Caco-2 cell permeability of flavonoids and saponins from Gynostemma pentaphyllum : the immortal herb

Gynostemma pentaphyllum (the immortal herb) has been an important component of Chinese Traditional Medicine for millennia. Recent clinical studies have revealed that the plant exhibits numerous beneficial biological activities, making it of interest to the pharmaceutical industry. An extract of the herb contains over 200 individual secondary metabolites including flavonol glycosides and dammarane saponins. To focus attention on the compounds most likely to be responsible for the biological activities, this study predicts the potential oral bioavailability of nine dammarane saponins and five flavonol glycosides from G. pentaphyllum using the Caco-2 cell monolayer permeability model. Two flavonoids, 8 and 9, and four saponins, 10, 11, 12, and 14, exhibited high permeability across the monolayers. The results indicated that a higher degree of glycosylation-facilitated permeability, suggestive of active transport. This study demonstrates the utility of the Caco-2 permeability assay as a method of identifying possible bioavailable compounds from medicinal herbal extracts

Synergistic inhibition of pro-inflammatory pathways by ginger and turmeric extracts in RAW 264.7 cells

Synergy plays a prominent role in herbal medicines to increase potency and widen the therapeutic windows. The mechanism of synergy in herbal medicines is often associated with multi-targeted behavior and complex signaling pathways which are challenging to elucidate. This study aims to investigate the synergistic mechanism of a combination (GT) of ginger (G) and turmeric (T) extracts by exploring the modulatory activity in lipopolysaccharides (LPS)-induced inflammatory pathways and key molecular targets. A Bioplex ProTM mouse cytokine 23-plex assay was utilized to assess the broad anti-cytokine activity of GT in LPS and interferon (IFN)-gamma (both at 50 ng/mL)-activated RAW 264.7 cells. The inhibitory effects of individual and combined G and T on major proinflammatory mediators including nitric oxide (NO), tumor necrosis factor (TNF) and interleukin (IL)-6 were tested using Griess reagents and ELISA assays, respectively. Immunofluorescent staining and Western blot were used to investigate the modulatory effect of GT on key proteins in the LPS/TLR4 signaling transduction. The regulation of murine microRNA miR-155-5p was tested using real-time PCR. The IC50 value and combination index (CI) values were used to demonstrate potency and synergistic interaction, respectively. GT synergistically attenuated a range of pro-inflammatory mediators including inducible NO, major cytokines (TNF and IL-6) and secondary inflammatory cytokines (GM-CSF and MCP-1). GT significantly inhibited LPS-induced NF-kB p65 translocation, the activation of TLR4, TRAF6, and phosphorylation of JNK and c-JUN. Moreover, the suppressive effect of GT on each of the protein targets in this axis was stronger than that of the individual components. Real-time PCR analysis showed that GT suppressed miR-155-5p to a greater extent than G or T alone in LPS-stimulated cells. Our study demonstrates the synergistic mechanism of GT in downregulating LPS-induced proinflammatory pathways at the miRNA and protein levels. Our results establish a scientific basis for the combined application of G and T as an advanced therapeutic candidate in inflammatory diseases with broad and synergistic anti-inflammatory activity and multi-targeted mechanisms

A monotone multigrid solver for two body contact problems in biomechanics

The purpose of the paper is to apply monotone multigrid methods to static and dynamic biomechanical contact problems. In space, a finite element method involving a mortar discretization of the contact conditions is used. In time, a new contact-stabilized Newmark scheme is presented. Numerical experiments for a two body Hertzian contact problem and a biomechanical application are reported

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m−2 LV+450 mg m−2 5-FU weekly, weeks 1–6, in 8 weeks cycles × 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61–1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45–1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS

An X-Ray Absorption Spectroscopy Study of Ball-Milled Lithium Tantalate and Lithium Titanate Nanocrystals

Previous work has shown that nanocrystalline samples of lithium tantalate and titanate prepared by high-energy milling show unusually high lithium ion conductivity. Here, we report an X-ray absorption spectroscopy (XAS) study at the Ti K-edge and the Ta L3 edge of samples that have been milled for various lengths of time. For both systems the results show that milling creates amorphous material whose quantity increases with the milling time. The more extensive data for the tantalate shows that milling for only 30 minutes generates ~25% amorphous content in the sample. The content rises to ~60% after 16 hours. It is suggested that it is the motion of the lithium ions through the amorphous content that provides the mechanism for the high ionic conductivity

Business constraints and growth potential of micro and small manufacturing enterprises in Uganda

Ugandan micro and small enterprises (MSEs) still perform poorly. Studies associating poor performance of manufacturers with lack of finance and low investment ignore micro enterprises. Those focusing on MSEs are either exploratory in nature or employ a descriptive analysis, which cannot show the extent to which business constraints explain the performance of MSEs. Thus, this paper tries to examine the extent to which the growth of MSEs is associated with business constraints while controlling for owners’ attributes and firms’ characteristics. The results reveal that MSEs’ growth potential is negatively associated with limited access to productive resources (finance and business development services), high taxes and lack of market access

Social Order and Adaptability in Animal and Human Cultures as Analogues for Agent Communities: Toward a Policy-Based Approach

Abstract. In this paper we discuss some of the ways social order is maintained in animal and human realms, with the goal of enriching our thinking about mechanisms that might be employed in developing similar means of ordering communities of agents. We present examples from our current work in human-agent teamwork, and we speculate about some new directions this kind of research might take. Since communities also need to change over time to cope with changing circumstances, we also speculate on means that regulatory bodies can use to adapt. 1

Synergistic immuno-modulatory activity in human macrophages of a medicinal mushroom formulation consisting of Reishi, Shiitake and Maitake

A key characteristic of mushroom polysaccharides that elicit an immunomodulatory response is that they are rich in β-glucans and low in α-glucans. In this study we analysed nine commercially available preparations from three mushroom species, Reishi (Ganoderma lucidum), Shiitake (Lentinula edodes) and Maitake (Grifola frondosa), for β- and α-glucan content. Based on β- and α-glucan content we selected three extracts to combine into a formula and evaluated the ability of the individual extracts and formula to impact on the expression of cytokines IL-1α, IL-6, IL-10 and TNF-α in human macrophages with and without LPS stimulation. The majority of mushroom extracts and the formula were found to be highly potent immuno-stimulators possessing EC values lower than 100 μg/mL. Interestingly the mushroom formula had lower EC values in TNF-α expression from LPS stimulated macrophages compared to the individual extracts, suggesting a potential synergistic effect of the mushroom formula. A response additivity graph and curve-shift analysis illustrated that indeed the mushroom formula exhibited an immuno-stimulatory synergistic effect on the expression of the majority of cytokines evaluated in both LPS stimulated and non-stimulated human macrophages, with IL-10 having an antagonistic response. This study represents the first report of a synergistic immuno-modulatory response in human macrophages elicited from a mushroom formula rationally derived from β- and α-glucan content