Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.

Germline predisposition to pediatric Ewing sarcoma is uniquely characterized by inherited pathogenic variants in DNA damage repair genes

More knowledge is needed around the role and importance of specific genes in germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. In this study, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out an ancestry-matched case-control analysis to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1138 individuals with pediatric sarcoma diagnoses (222 Ewing sarcoma cases) relative to identically processed cancer-free controls. Findings in Ewing sarcoma were validated with an additional cohort of 425 individuals, and 301 Ewing sarcoma parent-proband trios were analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the discovery Ewing sarcoma cohort (OR 14.4, 95% CI 3.5 - 51.2, p = 0.002, FDR = 0.28). This enrichment in FANCC heterozygous pathogenic variants was seen again in the Ewing sarcoma validation cohort (OR 5.1, 95% CI 1.2 - 18.5, p = 0.03, single hypothesis), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in Ewing sarcoma cases. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.

Phytochemical and Biological Investigation of Bridelia tomentosa Blume Growing in Bangladesh

Bridelia tomentosa Blume is a small evergreen tree which has enormous folklore applications in the treatment of colic, traumatic injury, epidemic influenza and neurasthenia. The main purpose of this study was to isolate bioactive compounds from the stem bark of B. tomentosa growing in Bangladesh. Extensive chromatographic separation and purification of the methanolic extract of stem bark of B. tomentosa led to the isolation of four compounds. The purified constituents were identified as friedoolean-5(6),14(15)-dien-3-one (1), β-taraxerol (2), D4- stigmasterone (3) and lupeol (4) by extensive analysis of NMR spectroscopic data. While compound 1 is appeared to be new, the other compounds (2-4) have been isolated for the first time from this plant. β-taraxerol (2) demonstrated significant cytotoxic activity against the brine shrimp Artemia salina and moderate to strong antimicrobial efficacy with the highest inhibitory potential against Salmonella Typhi (zone of inhibition = 21.3 mm) and Sarcina lutea (zone of inhibition =20.8 mm). In conclusion, B. tomentosa has been found to be a rich source of secondary metabolites and thus it may be studied further in order to isolate of more bioactive constituents. Dhaka Univ. J. Pharm. Sci. 20(2): 213-218, 2021 (December)

Biological Investigation of Amaryllidaceae Alkaloid Extracts from the Bulbs of Pancratium trianthum Collected in the Senegalese Flora

Amaryllidaceae plants are rich in alkaloids with biological properties. Pancratium trianthum is an Amaryllidaceae species widely used in African folk medicine to treat several diseases such as central nervous system disorders, tumors, and microbial infections, and it is used to heal wounds. The current investigation explored the biological properties of alkaloid extracts from bulbs of P. trianthum collected in the Senegalese flora. Alkaloid extracts were analyzed and identified by chromatography and mass spectrometry. Alkaloid extracts from P. trianthum displayed pleiotropic biological properties. Cytotoxic activity of the extracts was determined on hepatocarcinoma Huh7 cells and on acute monocytic leukemia THP-1 cells, while agar diffusion and microdilution assays were used to evaluate antibacterial activity. Antiviral activity was measured by infection of extract-treated cells with dengue virus (DENVGFP) and human immunodeficiency virus-1 (HIV-1GFP) reporter vectors. Cytotoxicity and viral inhibition were the most striking of P. trianthum’s extract activities. Importantly, non-cytotoxic concentrations were highly effective in completely preventing DENVGFP replication and in reducing pseudotyped HIV-1GFP infection levels. Our results show that P. trianthum is a rich source of molecules for the potential discovery of new treatments against various diseases. Herein, we provide scientific evidence to rationalize the traditional uses of P. trianthum for wound treatment as an anti-dermatosis and antiseptic agent.

A Peptidoform Matching Strategy in Bottom-Up Proteomics for Studying Functions of Post-Translational Modifications

Protein translational modifications (PTMs) generate an enormous, but as yet undetermined, expansion of the expressed proteoforms. In this Viewpoint, we firstly differentiate the concepts of proteoform and peptidoform by reviewing and discussing previous literature. We show that the current PTM biological investigation and annotation largely follow a PTM site-specific rather than proteoform-specific approach. We further illustrate a potentially useful matching strategy in which a particular “modified peptidoform” is matched to the corresponding “unmodified peptidoform” as a reference for the quantitative analysis between samples and conditions. We suggest this strategy could provide directly relevant information for learning the PTM site-specific biological functions. Accordingly, we advocate for the wider use of the nomenclature “peptidoform” in the future bottom-up proteomic studies.

Antioxidant and Anti-Inflammatory Activity of Cynanchum acutum L. Isolated Flavonoids Using Experimentally Induced Type 2 Diabetes Mellitus: Biological and In Silico Investigation for NF-κB Pathway/miR-146a Expression Modulation

Cynanchum acutum L. is a climbing vine that belongs to the family Apocynaceae. Using different chromatographic techniques, seven compounds were isolated from the methanolic extract of the plant. The isolated compounds include six flavonoid compounds identified as rutin (1), quercetin-3-O-neohesperidoside (2), quercetin-3-O-β-galactoside (3), isoquercitrin (4), quercetin (5), and kaempferol 3-O-β-glucoside (6), in addition to a coumarin, scopoletin (7). The structures of the compounds were elucidated based on 1D NMR spectroscopy and high-resolution mass spectrometry (HR-MS), and by comparison with data reported in the literature. The first five compounds were selected for in vivo investigation of their anti-inflammatory and antioxidant properties in a rat model of type 2 diabetes. All tested compounds significantly reduced oxidative stress and increased erythrocyte lysate levels of antioxidant enzymes, along with the amelioration of the serum levels of inflammatory markers. Upregulation of miR-146a expression and downregulation of nuclear factor kappa B (NF-κB) expression were detected in the liver and adipose tissue of rats treated with the isolated flavonoids. Results from the biological investigation and those from the validated molecular modeling approach on two biological targets of the NF-κB pathway managed to highlight the superior anti-inflammatory activity of quercetin-3-O-galactoside (3) and quercetin (5), as compared to other bioactive metabolites.

Differences in Gall Induction of Flower-like Galls on Haloxylon by Psyllids (Hemiptera: Aphalaridae), and the Emergence of Corresponding Parasitoids

Saxaul is a kind of dominant perennial psammophyte that widely distributes in arid and semi-arid desert areas, and it has multiple functions in preventing desertification, especially in windbreak and sand fixation. Various gall inducers induce galls on the saxaul, including the flower-like gall. Parasitoids have great potentiality in controlling gall inducers. However, studies about gall inducers and parasitoids of flower-like galls on Haloxylon, as well as the parasitic efficacy of the parasitoids, are rarely reported. In this study, the flower-like galls were observed on Haloxylon ammodendron and H. persicum in Fukang, Xinjiang, China. Two types of flower-like galls were found on H. ammodendron, while only one type was found on H. persicum. In total, five species of gall inducers and three species of parasitoids were obtained from the galls mentioned above. All the galls were induced by Caillardia (Hemiptera: Aphalaridae), which were mostly bivoltine in Fukang. Besides, their parasitoids Psyllaephagus caillardiae and P. longiventris could be observed on all the types of galls. Additionally, correlative studies on the parasitization indexes demonstrated that all the dominant parasitoids of diverse flower-like galls were P. caillardiae, which were slightly more in number than the P. ogazae discovered in the flower bud-like galls. In addition, the relevance between the emergence or lifespan of parasitoids and temperature was also investigated. The results showed that the number of parasitoids emerging decreased rapidly after a period of enhancement with the increase of temperature, including an optimum temperature, while the lifespan of wasps gradually shortened with the temperature rising. Our results highlight the importance of the biological investigation of parasitoids in the gall inducers lived in closed galls, which may provide critical evidence for us to understand its potential application in biological control.

Design and Engineering of “Green” Nanoemulsions for Enhanced Topical Delivery of Bakuchiol Achieved in a Sustainable Manner: A Novel Eco-Friendly Approach to Bioretinol

In the present work, we establish novel “environmentally-friendly” oil-in-water nanoemulsions to enhance the transdermal delivery of bakuchiol, the so-called “bioretinol” obtained from powdered Psoralea corylifolia seeds via a sustainable process, i.e., using a supercritical fluid extraction approach with pure carbon dioxide (SC-CO2). According to Green Chemistry principles, five novel formulations were stabilized by “green” hybrid ionic surfactants such as coco-betaine—surfactin molecules obtained from coconut and fermented rapeseed meal. Preliminary optimization studies involving three dispersion stability tests, i.e., centrifugation, heating, and cooling cycles, indicated the most promising candidates for further physicochemical analysis. Finally, nanoemulsion colloidal characterization provided by scattering (dynamic and electrophoretic light scattering as well as backscattering), microscopic (transmission electron and confocal laser scanning microscopy), and spectroscopic (UV–Vis spectroscopy) methods revealed the most stable nanocarrier for transdermal biological investigation. In vitro, topical experiments provided on human skin cell line HaCaT keratinocytes and normal dermal NHDF fibroblasts indicated high cell viability upon treatment of the tested formulation with a final 0.02–0.2 mg/mL bakuchiol concentration. This excellent biocompatibility was confirmed by ex vivo and in vivo tests on animal and human skin tissue. The improved permeability and antiaging potential of the bakuchiol-encapsulated rich extract were observed, indicating that the obtained ecological nanoemulsions are competitive with commercial retinol formulations.