Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids

With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic worthy of investigation. The in vitro activity of the first-generation IVM hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by Plasmodium parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of Plasmodium infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of P. falciparum and the hepatic stages of P. berghei have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents.

Prolonged Viability of Senecavirus A in Exposed House Flies (Musca domestica)

House flies (Musca domestica) are often present in swine farms worldwide. These flies utilize animal secretions and waste as a food source. House flies may harbor and transport microbes and pathogens acting as mechanical vectors for diseases. Senecavirus A (SVA) infection in pigs occurs via oronasal route, and animals shed high virus titers to the environment. Additionally, SVA possesses increased environmental resistance. Due to these reasons, we investigated the tenacity of SVA in house flies. Five groups of flies, each composed of ten females and ten males, were exposed to SVA, titer of 109.3 tissue culture infectious dose (TCID50/mL). Groups of male and female flies were collected at 0, 6, 12, 24, and 48 h post-exposure. For comparison purposes, groups of flies were exposed to Swinepox virus (SwPV). Infectious SVA was identified in all tested groups. Successful isolation of SVA demonstrated the titers varied between 106.8 and 102.8 TCID50/mL in female groups and varied from 105.85 to 103.8 TCID50/mL in male groups. In contrast, infectious SwPV was only detected in the female group at 6 h. The significant SVA infectious titer for prolonged periods of time, up to 48 h, indicates a potential role of flies in SVA transmission.

Separation and Identification of Resveratrol Butyrate Ester Complexes and Their Bioactivity in HepG2 Cell Models

Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception of resveratrol, five different structures of ester derivatives were separated from silica gel: 3,4′-di-O-butanoylresveratrol (ED2, 18.8%), 3-O-butanoylresveratrol (ED4, 35.7%), 4′-O-butanoylresveratrol (ED5, 4.4%), 3,5,4′-tri-O-butanoylresveratrol (ED6, 1.5%), and 3,5-di-O-butanoylresveratrol (ED7, 0.7%). Among the ester derivatives obtained, ED2 and ED4 were the main ester derivatives in the RBE complex. Thus, the cellular antioxidant activities of the RBE mixture, ED2, and ED4 were evaluated. Results showed that the antioxidant capacity of ED2 and ED4 was higher than that of the RBE mixture, demonstrating that the number and position of butyrate esterification sites are related to cell survival rate and antioxidant capacity. This study is the first to report the successful isolation, structural identification, and cellular biological antioxidant activity of RBE complex derivatives, which are key characteristics for the potential practical application of RBE complexes.

Bioactivity-guided Isolation of TRAIL-Resistance-Overcoming Activity Compounds From the Leaves of Murraya exotica

Fractionation of the leaf extract from Murraya exotica led to the successful isolation of 12 compounds (1-12) with TRAIL-resistance-overcoming activity. Xanthinosin (1), 11α, 13-dihydroxanthinin (2), 11β, 13-dihydroxanthinosin (3), 4α, 11α, 13-trihydroxanthuminol (4), desacetylxanthanol (5), and lasidiol p-methoxybenzoate (6) were sesquiterpenes isolated from this plant for the first time, and 3 was isolated from natural sources for the first time. Among them, compounds 1 and 5 showed strong TRAIL-resistance-overcoming activity, but their mechanisms have already been revealed. Furthermore, dihydroxanthinin (2), 1, 5-dicaffeoylquinic acid (7), and (-) loliolide (8), which belong to different phytochemical groups, were investigated for their effects on increasing apoptosis induction to overcome TRAIL resistance using Western blot analysis. The results demonstrated that 2, 7, and 8 promoted TRAIL-induced apoptosis by increasing the expression of several proapoptotic markers, including cleaved caspases −3 and −8, and suppressing anti-apoptotic protein Bcl-2.

Distinct and interchangeable growing patterns in colorectal cancer stem-like cells are regulated by Musashi-1

The dynamic and heterogeneous features of cancer stem-like cells (CSCs) have been widely recognized, but their nongenetic cellular plasticity mechanisms remain elusive. By using colorectal cancer organoids, we phenotypically tracked their spheroid formation and growth capacity to a single-cell resolution, and we discovered that the spheroid-forming cells exhibit a heterogeneous growth pattern, consisting of slow- and fast-growing spheroids. The isolated fast-growing spheroids seem to preserve a dual-growing pattern through multiple passages, whereas the isolated slow-growing spheroids are restricted to a slow-growing pattern. Notably, the spheroids of both patterns were tumorigenic. Moreover, the expression of CSC markers varied among the subpopulations with different growth patterns. The isolated slow-growing spheroids adopted the dual-growing pattern by various extrinsic triggers, in which Musashi-1 plays a key role. The slow-growing fraction was resistant to chemotherapy, and its successful isolation can provide an in vitro platform allowing us to elucidate their role in drug resistance.

A Crystalline Tri-thorium Cluster: When Metal σ-Aromaticity Just Isn’t Enough

Very recently, Liddle and coworkers extended the range of aromaticity to a record seventh row of the periodic table by successful isolation of the crystalline actinide cluster 3 containing at its heart the σ-aromatic tri-thorium ring. In this study we prove that the authors have misinterpreted the experimental Raman spectrum of 3, which eventually led to the wrong conclusions about the role of the σ-aromatic tri-thorium bonding in the synthesized cluster. We demonstrate that the thorium-thorium bond in 3 is not very different from the already known extremely weak actinide-actinide bonds, and the marginal σ-aromatic stabilization in the Th3 ring makes it hardly distinguishable from ordinary non-aromatic rings. Also, we show that the multicenter charge-shift bonding in the Th3Cl6 cage is a vital factor that determines the uniqueness and remarkable thermodynamic stability of 3. By clarifying the misleading conclusions of the original Nature paper and drawing special attention to the essential stabilizing role of actinide-halogen charge-shift bonding, this study may have broader implications for understanding the chemistry of actinides and future attempts to design and synthesize new stable actinide complexes.

Using Oxidative Electrodes to Enrich Novel Members in the Desulfobulbaceae Family from Intertidal Sediments

Members in the family of Desulfobulbaceae may be influential in various anaerobic microbial communities, including those in anoxic aquatic sediments and water columns, and within wastewater treatment facilities and bioelectrochemical systems (BESs) such as microbial fuel cells (MFCs). However, the diversity and roles of the Desulfobulbaceae in these communities have received little attention, and large portions of this family remain uncultured. Here we expand on findings from an earlier study (Li, Reimers, and Alleau, 2020) to more fully characterize Desulfobulbaceae that became prevalent in biofilms on oxidative electrodes of bioelectrochemical reactors. After incubations, DNA extraction, microbial community analyses, and microscopic examination, we found that a group of uncultured Desulfobulbaceae were greatly enriched on electrode surfaces. These Desulfobulbaceae appeared to form filaments with morphological features ascribed to cable bacteria, but the majority were taxonomically distinct from recognized cable bacteria genera. Thus, the present study provides new information about a group of Desulfobulbaceae that can exhibit filamentous morphologies and respire on the oxidative electrodes. While the phylogeny of cable bacteria is still being defined and updated, further enriching these members can contribute to the overall understanding of cable bacteria and may also lead to identification of successful isolation strategies.

Third-generation laser balloon ablation: rapid mode applicability is associated with shorter time to pulmonary vein isolation

Background The rapid mode feature implemented in the latest version of the laser balloon system (LB3, HeartLight, X3, Cardiofocus) offers an automated continuous 360° lesion for pulmonary vein isolation (PVI). However, data on its clinical applicability and the potential reduction of procedural times are not yet available. Purpose To explore the use of the rapid mode and its association with PV total and fluoroscopy times in our initial experience with LB3. Methods This analysis included consecutive patients who underwent PVI procedure with LB3. We attempted to perform a complete circular ablation line using the rapid mode at 13 W, but if needed to achieve successful isolation, rapid mode was interrupted and manual mode (5.5–8.5 W) applications were used. The percentage of rapid mode use on the 360° lesion was measured for each PV. Total and fluoroscopy times to complete PVI were also collected. Results A total of 110 PVs were identified in 27 LB3 procedures and successfully isolated with a mean procedural time of 85±31 min. Sixty (55%) PVs were treated by using rapid mode for more than 50% (180°) lesion and 13 (12%) of them had a pure rapid mode ablation (without necessity of manual mode applications). Right inferior PV had the highest use of rapid mode (median value 70%). The main reasons for manual applications were poor PV occlusion, imperfect ostium visualization and presence of blood. PVs with >50% rapid mode use were treated in a significantly shorter time (21.2±13.7 vs 26.8±12.4, p=0.043). Fluoroscopy time did not differ significantly (4.7±4.2 vs 5.4±4.9, p=0.48). Three pinhole balloon ruptures were observed during rapid mode energy application in the second, third and twenty-fifth procedure. No other complications occurred. Conclusions Few PVs could be isolated using pure rapid mode; however, its applicability for more than 50% lesion was observed more frequently and significantly reduced the time to isolation. FUNDunding Acknowledgement Type of funding sources: None. Time to isolation using Rapid Mode