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The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.

Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) infection appears to be a necessary factor in the development of almost all cases (>95%) of cervical cancer. HPV E6 induces a change of control of p53 stabilization from Hdm2 to E6/E6AP in HPV-infected cells. It is well known that the LxxLL motif of cellular ubiquitin ligase E6AP binds to the pocket of E6 and causes a conformational change to enable E6 to bind p53 competently. In the ternary complex E6/E6AP/p53, p53 is polyubiquitinated by E6AP and subsequently degraded by a proteasome. Therefore, these cells are deficient in the processes regulated by p53, including apoptosis, damaged DNA repair, and the cell cycle. In the present study, it was demonstrated that quercetin induced G2 phase cell cycle arrest and apoptosis in both HeLa and SiHa cells, accompanied by an increase of p53 and its nuclear signal. It was also observed that quercetin increased the level of the p21 transcript and the pro-apoptotic Bax protein, which are two p53-downstream effectors. However, quercetin did not alter the expression of the HPV E6 protein in cervical cancer cells; therefore, the increase in p53 occurred in an E6 expression-independent manner. Furthermore, molecular docking demonstrated that quercetin binds stably in the central pocket of E6, the binding site of E6AP. These data suggest that quercetin increases the nuclear localization of p53 by interrupting E6/E6AP complex formation in cervical cancer cells.

Bovine viral diarrhea virus (BVDV) is a pathogen of worldwide economic importance. In Uruguay, BVDV is endemic, with seroprevalence >80% at the farm level. This study analyzed 912 samples collected from January 2018 to October 2024 by reverse transcription PCR and sequencing, from calves with diarrhea, aborted fetuses, heifers with a history of abortions, and animals exhibiting symptoms of Mucosal Disease. This work summarizes ten years (2014–2024) of molecular epidemiology and evolution of BVDV. Analysis of the BVDV 5′UTR/Npro genomic region revealed that the BVDV-1a, 1e, 1i, and 2b subtypes circulate in Uruguay. BVDV-1a remains the most prevalent subtype, followed by BVDV-2b, whose prevalence has been increasing. Our previous studies revealed that BVDV-1a showed geographical diversification in Uruguay. In this work, evolutionary studies conducted with Npro genomic region showed that BVDV-2b is evolving at a substitution rate of 6.09 × 10−4 substitutions/site/year and has been introduced from Brazil in six separate events between 1870 and 1928, showing no geographical diversification. This work demonstrates that BVDV-1a and BVDV-2b are evolving differently in Uruguay. This evolutionary divergence is notable when comparing patterns observed in other countries where these subtypes circulate. Our findings provide crucial knowledge that should be considered for developing effective BVDV control measures in Uruguay.

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2′,4′-dihydroxychalcone (2′,4′-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure–activity relationship (QSAR) model was developed to study the chimeric compounds’ anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2′,4′-DHC (A) and the chimeric compound 2′-hydroxy,4′-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C–K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.

Paclitaxel (PTX) is currently used as a front-line chemotherapeutic agent for several types of cancer, including ovarian carcinoma; however, PTX-resistance frequently arises through multiple mechanisms. The development of new strategies using natural compounds and PTX in combination has been the aim of several prior studies, in order to enhance the efficacy of chemotherapy. In this study, we found the following: (i) gallic acid (GA), a phenolic compound, potentiated the capacity of PTX to decrease proliferation and to cause G2/M cycle arrest in the PTX-resistant A2780AD ovarian cancer cell line; (ii) GA exerted a pro-oxidant action by increasing the production of reactive oxygen species (ROS), and co-treatment with the antioxidant agent N-acetyl-L-cysteine (NAC) prevented GA+PTX-induced cell proliferation inhibition and G2/M phase arrest; (iii) PTX stimulated ERK phosphorylation/activation, and co-treatment with the MEK/ERK inhibitor PD98049 potentiated the proliferation inhibition and G2/M phase arrest; (iv) and finally, GA abrogated the PTX-induced stimulation of ERK phosphorylation, a response that was prevented by co-treatment with NAC. Taken together, these results indicate that GA sensitizes PTX-resistant ovarian carcinoma cells via the ROS-mediated inactivation of ERK, and suggest that GA could represent a useful co-adjuvant to PTX in ovarian carcinoma treatment.

Among aquatic organisms, marine dinoflagellates are essential sources of bioactive metabolites. The benthic dinoflagellate Coolia malayensis produces metabolites that have exhibited substantial and specific cytotoxicity on cancer cells; however, isolation and identification of the purified compounds remain a challenge. This study reports C. malayensis biomass multi-step extraction plus chemical analyses for identifying compounds with antineoplastic activity. Through bio-directed fractionation, the cytotoxicity of extracts and fractions was tested on H1299 (lung), PC-3 (prostate), HeLa (cervical), and MCF-7 (breast) cancer cell lines. Dichloromethane (DCM) phase, hydroalcoholic (HYD) secondary extract, and methanolic (MET) extract showed cytotoxic effects on all cell lines. Active extracts and fractions were analyzed by HPLC-QTOF-MS, 1H, and 13C NMR. Cell lines H1299 and PC-3 treated with fractions F4, F7, and DCM2-AQ-Ch sub-extract showed morphological changes resembling those observed in the apoptosis control, and no signs of necrosis were observed. The selectivity of fraction F7 was above 100 μg mL−1 for healthy cells, while cytotoxic activity was observed in cancer cells. This fraction was identified as mostly fatty acids (FA) by NMR. Seventeen compounds with reported biological activities, such as antioxidant, analgesic, antiviral, and anticancer, were identified from C. malayensis extracts and fractions. Among them, the phycotoxins gambieric acid A and B, okadaic acid, and dinophysistoxin-1 were detected. Further studies are needed to reveal more significant anti-cancer potential from C. malayensis.

Preliminary bioassay-guided fractionation was performed to identify cytotoxic compounds from Hechtia glomerata, a plant that is used in Mexican ethnomedicine. Organic and aqueous extracts were prepared from H. glomerata’s leaves and evaluated against two cancer cell lines. The CHCl3/MeOH (1:1) active extract was fractionated, and the resulting fractions were assayed against prostate adenocarcinoma PC3 and breast adenocarcinoma MCF7 cell lines. Active fraction 4 was further analyzed by high-performance liquid chromatography–quadrupole time-of-flight–mass spectrometry analysis to identify its active constituents. Among the compounds that were responsible for the cytotoxic effects of this fraction were flavonoids, phenolic acids, and aromatic compounds, of which p-coumaric acid (p-CA) and its derivatives were abundant. To understand the mechanisms that underlie p-CA cytotoxicity, a microarray assay was performed on PC3 cells that were treated or not with this compound. The results showed that mitogen-activated protein kinases (MAPKs) that regulate many cancer-related pathways were targeted by p-CA, which could be related to the reported effects of reactive oxygen species (ROS). A molecular docking study of p-CA showed that this phenolic acid targeted these protein active sites (MAPK8 and Serine/Threonine protein kinase 3) at the same binding site as their inhibitors. Thus, we hypothesize that p-CA produces ROS, directly affects the MAPK signaling pathway, and consequently causes apoptosis, among other effects. Additionally, p-CA could be used as a platform for the design of new MAPK inhibitors and re-sensitizing agents for resistant cancers.

Members of the benthic marine dinoflagellate genus Amphidinium produce a variety of bioactive compounds, exhibiting potent cytotoxicity in cell assays. Crude methanolic extracts from three genetically distinct cultured strains of A. eilatiense J.J. Lee were screened for cytotoxicity against three human breast and four lung cancer cell lines to evaluate potential applications in anticancer therapy. A standard tetrazolium cell viability assay demonstrated that the methanolic crude extract (100 µg mL−1) from strain AeSQ181 reduced cell viability by 20–35% in five cancer cell lines. Further bioassay-guided fractionation of these crude extracts yielded non-polar fractions (FNP-5 and FNP-6) with particularly high cytotoxic activity against lung (H1563) and breast (MDA-MB-231) adenocarcinoma cell lines. Untargeted metabolomic analysis of cytotoxic fractions by liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) revealed a much richer chemical diversity profile than previous toxigenicity studies on Amphidinium that exclusively focused on linear and cyclic polyethers and their macrolide analogs as putative cytotoxins. This untargeted metabolomic study showed substantial differences in chemical composition between the biologically active and non-active fractions. Preliminary biological and chemical characterization of these A. eilatiense fractions confirms that this species is a rich source of bioactive natural products with potential applications such as anticancer therapeutics.

Three polyisoprenoid alcohols were isolated from the leaves of Tournefortia hirsutissima by a bioassay-guided phytochemical investigation. The compounds were identified as 16-hydroxy-lycopersene (Compound 1), (Z8,E3,ω)-dodecaprenol (Compound 2) and (Z9,E3,ω)-tridecaprenol (Compound 3). Compound 1, an unusual polyisoprenoid, was characterized by 1D and 2D NMR. We also determined the absolute configuration at C-16 by the modified Mosher’s method. The in vitro antiproliferative and anti-inflammatory activities of the isolated compounds were evaluated. Among isolates, Compound 1 moderately inhibited the nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. On the other hand, Compound 1 displayed selective antiproliferative activity against HeLa, PC3, HepG2 and Hep3B cancer cells and was less potent against IHH non-cancerous cells. Compound 1 in Hep3B cells showed significant inhibition of cell cycle progression increasing the sub-G1 phase, suggesting cell death. Acridine orange/ethidium bromide staining and Annexin V-FITC/PI staining demonstrated that cell death induced by Compound 1 in cells Hep3B was by apoptosis. Further study showed that apoptosis induced by Compound 1 in Hep3b cells is associated with the increase of the ratio of Bax/Bcl-2, and caspase 3/7 activation. These results suggest that Compound 1 induce apoptotic cell death by the mitochondrial pathway. To our knowledge, this is the first report about the presence of polyprenol Compounds 1–3 in T. hirsutissima, and the apoptotic and anti-inflammatory action of Compound 1.

Caesalpinia coriaria (C. coriaria), also named cascalote, has been known traditionally in México for having cicatrizing and inflammatory properties. Phytochemical reports on Caesalpinia species have identified a high content of phenolic compounds and shown antineoplastic effects against cancer cells. The aim of this study was to isolate and identify the active compounds of a water:acetone:ethanol (WAE) extract of C. coriaria pods and characterize their cytotoxic effect and cell death induction in different cancer cell lines. The compounds isolated and identified by chromatography and spectroscopic analysis were stigmasterol, ethyl gallate and gallic acid. Cytotoxic assays on cancer cells showed different ranges of activities. A differential effect on cell cycle progression was observed by flow cytometry. In particular, ethyl gallate and tannic acid induced G2/M phase cell cycle arrest and showed interesting effect on microtubule stabilization in Hep3B cells observed by immunofluorescence. The induction of apoptosis was characterized by morphological characteristic changes, and was supported by increases in the ratio of Bax/Bcl-2 expression and activation of caspase 3/7. This work constitutes the first phytochemical and cytotoxic study of C. coriaria and showed the action of its phenolic constituents on cell cycle, cell death and microtubules organization.