Saponins from Panax japonicus ameliorate age-related renal fibrosis by inhibition of inflammation mediated by NF-κB and TGF-ß1/Smad signaling and suppression of oxidative stress via activation of Nrf2-ARE signaling.

BACKGROUND: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. METHODS: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), ß2-microglobulin (ß2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. RESULTS: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and ß2-MG in 24-month group were significantly increased (p < 0.05). Compared with those in the 24-month group, the levels of serum UA, Cys C and ß2-MG in the SPJ-H group were significantly decreased. While ECM was reduced and the levels of MMP-2 and MMP-9 were increased, the levels of TIMP-1, TIMP-2 and transforming growth factor-ß1 (TGF-ß1)/Smad signaling were decreased; the expression level of phosphorylated nuclear factor kappa-B (NF-κB) was down-regulated with reduced inflammatory factors; meanwhile, the expression of nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling was aggrandized. CONCLUSION: These results suggest that SPJs treatment can improve age-associated renal fibrosis by inhibiting TGF-ß1/Smad, NFκB signaling pathways and activating Nrf2-ARE signaling pathways and that SPJs can be a potentially valuable anti-renal fibrosis drug.

The TGF-ß1/COX-2-dependant pathway serves a key role in the generation of OKC-induced M2-polarized macrophage-like cells and angiogenesis.

An odontogenic keratocyst (OKC) is a common oral cyst arising from the odontogenic epithelium, which has the characteristics of a tumor. Previous studies have demonstrated that M2-polarized macrophages and angiogenesis have important roles in the progression of OKCs. As transforming growth factor (TGF)-ß1 is important in growth and developmental processes, and early studies have indicated that TGF-ß1 is upregulated in OKCs, the present study aimed to investigate the expression levels of TGF-ß1 as a first step. Flow cytometric analysis suggested that TGF-ß1 induced M2-polarization of macrophages in a dose-dependent manner. Expression levels of cyclooxygenase (COX)-1 and -2 were measured after treatment of M2 macrophages with TGF-ß1 and OKC homogenate supernatant. COX-2 expression was influenced by TGF-ß1 in a concentration-dependent manner and in OKC induction. In addition, inhibition of COX-2 resulted in the induction of M2-polarization of macrophages via TGF-ß1 and OKC disruption. Because the extracellular matrix (ECM) is altered in individuals with chronic diseases, the present study analyzed the expression of matrix metalloproteinase (MMP)-9, which is able to degrade the ECM. The present study observed a decrease in MMP-9 activity following treatment with TGF-ß1 and OKC homogenate supernatant. Additionally, the present study analyzed tube formation caused by OKC with or without a COX-2 inhibitor. The results of the present study suggested that angiogenesis increased following treatment with OKC homogenate supernatant but decreased after treatment with a COX-2 inhibitor. These findings indicated that the TGF-ß1/COX-2 pathway may have an important role in the progression of OKC.

Assessment of tumor growth factor-ß1 neutralizing antibody in the treatment of allergic rhinitis and asthma.

To identify a novel and effective therapy for allergic rhinitis and asthma (ARA), the present study focused on treatment with tumor growth factor (TGF)-ß1 neutralizing antibody. In the present study, four medications were administered to mice with ovalbumin-induced allergic inflammation. Allergic symptoms in the lungs and nasal mucosa were evaluated by detecting the secretion of cytokines from helper T cells (Th) in the peripheral blood, nasal lavage fluid and bronchoalveolar lavage fluid using ELISA. Defects in regulatory T (Treg) cells in peripheral blood mononuclear cells were also detected using flow cytometry. Furthermore, the expression of TGF-ß1 and activation of Smad2/3 pathways were assessed using immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction, and western blotting. It was observed that TGF-ß1 neutralizing antibody inhibited symptoms of inflammation in the upper and lower airways. TGF-ß1 neutralizing antibody also restored the Th1/Th2 balance and ameliorated Treg cell defects induced by ARA. Furthermore, the therapeutic effects of TGF-ß1 neutralizing antibody were related to its inhibitory effects on TGF-ß1 expression and Smad2/3 signaling in nasal and lung tissues. Therefore, TGF-ß1 neutralizing antibody may be an effective medicine for the treatment of ARA.

Serum adipokines in inflammatory bowel disease.

AIM: To investigate serum adipokine levels in inflammatory bowel disease (IBD) patients before treatment and after achieving clinical remission. METHODS: Serum concentrations of six adipokines (tissue growth factor-ß1, adiponectin, leptin, chemerin, resistin, and visfatin) were studied in 40 subjects with active IBD [24 subjects with Crohn's disease (CD) and in 16 subjects with ulcerative colitis (UC)] before and after three months of therapy with corticosteroids and/or azathioprine. Clinical diagnoses were based on ileocolonoscopy, computed tomography or magnetic resonance enterography and histological examination of mucosal biopsies sampled during endoscopy. Serum levels of adipokines were assessed by an indirect enzyme-linked immunosorbent assay. The control group was comprised of 16 age- and sex-matched healthy volunteers. RESULTS: Baseline leptin concentrations were significantly decreased in both types of IBD compared to controls (8.0 ± 9.1 in CD and 8.6 ± 6.3 in UC vs 16.5 ± 10.1 ng/mL in controls; P < 0.05), and significantly increased after treatment only in subjects with CD (14.9 ± 15.1 ng/mL; P < 0.05). Baseline serum resistin concentrations were significantly higher in CD (19.3 ± 12.5 ng/mL; P < 0.05) and UC subjects (23.2 ± 11.0 ng/mL; P < 0.05) than in healthy controls (10.7 ± 1.1 ng/mL). Treatment induced a decrease in the serum resistin concentration only in UC subjects (14.5 ± 4.0 ng/mL; P < 0.05). Baseline serum concentrations of visfatin were significantly higher in subjects with CD (23.2 ± 3.2 ng/mL; P < 0.05) and UC (18.8 ± 5.3 ng/mL; P < 0.05) than in healthy controls (14.1 ± 5.3 ng/mL). Treatment induced a decrease in the serum visfatin concentrations only in CD subjects (20.4 ± 4.8 ng/mL; P < 0.05). Serum levels of adiponectin, chemerin and tissue growth factor-ß1 did not differ between CD and UC subjects compared to healthy controls and also were not altered by anti-inflammatory therapy. Clinical indices of IBD activity did not correlate with adipokine levels. CONCLUSION: IBD modulates serum adipokine levels by increasing resistin and visfatin release and suppressing leptin production.

Microenvironment and tumor cell plasticity: an easy way out.

Cancer cells undergo genetic changes allowing their adaptation to environmental changes, thereby obtaining an advantage during the long metastatic route, disseminated of several changes in the surrounding environment. In particular, plasticity in cell motility, mainly due to epigenetic regulation of cancer cells by environmental insults, engage adaptive strategies aimed essentially to survive in hostile milieu, thereby escaping adverse sites. This review is focused on tumor microenvironment as a collection of structural and cellular elements promoting plasticity and adaptive programs. We analyze the role of extracellular matrix stiffness, hypoxia, nutrient deprivation, acidity, as well as different cell populations of tumor microenvironment.