Alpinetin is a naturally occurring flavonoid from the ginger plants. We previously reported the identification of alpinetin as a ligand of human pregnane X receptor (hPXR). The current study ...investigated the role of alpinetin as a putative PXR activator in ameliorating chemically induced inflammatory bowel disease (IBD). We found that oral administration of alpinetin significantly alleviated the severity of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration, the levels of the pro-inflammatory mediators, and the PXR target genes in the colon.
, alpinetin blocked the nuclear translocation of p-p65 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Further, alpinetin significantly upregulated PXR target genes and inhibited TNF-α-induced NF-κB-luciferase activity in LS174T colorectal cells; however, this regulatory effects were lost when cellular PXR gene was knocked down. In PXR transactivation assays, alpinetin increased both mouse and human PXR transactivation in a dose-dependent manner. Ligand occluding mutants, S247W/C284W and S247W/C284W/S208W, in hPXR-reporter assays, abrogated alpinetin-induced hPXR transactivation. Finally, alpinetin bound to the hPXR-ligand-binding domain (LBD) was confirmed by competitive ligand binding assay. The current study significantly extends prior observations by validating a PXR/NF-κB regulatory mechanism governing alpinetin's anti-inflammatory effects in a murine model of IBD.
Acacetin, a natural dietary flavonoid abundantly found in acacia honey and citrus fruits, reportedly exerts several biological effects, such as anti-tumor, anti-inflammatory, and anti-oxidative ...effects. However, the effects of acacetin on intestinal inflammation remain unclear. We sought to investigate whether acacetin ameliorates inflammatory bowel disease (IBD) in mice with dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Our results suggest that acacetin alleviates the clinical symptoms of DSS-induced colitis, as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration, and histological injury. Further studies showed that acacetin remarkably inhibited both the macrophage inflammatory response
and levels of inflammatory mediators in mice with colitis. In addition, some features of the gut microbiota were disordered in mice with DSS-induced colitis, as evidenced by a significant reduction in microbiota diversity and a marked shift in bacterial profiles. However, acacetin treatment improved this imbalance and restored gut microbiota to levels that were similar to those in normal mice. In conclusion, our work presents evidence that acacetin attenuates DSS-induced colitis in mice, at least in part, by inhibiting inflammation and regulating the intestinal microbiota.
Fargesin is a bioactive lignan from
, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental ...inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly attenuated the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration and myeloperoxidase (MPO) activity, reducing tumor necrosis factor (TNF)-α secretion, and inhibiting nitric oxide (NO) production in colitis mice. The degradation of inhibitory κBα (IκBα), phosphorylation of p65, and mRNA expression of nuclear factor κB (NF-κB) target genes were inhibited by fargesin treatment in the colon of the colitis mice. In vitro, fargesin blocked the nuclear translocation of p-p65, downregulated the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and dose-dependently inhibited the activity of NF-κB-luciferase in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Taken together, for the first time, the current study demonstrated the anti-inflammatory effects of fargesin on chemically induced IBD might be associated with NF-κB signaling suppression. The findings may contribute to the development of therapies for human IBD by using fargesin or its derivatives.
Obacunone, a limonoid abundantly found in Citrus fruits, exhibits a variety of bioactivities.
To investigate the effects of obacunone on a colorectal cancer (CRC) mouse model, and clarify its ...potential molecular mechanisms.
The male Balb/c mice were induced with azoxymethane and dextran sulfate sodium for 12 weeks. Obacunone (50 mg/kg) was administered via oral gavage three times every week until the end of the experiment. Disease indexes including body weight, spleen weight, bloody diarrhea, colon length, histopathological score, and tumor size were measured. The anti-proliferation activities of obacunone were analyzed by MTT or flow cytometry. The expression of protein and mRNA related to cell proliferation or inflammatory cytokines was determined by Western blot, q-PCR and IHC.
Obacunone significantly alleviated bloody diarrhea, colon shortening (7.35 ± 0.2128 vs. 8.275 ± 0.2169 cm), splenomegaly, histological score (9 ± 0.5774 vs. 6 ± 0.5774) and reduced tumor size (4.25 ± 0.6196 vs. 2 ± 0.5669). Meanwhile, the expression of protein and mRNA related to cell proliferation or inflammatory cytokines was remarkably decreased in tumor tissue. Obacunone inhibited the proliferation activities of colorectal cancer cells. Moreover, obacunone induced colorectal cancer cells G1 and G2 phases arrest, and suppressed the expression of cell cycle genes.
Obacunone could alleviate CRC via inhibiting inflammatory response and tumor cells proliferation. The results may contribute to the effective utilization of obacunone or its derivatives in the treatment of human CRC.
With respect to conventional tubing with threaded connections, coiled tubing has the advantage of not screwing on and off in the lifting pipe string. It is widely used in drilling and repairing ...wells. Coiled tubing experiences 6 bend-straighten plastic deformations in each lifting pipe string. Low working life and high cost are the key technical issues for coiled tubing in downhole operations. Based on the work state of the coiled tubing, a dedicated experimental device for fatigue life and specimen is designed in this article. Fatigue life tests were carried out on 23/8″ diameter tubes which are commonly used in industry. The experiments were carried out on the bending and straightening devices for the coiled tubing with the damage of ovality and reduction of wall thickness monitored. A large number of experimental data were obtained. The formulas for ovality and wall thickness with the cycle of bending–straightening were fitted based on mathematical regression method, and then the formulas for the low cycle fatigue life with damage of ovality and reduction of wall thickness are given for the coiled tubing. Comparing with the results of theoretical formula and laboratory experiments, the maximum error was 3.03%. Therefore, the calculation method will provide a theoretical basis for the coiled tubing failure prediction and control.
Treatments on dynamic interfaces and fluid-solid coupling are critical in systems of tubes vibrating in fluids that are common in tube-strings of deep-water oil drilling systems, marine cluster wells ...and heat exchangers. This paper proposes a “weakly” coupled algorithm for modeling vortex induced vibrations of elastic tubes submerged in cross flows. In the present algorithm, the elastic tube is discretized with beam elements and the fluid is discretized with volume elements, and the grids for both the tube and fluid is perfectly marched on the interface. Using the shape functions of beam elements, the formula for displacement, velocity, and force approximations are carried out, and convergence criterion analyses are also performed for the fluid-solid coupling interfaces. The present weakly coupling algorithm is developed with a sub-iteration loop to ensure accuracy in handling the dynamic coupling between the elastic tube and fluid. The vortex-induced vibrating characteristics are then analyzed for various elastic tubes at different natural frequencies. Intensive numerical studies are also conducted to examine the effects of the ratio of the elastic tube's natural frequency to the static flow's frequency. It is found that the change of frequency ratio has less effect on the fluid pressure and velocity distributions on the surface of the elastic tube, but more effects on the vibration of the tube. When the frequency ratio is less than 1.009, the vibrating amplitude, period and trajectory of elastic tube decrease with the increase of frequency ratio. While if the frequency ratio is more than 1.009, the vibrating amplitude, period and trajectory are almost unchanged and the elastic tube behaves similarly to a rigid tube. It is also found that there is a critical frequency ratio for a vortex-induced vibration to occur for tubes in cross flows. This finding is important for the prevention of violent vibrations of tubular structures in flows, such as deep-water oil drilling tube-strings, marine cluster wells and heat exchangers.
•This paper proposes a “weakly” coupled algorithm for vortex induced vibrations of elastic tubes submerged in cross flows.•The weakly coupling algorithm is developed with a sub-iteration loop to ensure accuracy in handling the dynamic coupling.•Numerical studies are conducted to examine effects of the ratio of elastic tube’s natural frequency to the static flow’s frequency.
Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated ...that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory mediators, including nuclear factor-kappa B (NF-κB) activation. In vitro, ALA inhibited NF-κB nuclear translocation and dose-dependently activated human/mouse pregnane X receptor (PXR), a key regulator gene in inflammatory bowel disease (IBD) pathogenesis. However, the pocket occluding mutants of the ligand-binding domain (LBD) of hPXR, abrogated ALA-mediated activation of the receptor. Overexpression of hPXR inhibited NF-κB-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-κB-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-κB activation by ALA. Finally, molecular docking studies confirmed the binding affinity between hPXR-LBD and ALA. Collectively, the current study indicates a beneficial effect of ALA on experimental IBD possibly via PXR-mediated suppression of the NF-κB inflammatory signaling.
Pinocembrin, a plant-derived flavonoid, has a variety of pharmacological activities, including anti-infection, anti-cancer, anti-inflammation, cardiovascular protection, etc. However, the mechanism ...of pinocembrin on the anti-colitis efficacy remains elusive and needs further investigation. Here, we reported that pinocembrin eased the severity of dextran sulfate sodium (DSS)-induced colitis in mice by suppressing the abnormal activation of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signal pathway in vivo. In addition, the gut microbiota was disordered in DSS colitis mice, which was associated with a significant decrease in microbiota diversity and a great shift in bacteria profiles; however, pinocembrin treatment improved the imbalance of gut microbiota and made it similar to that in normal mice. On the other hand, in vitro, pinocembrin down-regulated the TLR4/NF-κB signaling cascades in lipopolysaccharide (LPS)-stimulated macrophages. At the upstream level, pinocembrin competitively inhibited the binding of LPS to myeloid differentiation protein 2 (MD2), thereby blocking the formation of receptor multimer TLR4/MD2·LPS. Furthermore, pinocembrin dose-dependently promoted the expression of tight junction proteins (ZO-1, Claudin-1, Occludin and JAM-A) in Caco-2 cells. In conclusion, our work presented evidence that pinocembrin attenuated DSS-induced colitis in mouse, at least in part, via regulating intestinal microbiota, inhibiting the over-activation of TLR4/MD2/NF-κB signaling pathway, and improving the barriers of intestine.
Nonlinear vibrations that occur in such bundle structures caused collisions between tubes and cross flows of the surrounding fluid. This paper presents modeling techniques for simulating the FSI ...dynamics of bundle tubes vibrating and colliding in fluids. A typical configuration of a three-dimensional tube bundles submerged in fluid of a cylindrical container is studied. Coupling conditions of displacement, velocity and forces are considered on the fluid-structure coupling interfaces. Contacts boundary between tubes and topological domain changes of the fluid are also considered on the fluid-structure coupling interface. Modeling techniques and algorithm are then established for flow-induced vibrations of the tubes, and collisions between tubes in fluids. The examples are presented to demonstrate the effectiveness of the proposed techniques. It has confirmed that our code produces the correct physics of the FSI problem, and capable of revealing the complex nonlinear mechanism with solid-solid contacts together with fluid-solid interactions.
PDF
