Tyrosol Derivatives, Bearing 3,5-Disubstituted Isoxazole and 1,4-Disubstituted Triazole, as Potential Antileukemia Agents by Promoting Apoptosis

In the present study, we assess tyrosol derivatives bearing 3,5-disubstituted isoxazoles and 1,4-disubstituted triazoles for their ability to inhibit the proliferation of K562 cells derived from leukemia as well as primary chronic myeloid leukemia (CML) cells obtained from the peripheral blood of 15 CML patients including 10 patients with untreated chronic phase and 5 patients with resistance against imatinib or multiple TKI. Our results showed that most derivatives displayed significant anti-proliferative activity against K562 cells in a dose-dependent manner. Among them, compounds 3d and 4a exhibited greater potent anticancer activity with respective IC50 values of 16 and 18 µg/mL (45 µM and 61 µM). Interestingly, compound 3d inhibited CML cell proliferation not only in newly diagnosed but also in imatinib-resistant patients. We demonstrated that the anti-proliferative effect of this compound is mediated by a pro-apoptotic activity by promoting oxidative stress and modulating the activity of the Akt, p38 MAPK and Erk 1/2 pathways. In conclusion, our data highlight the potential of this class of derivative as a novel promising therapeutic agent for CML therapy

ACE Inhibitory and Antioxidant Activities of Novel Peptides from Scorpaena notata By-product Protein Hydrolysate

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Antioxidant, Anti-Inflammatory, and Antitumoral Effects of Aqueous Ethanolic Extract from Phoenix dactylifera L. Parthenocarpic Dates

The aim of this study was to evaluate the antioxidant, the anti-inflammatory, and the antitumoral activities of the aqueous ethanolic extract from Phoenix dactylifera L. parthenocarpic dates. The antioxidant activity was carried using DPPH radical scavenging activity. The result showed that parthenocarpic dates had strongly scavenging activity on DPPH reaching 94% with an IC50 value of 0.15 ± 0.011 mg/mL (p < 0.05). The anti-inflammatory potential was determined by the inhibitory effect of the aqueous ethanolic extract on phospholipase A2 activity as well as on carrageenan-induced paw oedema in mice. The in vitro study showed that the extract inhibited the phospholipase A2 activity with an IC50 value of 130 μg/mL and the in vivo study showed a significantly decrease in the paw oedema after 1 h compared to the control group. Finally, the antiproliferative activity of the aqueous ethanolic extract was assessed by MTT test against MCF-7 and MDA-MB-231 cancer cell lines. This extract was effective in inhibiting MDA-MB-231 and MCF-7 cancer cells growth with IC50 values of 8 and 18 mg/mL, respectively, after 72 h treatment. These results confirm the ethnopharmacological significance of Phoenix dactylifera L. parthenocarpic dates, which could add support for its pharmaceutical use

La famille Kunitz/BPTI des venins de serpents: Structure, classification et potentiel pharmacologique

International audienceSnake venoms are rich sources of serine proteinase inhibitors that are members of the Kunitz/BPTI (bovine pancreatic trypsin inhibitor) family. Generally, these inhibitors are formed by 60 amino acids approximately. Their folding is characterised by a canonical loop that binds in a complementary manner to the active site of serine protease. Some variants from snake venoms show only weak inhibitory activity against proteases while others are neurotoxic. Moreover, proteases inhibitors are involved in various physiological processes, such as blood coagulation, fibrinolysis, and inflammation. Also, these molecules showed an anti-tumoral potent and anti-metastatic effect. Interestingly, Kunitz/BPTI peptides can have exquisite binding specificities and possess high potency for their targets making them excellent therapeutic candidates.Les venins des serpents sont riches en inhibiteurs de sérine protéases qui sont membres de la famille Kunitz / BPTI (inhibiteur de la trypsine pancréatique bovine). Ces inhibiteurs sont en général formés par environ 60 acides aminés. Leur modèle structural est caractérisé par la présence d’une boucle canonique qui se lie d’une manière complémentaire au site actif des sérines protéases. Certains inhibiteurs ne montrent qu'une faible activité inhibitrice contre la protéase tandis que d'autres sont neurotoxiques. De plus, ces peptides sont impliqués dans de divers processus physiologiques, tels que la coagulation sanguine, la fibrinolyse et l'inflammation. En outre, ces molécules ont montré un puissant effet anti-tumoral et anti-métastatique. Ainsi, les inhibiteurs de type Kunitz/BPTI peuvent avoir des spécificités de liaison et possèdent un potentiel élevé envers leurs cibles qui les rend d'excellents candidats thérapeutiques

Snake Venom Proteins Isolated from Tunisian Vipers: Pharmacological and Therapeutic Overview

: The venoms of Tunisian wildlife snakes are complex mixtures containing proteins/ peptides and non-protein molecules. Proteins and peptides are the most abundant compounds responsible for the biological effects of venoms. Snake venoms proteins have enzymatic or nonenzymatic activities, which are grouped into different families, including C-type lectin proteins, disintegrins (long, medium and short disintegrins), Kunitz-type serine protease inhibitors, natriuretic- like peptides, vascular endothelial growth factor-related proteins, L-amino acid oxidases, phospholipases A2 and serine proteinases. With technological advancements, the toxic effects of venoms were turned into potential benefits for clinical diagnosis, basic research and development of new research tools and drugs of potential clinical use. Our research team has shown that Macrovipera lebetina and Cerastes cerastes venom components of Tunisian wildlife snakes had great potential for the development of new drugs for the treatment of cancer, angiogenesis disorders or cardiovascular diseases. This review is an overview of snake venom proteins from Macrovipera lebetina and Cerastes cerastes and their biochemical, pharmacological and molecular characterization and their importance as protein resources with therapeutic potential

Phthalimido-ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity

International audienceSeveral ferrocenyl analogues of tamoxifen have already showed strong antiproliferative activity in experimental glioma models. Nevertheless, these compounds are very poorly soluble in water and an adapted formulation is needed. In this work, we have tailored and optimized methylated cyclodextrin soluble complexes of phthalimido-ferrocidiphenol for the first time. The complexes were characterized, and the optimized formulation was tested for in vitro efficacy and cell proliferation assays on U87, human glioblastoma cancer cells. Molecular modeling can provide accurate information about the inclusion process. The inclusion of all the moieties at the same time (i.e., ferrocene, phthalimidylpropyl, 2 phenols) is not possible due to the steric hindrance of the 1:4 system. The 1:3 systems are possible but do not seem very relevant. However, various 1:2 and 1:1 complexes are mostly present in aqueous solutions. Some experiments have confirmed our hypothesis. First, interactions between the phenol, phthalimidylpropyl and ferrocenyl groups have been observed in our NMR experiments. Second, the inclusion of phthalimidylpropyl was detected by UV-vis spectrophotometry with an apparent 1:1 interaction, which was observed through the Benesi-Hildebrand method. The complex is readily soluble in water and keeps its pharmacological activity against U87 tumor cells (IC50=0.028 ± 0.007 μM vs. 0.018 ± 0.003 μM for PhtFerr)

Anti-hemolytic and Anti-cytotoxic Effect of Two Artemisia Species (A. campestris and A. herba-alba) Essential Oil against Snake Venom

International audienceIn this study, we verify the possible activity of Artemisia herba-alba and A. campestris (Asteraceae) essential oil against the snake venoms. The leaves of A. campestris has been used in the folk medicine against snake moisture. The aerial part extracts of both plants have been tested for their action against snake venom. Interaction of A. campestris (E1) and A. herba alba (E2) essential oils with proteins extracted from snake venom has been tested. Lethality in mice, inflammation and cytotoxicity induced by Cerastes cerastes venoms were significantly inhibited by the mixture of different amounts of E1 and E2 and the venom. However, both extracts showed neutralization of the venoms hemolytic activity which is more important with E2. Chemical characterization of E1 and E2 revealed there is an important amount of polyphenols and tannins which are known by their bio-active effect. The result could lead as to think that these components have an action by inhibiting the toxicity of snake venoms in vitro. We can conclude therefore that the use of the essential oil from the two Artemisia species have a curative effect on the snake venom. These results confirmed the traditional use of A. campestris and we discovered a similar effect of A. herba-alba. No data have been reported till now about the essential oil curative effect of both species

Targeting α1 inserted domain (I) of α1β1 integrin by Lebetin 2 from M. lebetina transmediterranea venom decreased tumorigenesis and angiogenesis.

International audienceThrough the recent development of knowledge in biotechnology and bioinformatics, snake venoms are widely used to develop new drugs to treat diseases such as hypertension and cancer. We have previously reported that Lebetin 2 isolated from Macrovipera lebetina transmediterranea venom displays a potent anti-platelet activity and exerts a cardioprotective effect in ischemia-reperfusion (IR) injury model. Here, we report that Lebetin 2 possess an anti-tumor effect by targeting the integrin receptor function. It was thus able to inhibit both adhesion and migration of pheochromocytoma cells (PC12) and α1β1 integrin-expressing CHO cells (CHO-α1) to type I and IV collagens. Moreover, this peptide affects proliferation of PC12 cells by modulating AKT phosphorylation. Furthermore, Lebetin 2 exhibits a potent anti-angiogenic effect as assessed in vitro and ex vivo, using both the embryo chick chorioallantoic membrane model (CAM) and rat aortic ring assay. Interestingly, the interaction mode of Lebetin 2 with the integrin α1β1, assessed in silico, showed that the peptide represents a steric obstruction preventing the collagen from enforcing the interactions with the integrin

PIVL, a snake venom Kunitz-type serine protease inhibitor, inhibits in vitro and in vivo angiogenesis.

International audience: Development and homeostasis of the vascular system requires integrin-promoting endothelial cell adhesion, migration and survival. Nowadays, integrins represent potential targets for pharmacological agents and open new avenues for the control of metastatic spread in the treatment of tumor malignancies. We have already reported that PIVL, a serine protease inhibitor isolated from Macrovipera lebetina venom, displays an anti-tumor effect through the interference with integrin receptor function. Here, we report that PIVL inhibits human vascular endothelial cell adhesion and migration onto fibrinogen and fibronectin in a dose-dependent manner without any cytotoxicity. Furthermore, we show that PIVL increases microtubule dynamic instability in HMEC-1 transfected with EGFP-tagged α-tubulin. Using Matrigel™ and chick chorioallantoic membrane assays, we demonstrate that PIVL exhibits a strong anti-angiogenic effect both in vitro and in vivo. Interestingly, results herein reveal that the potent anti-angiogenic properties of PIVL are mediated by its RGD-like motif ((41)RGN(43))

Pharmacological Investigation of CC-LAAO, an L-Amino Acid Oxidase from Cerastes cerastes Snake Venom

International audienceSnake venom proteins, which are responsible for deadly snakebite envenomation, induce severe injuries including neurotoxicity, myotoxicity, cardiotoxicity, hemorrhage, and the disruption of blood homeostasis. Yet, many snake-venom proteins have been developed as potential drugs for treating human diseases due to their pharmacological effects. In this study, we evaluated the use of, an L-amino acid oxidase isolated from Cerastes cerastes snake venom CC-LAAO, as a potential anti-glioblastoma drug, by investigating its in vivo and in vitro pharmacological effects. Our results showed that acute exposure to CC-LAAO at 1 and 2.5 µg/mL does not induce significant toxicity on vital organs, as indicated by the murine blood parameters including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) activities, and creatinine levels. The histopathological examination demonstrated that only at high concentrations did CC-LAAO induce inflammation and necrosis in several organs of the test subjects. Interestingly, when tested on human glioblastoma U87 cells, CC-LAAO induced a dose-dependent apoptotic effect through the H2O2 generated during the enzymatic reaction. Taken altogether, our data indicated that low concentration of CC-LAAO may be safe and may have potential in the development of anti-glioblastoma agents