Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

In vitro Anticancer Screening of 24 Locally Used Nigerian Medicinal Plants

Background: Plants that are used as traditional medicine represent a relevant pool for selecting plant candidates that may have anticancer properties. In this study, the ethnomedicinal approach was used to select several medicinal plants native to Nigeria, on the basis of their local or traditional uses. The collected plants were then evaluated for cytoxicity. Methods: The antitumor activity of methanolic extracts obtained from 24 of the selected plants, were evaluated in vitro on five human cancer cell lines. Results: Results obtained from the plants screened indicate that 18 plant extracts of folk medicine exhibited promising cytotoxic activity against human carcinoma cell lines. Erythrophleum suaveolens (Guill. & Perr.) Brenan was found to demonstrate potent anti-cancer activity in this study exhibiting IC50 = 0.2-1.3 $\mu$g/ml. Conclusions: Based on the significantly potent activity of some plants extracts reported here, further studies aimed at mechanism elucidation and bio-guided isolation of active anticancer compounds is currently underway.Chemistry and Chemical Biolog

Effectiveness of two biopesticides against the invasive tomato pest Tuta absoluta

International audienceTuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is among the most devastating pests worldwide of solanaceous plants, particularly of tomato (Solanum lycopersicum L.). Since its recent introduction into sub-Saharan Africa, it has become an additional widespread tomato pest throughout the region. When no control measures are taken, yield losses caused by T. absoluta larvae can reach 100%. Chemical control remains the primary management option despite its many adverse effects and increasing inefficiency due to the species' endophytic habits and ability to develop insecticide resistance. Safer and more effective alternatives are therefore urgently required. Here, we investigated the effectiveness of two bioinsecticides compared to that of a widely used deltamethrin-based synthetic insecticide, in preventing damage caused by T. absoluta larvae to tomato leaves and fruits, thereby affecting tomato yield. A field trial was conducted in 2018 and 2019 in northwestern Senegal using a randomized complete block design. Damage caused by T. absoluta affected approximately 65% of total leaf area and 3-24% of the fruits. Damage to the leaves caused by other insect species or other factors was less significant. At the dose applied, the chemical insecticide did not significantly reduce the surface area of leaflets affected by T. absoluta or other causal agents, the number of T. absoluta mines on the leaflets, or the proportion of fruits damaged. In contrast, the azadirachtin and Bacillus thuringiensis (Bt) formulations rapidly and significantly reduced damage to both leaves and fruits. The proportion of fruits damaged was reduced by a factor two and the total tomato yield was improved, particularly when the Bt formulation was used. In addition to their effectiveness in reducing damage caused by T. absoluta larvae to tomato leaves and fruit, and increasing the yield of marketable fruits, the viability of these organic alternatives was shown. The scope of our results is discussed in the context of T. absoluta control, in particular in integrated pest management programmes for tomato crops

Intravenous delivery of HIV-based lentiviral vectors preferentially transduces F4/80+ and Ly-6C+ cells in spleen, important target cells in autoimmune arthritis

Contains fulltext : 118684.pdf (publisher's version ) (Open Access)Antigen presenting cells (APCs) play an important role in arthritis and APC specific gene therapeutic targeting will enable intracellular modulation of cell activity. Viral mediated overexpression is a potent approach to achieve adequate transgene expression levels and lentivirus (LV) is useful for sustained expression in target cells. Therefore, we studied the feasibility of lentiviral mediated targeting of APCs in experimental arthritis. Third generation VSV-G pseudotyped self-inactivating (SIN)-LV were injected intravenously and spleen cells were analyzed with flow cytometry for green fluorescent protein (GFP) transgene expression and cell surface markers. Collagen-induced arthritis (CIA) was induced by immunization with bovine collagen type II in complete Freund's adjuvant. Effect on inflammation was monitored macroscopically and T-cell subsets in spleen were analyzed by flow cytometry. Synovium from arthritic knee joints were analyzed for proinflammatory cytokine expression. Lentiviruses injected via the tail vein preferentially infected the spleen and transduction peaks at day 10. A dose escalating study showed that 8% of all spleen cells were targeted and further analysis showed that predominantly Ly6C+ and F4/80+ cells in spleen were targeted by the LV. To study the feasibility of blocking TAK1-dependent pathways by this approach, a catalytically inactive mutant of TAK1 (TAK1-K63W) was overexpressed during CIA. LV-TAK1-K63W significantly reduced incidence and arthritis severity macroscopically. Further histological analysis showed a significant decrease in bone erosion in LV-TAK1-K63W treated animals. Moreover, systemic Th17 levels were decreased by LV-TAK1-K63W treatment in addition to diminished IL-6 and KC production in inflamed synovium. In conclusion, systemically delivered LV efficiently targets monocytes and macrophages in spleen that are involved in autoimmune arthritis. Moreover, this study confirms efficacy of TAK1 targeting in arthritis. This approach may provide a valuable tool in targeting splenic APCs, to unravel their role in autoimmune arthritis and to identify and validate APC specific therapeutic targets