Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

Cancer-associated thrombosis: How many patients seen in clinical practice would be eligible for a direct oral anticoagulant randomized controlled trial?

Based on the results of randomized clinical trials (RCT) assessing direct oral anticoagulants (DOACs) for the treatment of patients with cancer-associated thrombosis (CAT), DOACs have been proposed as alternative to low molecular weight heparin by several international guidelines. However, the proportion of CAT patients who would have not been eligible for such trials is currently unknown. Our primary aim was to assess the proportion of patients seen in clinical practice for acute CAT who would not have been eligible for CARAVAGGIO or HOKUSAI-VTE RCT. Secondary aim was to describe patients outcomes according to eligibility. In a multicenter, observational study, all patients consecutively admitted from January 2017 to December 2019 for an acute CAT event were retrospectively analyzed. Patients were classified according to the presence or absence of non-inclusion criteria for CARAVAGGIO or HOKUSAI-VTE RCT. Event free survival during a 6-month follow-up were analyzed as secondary endpoints. Among the 302 patients (women: 53 %, mean age: 67.9 ± 13.2) analyzed, 138 (46 %) for HOKUSAI-VTE cancer and 161 (53 %) for CARAVAGGIO met one or more non-inclusion criteria. Main criteria were upper limb and unsual site thrombosis (n = 63, 18.5 %), anemia/thrombopenia (n = 43, 14.2 %), brain tumors (n = 33, 10.9 %), ECOG PS >2 (n = 28, 9.3 %), severe renal failure (n = 16, 5.3 %). At 6 months, the event-free survival rate was not statistically different between the two groups. Almost half of CAT patients would have not been able to participate to a modern DOAC RCT. Evaluation of DOACs safety and efficacy in this subset of patients deserves further research.

Antiviral miliusanes and isolation of an unprecedented miliusane dimer from Miliusa balansae.

In an extensive screening endeavor for anti-coronaviral compounds, we examined 824 tropical plant extracts from the Annonaceae and Rutaceae families. The screening identified an ethyl acetate extract from the aerial parts of Miliusa balansae for its potent inhibitory activity against Human coronavirus HCoV-229E. Subsequent bioassay-guided fractionation of this extract revealed two unreported miliusanes including a complex dimeric structure and seven known compounds, comprising miliusane XXXVI, (+)-miliusol, bistyryls, styryl-pyranones, and the flavonoid rhamnetin. The absolute configuration of the new dimeric miliusane was determined by X-ray crystallography and a putative biogenetic origin was proposed. Investigation of the antiviral effect of these nine phytochemicals within HCoV-229E-infected Huh-7 cells showed that (+)-miliusol and miliusane XXXVI exert antiviral activity at non-cytotoxic concentrations, with IC50 values of 1.15 µM and 19.20 µM, respectively. Furthermore, these compounds significantly inhibited SARS-CoV-2 infection in Vero cells, presenting IC50 values of 11.31 µM for (+)-miliusol and 17.92 µM for miliusane XXXVI. Additionally, both compounds exhibited a potent antiviral effect against the emergent mosquito-borne Zika virus, with IC50 values of 1.34 µM and 23.45 µM, respectively. Time-of-addition assays suggest that their mechanism of action might target later stages of the viral cycle, indicating potential modulation of specific cellular pathways. These findings reinforce the invaluable contribution of medicinal flora as reservoirs of natural antiviral agents and emphasize their prospective role in combatting viruses of medical interest.

Anti-phytopathogen terpenoid glycosides from the root bark of Chytranthus macrobotrys and Radlkofera calodendron.

Chytranthus macrobotrys and Radlkofera calodendron are two Sapindaceae characterized by a lack of phytochemical data. Both root barks from the two Sapindaceae species were processed by ethanol extraction followed by the isolation of their primary constituents by liquid chromatography. This process yielded four previously undescribed terpenoid glycosides together with eight known analogues. Extracts and isolated compounds from C. macrobotrys and R. calodendron were then screened for antimicrobial activity against fifteen phytopathogens. The biological screening also involved extracts and pure compounds from Blighia unijugata and Blighia welwitschii, two Sapindaceae previously studied by our group. Phytopathogens were chosen based on their economic impact on agriculture worldwide. The selection was composed primarily of fungal species including; Pyricularia oryzae, Gaeumannomyces graminis var. tritici, Zymoseptoria tritici, Fusarium oxysporum, Botrytis cinerea, Pythium spp., Trichoderma spp. and Rhizoctonia solani. Furthermore, pure terpenoid glycosides were tested for the first time against wood-inhabiting phytopathogens such as; Phaeomoniella chlamydospora, Phaeoacremonium minimum, Fomitiporia mediterranea, Eutype lata and Xylella fastidiosa. Raw extracts exhibited different levels of activity dependent on the organism. Some pure compounds, including 3-O-α-L-arabinopyranosyl-(1 â†’ 4)-ß-D-xylopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranosylhederagenin, 3-O-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranosylhederagenin (α-hederin), 3-O-ß-D-glucopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranosylhederagenin (macranthoside A) and 3-O-α-L-arabinopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranosylhederagenin (clemontanoside C), exhibited significant growth inhibitions on Pyricularia oryzae, Gaeumannomyces graminis var. tritici, Fomitiporia mediterranea and Zymoseptoria tritici. Monodesmoside triterpene saponins, in particular, exhibited MIC (IC100) values as low as 25 µg/ml and IC50 values as low as 10 µg/ml against these phytopathogens. Structure-activity relationships, as well as plant-microbe interactions, were discussed.

Triterpene glycosides from Blighia welwitschii and evaluation of their antibody recognition capacity in multiple sclerosis.

Multiple sclerosis (MS) in a multifactorial autoimmune disease in which reliable biomarkers are needed for therapeutic monitoring and diagnosis. Autoantibodies (autoAbs) are known biomarker candidates although their detection in biological fluids requires a thorough characterization of their associated antigens. Over the past twenty years, a reverse chemical-based approach aiming to screen putative autoantigens has underlined the role of glycans, in particular glucose, in MS. Despite the progress achieved, a lack of consensus regarding the nature of innate antigens as well as difficulties proposing new synthetic glucose-based structures have proved to be obstacles. Here is proposed a strategy to extend the current methodology to the field of natural glycosides, in order to dramatically increase the diversity of glycans that could be tested. Triterpene saponins from the Sapindaceace family represent an optimal starting material as their abundant description in the literature has revealed a prevalence of glucose-based oligosaccharides. Blighia welwitschii (Sapindaceae) was thus selected as a case study and twelve triterpene saponins were isolated and characterized. Their structures were elucidated on the basis of 1D and 2D NMR as well as mass spectrometry, revealing seven undescribed compounds. A selection of natural glycosides exhibiting various oligosaccharide moieties were then tested as antigens in enzyme-linked immunosorbent assay (ELISA) to recognize IgM antibodies (Abs) in MS patients' sera. Immunoassay results indicated a correlation between the glycan structures and their antibody recognition capacity, allowing the determination of structure-activity relationships that were coherent with previous studies. This approach might help to identify sugar epitopes putatively involved in MS pathogenesis, which remains poorly understood.

Hederagenin glycosides from the fruits of Blighia unijugata.

A phytochemical investigation of Blighia unijugata led to the isolation of eleven hederagenin glycosides. Among these compounds, six are previously undescribed, two are described in their native forms for the first time and three are known whereas firstly isolated from Blighia unijugata. The structure of the undescribed compounds was elucidated on the basis of 2D NMR and mass spectrometry analyses as 3-O-ß-D-xylopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3-O-ß-D-xylopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-3-O-acetyl-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3-O-ß-D-glucopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3-O-ß-D-xylopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3-O-ß-D-xylopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 4)-3-O-acetyl-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3-O-α-L-arabinopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28-O-ß-D-glucopyranosyl-(1 → 6)-ß-D-glucopyranosyl ester, 3-O-α-L-arabinopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28-O-ß-D-glucopyranosyl ester and 3-O-ß-D-xylopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28-O-ß-D-glucopyranosyl ester. These results revealed the existence of several conserved structural features that could be used as chemotaxonomic markers for the Blighia genus such as the glycosidic sequence 3-O-α-L-arabinopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosyl, the occurrence of 3-O-acetylated ß-D-glucopyranosyl units and the systematic presence of hederagenin as aglycone.