Dawley rats were randomly divided into a sham group, ischemia-reperfusion injury group (I/R group), and melatonin-treated group (M + I/R group). The rats in the I/R group were subjected to 70% hepatic ischemia for 45 min, followed by 5 or 24 h of reperfusion. The rats in the M + I/R group were injected with melatonin (10 mg/kg, intravenous injection) 15 min prior to ischemia and immediately before reperfusion. Serum and samples of ischemic liver lobes were harvested for future analysis, and the 7-day survival rate was assessed after hepatic ischemia-reperfusion surgery.ResultsIn comparison with the I/R group, the M + I/R group showed markedly decreased expression levels of inflammatory cytokines (IL-6 and TNF-α) and numbers of apoptotic hepatocytes (P < 0.05). Immunoblotting showed that the expression levels of IL-6, p-NF-κBp65/t-NF-κBp65 and p-IκB-α/t-IκB-α in the M + I/R group were significantly lower than those in the I/R group, and immunofluorescence staining showed that the expression level of p-NF-κBp65 in the M + I/R group was lower than that in the I/R group (P < 0.05). The 7-day survival rates were 20% in the I/R group and 50% in the M + I/R group (P < 0.05).ConclusionsMelatonin downregulated the activity of the NF-κB signaling pathway in the early and late stages of hepatic ischemia-reperfusion injury, alleviated the inflammatory response, protected the liver from ischemia-reperfusion injury, and increased the survival rate.     

The role of HDAC2 in cigarette smoke–induced airway inflammation in a murine model of asthma and the effect of intervention with roxithromycin

Background: Cigarette smoke is well known to worsen asthma symptoms in asthmatic patients and to make them refractory to treatment, but the underling molecular mechanism is unclear. We hypothesized that cigarette smoke can reduce the expression of HDAC2 in asthma and the process was achieved by activating the PI3K-δ/Akt signaling pathway. We further hypothesized that roxithromycin (RXM) can alleviate the impacts by cigarette smoke. Methods: A murine model of asthma induced by ovalbumin (OVA) and cigarette smoke has been established. The infiltration of inflammatory cells and inflammatory factors was examined in this model. Finally, we evaluated the expression of HDAC2, Akt phosphorylation levels, and the effects of RXM treatment on the model described earlier. Results: Cigarette smoke exposure reduced HDAC2 protein expression by enhancing the phosphorylation of Akt in PI3K-δ/Akt signaling pathway. Furthermore, RMX reduced the airway inflammation and improved the level of expression of HDAC2 in the cigarette smoke–exposed asthma mice. Conclusions: This study provides a novel insight into the mechanism of cigarette smoke exposure in asthma and the effects of RXM treatment on this condition. These results may be helpful for treating refractory asthma and emphasizing the need for a smoke-free environment for asthmatic patients.     

From the Cover: Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-α–induced NF-κB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-α- or LPS-induced up-regulation of proinflammatory mediators, including TNF-α, IL-1β, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-α- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-κB–dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca²⁺ regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.