Treatment of Chikungunya Virus (CHIKV) Using Targeted Immunotherapy

Chikungunya virus (CHIKV) is the most common mosquito-borne Alphavirus infecting humans worldwide. Up to date, there are no antiviral treatments or vaccines approved to treat or prevent CHIKV for which treatments remain symptomatic based on clinical manifestations. Hence, designing effective therapies to either prevent or treat CHIKV infection is of paramount importance. Interestingly, monoclonal antibodies (mAbs) are known to be significantly important in mediating protective immunity in CHIV infection. During the last decades, numerous animal studies have reported the protective and prophylactic efficacy of human and mouse anti-CHIKV mAbs isolated from convalescent patients. However, the therapeutic benefits of these anti-CHIKV mAbs can be limited by multiple factors. Thus, it becomes pertinent to better understand the CHIKV infection dynamics, mitigate the undesired mAbs-associated effects and improve therapies. In this review, we critically discuss CHIKV antiviral infectious mechanisms and address how the improved understanding of the latter may pave the way to better targeted immunotherapies

Contribution à l'analyse du rôle de RB18A/MED1, un co-facteur de transcription, dans le pouvoir tumorigène de mélanomes humains

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Down-regulation of the expression of RB18A/MED1, a cofactor of transcription, triggers strong tumorigenic phenotype of human melanoma cells

International audienceThe RB18A/MED1 human gene, also named TRAP220, DRIP205 and PBP, encodes for a single 205 kDa component, which interacts with nuclear receptors and transcription factors. RB18A/MED1 chromosome localization on locus 17q12-q21.1 suggests its involvement in human cancers. We herein analyzed RB18A/MED1 expression in human melanoma cell lines. We found that RB18A/MED1 is either highly or weakly expressed in melanoma cells, depending on their respectively non or highly-tumorigenic phenotype. We therefore investigated the possible existence of a relationship between the RB18A/MED1 expression level and melanoma cell phenotype. For this purpose, we down-regulated RB18A/MED1 expression by transfecting melanoma cells with a RB18A/MED1 small interfering RNA (siRNA), specific to the 3'-untranslated region of native RB18A/MED1 RNA, already demonstrated to inhibit specifically RB18A/MED1 protein expression. A nonspecific (scrambled) siRNA was used as control. This RB18A/MED1 siRNA did not modify the expression of cathepsin L forms or lamin A/C, nor the secretion of procathepsin L and MMP2 in transfected cells. Analysis using a microarray membrane with 113 cancer-related genes, western blot and specific tests, demonstrated that RB18A/MED1 knockdown significantly inhibits tissue inhibitor of metalloproteinase-3 expression, and increases uPAR expression, two genes well known to be involved in melanoma cell invasion, through modifications of the tumor microenvironment. Indeed, RB18A/MED1 knockdown in melanoma cells in vitro increased their invasive properties, without modification of cell proliferation. Furthermore, RB18A/MED1 knockdown in vivo switched melanoma phenotype from non to strongly-tumorigenic in nude mice. Our data thus demonstrated for the first time that a decrease of RB18A/MED1 expression in human melanoma cells increases their tumorigenic phenotype

Phytochemical studies, antiangiogenic, anti-inflammatory and antioxidant activities of Scyphocephalium ochocoa Warb. (Myristicaceae), medicinal plant from Gabon

Abstract Background The search for new anti-cancer molecules is one of the main concerns of oncology researchers. Scyphocephalium ochocoa is a plant of Myristicaceae family, used in traditional medicine against inflammatory diseases and several types of cancer. It is well established that free radicals, chronic inflammation and angiogenesis play an important role in initiation, tumor progression and metastasis formation. The aim of this study was to carry out a phytochemical screening, to determine the phenolic compounds content, to investigate the antiangiogenic, anti-inflammatory and antioxidant activities of water, water-ethanol and ethanol extracts of S. ochocoa. Methods Phytochemical screening and determination of phenolic compounds content were performed using standard methods. Antiangiogenic activity was assessed using chick chorioallantoic membrane (CAM) model and Drabkin test. Anti-inflammatory activity was estimated by protein denaturation and erythrocyte membrane stabilization method. Finally the antioxidant activity was appreciated by DPPH radical inhibition and phosphomolybdenum assay. Results The results of phytochemical studies show that extracts of bark of S. ochocoa are rich in polyphenols, tannins, flavonoids, proantocyanidins, saponosides, flavonols, flavanonols, sterol and triterpenes. The water extract showed good antiangiogenic activity (IC50 = 1.153 μg/mL). Strong anti-inflammatory activity was observed with all extracts, IC50 ranging from 34.775 ± 2.543 μg/mL to 74.577 ± 3.456 μg/mL for protein denaturation inhibition test and IC50 values ranging from 36.793 ± 0.529 μg/mL at 48.912 ± 0.957 μg/mL for antihemolytic activity. In addition, all extracts showed good antioxidant activity marked by a strong inhibition of the DPPH radical (IC50 ranging from 4.969 ± 0.263 μg/mL to 16.188 ± 0.336 μg/mL and AAI ranging from 3.090 ± 0.065 to 10.080 ± 0.517) and by greater total antioxidant capacity (with contents ranging from 37.654 ± 0.995 to 131.302 ± 1.102 VtCE (mg)/g dry extract). Conclusion Ultimately, these results could justify the use of S. ochocoa extracts in traditional medicine in the treatment of diseases related to angiogenesis and cancer, inflammatory diseases and diseases due to oxidative stress. A phyto-product with such a pharmacological profile could be a good candidate for the development of anticancer

Correction to: Phytochemical studies, antiangiogenic, antiinflammatory and antioxidant activities of Scyphocephalium ochocoa Warb. (Myristicaceae), medicinal plant from Gabon

Following the publication of this article [1], the authors noticed that Figs. 1, 2 and 3 were in the incorrect order and thus had incorrect captions. The images that were incorrectly published as Figs. 1, 2 and 3 should have been published as Figs. 2, 3 and 1 respectively

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PP i), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PP i synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PP i breakdown, further contributing to PP i accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase- α enzyme therapy aimed at reducing PP i concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PP i homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically