The structure design of biotransformed unsymmetrical nitro-contained 1,5-diaryl-3-oxo-1,4-pentadienyls for the anti-parasitic activities

AbstractTwo 1,5-diaryl-3-oxo-1,4-pentadienyls (1 and 2) having nitro group attached exhibited potent anti-parasitic activity when evaluated against Trypanosoma cruzi and Leishmania amazonensis. In the present work, metabolomic analysis revealed that enzymatic action of T. cruzi reduces the CC bonds and let the nitro groups intact. Further, these two reduced compounds along with six other congeners were produced by chemical or microbiological methods and evaluated against T. cruzi. All reduced compounds showed less potency than compounds 1 and 2, proving the importance of unsaturated moieties for activity. This investigation provides insight into the mechanism of action of nitro unsaturated diarylpentadienones reinforcing previous studies showing their interference in the redox metabolism of T. cruzi. In the result increase in reactive oxygen and nitrogen species occurs, altering mitochondrial function and depleting the whole antioxidant system, which ultimately causes parasite death. Docking studies using trypanothione oxy-reductase as target helped understanding the activities. The present investigation confirms that enzymes play a pivotal role in drug activation

Proanthocyanidin Polymer-Rich Fraction of Stryphnodendron adstringens Promotes in Vitro and in Vivo Cancer Cell Death via Oxidative Stress

Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16-positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL-2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment

Oxidative Stress Triggered by Apigenin Induces Apoptosis in a Comprehensive Panel of Human Cervical Cancer-Derived Cell Lines

Recently, the cytotoxic effects of apigenin (4′,5,7-trihydroxyflavone), particularly its marked inhibition of cancer cell viability both in vitro and in vivo, have attracted the attention of the anticancer drug discovery field. Despite this, there are few studies of apigenin in cervical cancer, and these studies have mostly been conducted using HeLa cells. To evaluate the possibility of apigenin as a new therapeutic candidate for cervical cancer, we evaluated its cytotoxic effects in a comprehensive panel of human cervical cancer-derived cell lines including HeLa (human papillomavirus/HPV 18-positive), SiHa (HPV 16-positive), CaSki (HPV 16 and HPV 18-positive), and C33A (HPV-negative) cells in comparison to a nontumorigenic spontaneously immortalized human epithelial cell line (HaCaT). Our results demonstrated that apigenin had a selective cytotoxic effect and could induce apoptosis in all cervical cancer cell lines which were positively marked with Annexin V, but not in HaCaT (control cells). Additionally, apigenin was able to induce mitochondrial redox impairment, once it increased ROS levels and H2O2, decreased the Δψm, and increased LPO. Still, apigenin was able to inhibit migration and invasion of cancer cells. Thus, apigenin appears to be a promising new candidate as an anticancer drug for cervical cancer induced by different HPV genotypes

Heparosan as a potential alternative to hyaluronic acid for the design of biopolymer-based nanovectors for anticancer therapy

International audienceGlycosaminoglycans (GAGs) are important components of the extracellular matrix that have attracted great interest for drug delivery and pharmaceutical applications due to their diverse biological functions. Among GAGs, heparosan (Hep), a biosynthetic precursor of heparin, has recently emerged as a promising building block for the design of nanoparticles with stealth properties. Though this non-sulfated polysaccharide has a chemical structure very close to that of hyaluronic acid (HA), it distinguishes from HA in that it is biologically inert in the extracellular spaces in the body. In this study, we designed Hep- and HA-based nanogels (NGs) that differ only in the chemical nature of the hydrophilic shell. The nanogels were prepared in a very straightforward way from Hep and HA modified with a thermoresponsive copolymer properly designed to induce self-assembly below room temperature. This versatile synthetic approach also enabled further shell-crosslinking allowing an increase in the colloidal stability. After careful characterization of the un-crosslinked and crosslinked Hep and HA NGs in terms of size (Z-average diameters of un-crosslinked and crosslinked NGs ∼110 and 150 nm) and morphology, they were injected intravenously into tumor-bearing mice for biodistribution experiments. Interestingly, these show that the liver uptake of Hep nanogels is remarkably reduced and tumor accumulation significantly improved as compared to HA nanogels (intensity ratios of tumor-to-liver of 2.2 and 1.4 for the un-crosslinked and crosslinked Hep NGs versus 0.11 for the un-crosslinked and crosslinked HA ones). These results highlight the key role played by the shell-forming GAGs on the in vivo fate of nanogels, which correlates with the specific biological properties of Hep and HA

CHEMICAL STUDY AND ANTIPROLIFERATIVE, TRYPANOCIDAL AND LEISHMANICIDAL ACTIVITIES OF Maxillaria picta

The chemical study of the orchid Maxillaria picta resulted in the isolation of the bioactive stilbenes phoyunbene B and phoyunbene C, in addition to four phenolic acids, one xanthone, steroidal compounds and two triterpenes. Crude extract, fractions, subfractions and the isolated xanthone were evaluated for anticancer activity against human tumor cell lines and against evolutionary forms of T. cruzi and L. amazonensis. The structures of the compounds were determined by GC-MS, and ¹H NMR, 13C NMR spectral methods as well as bidimensional techniques

Fluorescence properties of curcumin-loaded nanoparticles for cell tracking

Background: Posttransplant cell tracking, via stem cell labeling, is a crucial strategy for monitoring and maximizing benefits of cell-based therapies. The structures and functionalities of polysaccharides, proteins, and lipids allow their utilization in nanotechnology systems. Materials and methods: In the present study, we analyzed the potential benefit of curcumin-loaded nanoparticles (NPC) using Vero cells (in vitro) and NPC-labeled adipose-derived mesenchymal stem cells (NPC-ADMSCs) (in vivo) in myocardial infarction and sciatic nerve crush preclinical models. Thereafter, transplantation, histological examination, real time imaging, and assessment of tissue regeneration were done. Results: Transplanted NPC-ADMSCs were clearly identified and revealed potential benefit when used in cell tracking. Conclusion: This approach may have broad applications in modeling labeled transplanted cells and in developing improved stem cell therapeutic strategies.Fil: Mogharbel, Bassam Felipe. Pelé Pequeno Príncipe Institute; BrasilFil: Francisco, Julio Cesar. Pelé Pequeno Príncipe Institute; BrasilFil: Irioda, Ana Carolina. Pelé Pequeno Príncipe Institute; BrasilFil: Dziedzic, Dilcele Silva Moreira. Pelé Pequeno Príncipe Institute; BrasilFil: Ferreira, Priscila Elias. Pelé Pequeno Príncipe Institute; BrasilFil: de Souza, Daiany. Pelé Pequeno Príncipe Institute; BrasilFil: de Souza, Carolina Maria Costa Oliveira. Pelé Pequeno Príncipe Institute; BrasilFil: Neto, Nelson Bergonse. Pelé Pequeno Príncipe Institute; BrasilFil: Guarita Souza, Luiz Cesar. Universidade Federal do Paraná; BrasilFil: Franco, Celia Regina Cavichiolo. Universidade Federal do Paraná; BrasilFil: Nakamura, Celso Vataru. Universidade Estadual de Maringá; BrasilFil: Kaplum, Vanessa. Universidade Estadual de Maringá; BrasilFil: Mazzarino, Letícia. Universidade Federal de Santa Catarina; BrasilFil: Lemos Senna, Elenara. Universidade Federal de Santa Catarina; BrasilFil: Borsali, Redouan. Universite Grenoble Alpes; FranciaFil: Soto, Paula Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Setton, Clara Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Abdelwahid, Eltyeb. Northwestern University; Estados UnidosFil: Athayde Teixeira de Carvalho, Katherine. Pelé Pequeno Príncipe Institute; Brasi

X-ray structure of O-methyl-acrocol and anti-cancer, anti-parasitic, anti-bacterial and anti-Zika virus evaluations of the Brazilian palm tree Acrocomia totai

Acrocomia totai Mart ("macauba") is a palm tree native from Brazil, whose potential for biodiesel production has been widely explored. In spite of the industrial interest in the oil from the nuts, little is known about the potential applications of other parts of the plant, especially in the pharmacological area. A phytochemical study of the plant thorns led to the identification of a new compound 3-(R)-methoxy-21-(R)-H-hop-22(29)-en-30-ol 1, two known triterpenes 2-3, four steroids 4-7 and a stilbene, piceatannol 8. The structures were elucidated by spectroscopic analyses, including 1D and 2D NMR and low and high resolution mass spectrometry. Compound 1 was purified as crystals, which allowed the determination of the absolute configuration of the asymmetric carbons by analysis of the X-ray diffraction spectrum. Biological tests were performed with crude extract (CE), fractions and isolated compound. The assays showed activity for CE against lung carcinoma (GI(50) 59.2 mu g mL(-1)). The ethyl acetate fraction (EAF) showed efficacy against many tumor cell lines, and the tests showed the most prominent activity for breast cancer (GI(50) 10.4 mu g mL(-1)), glioma (GI(50) 77.3 mu g mL(-1)), uterine cervix (SiHa) HPV 16 (IC50 39.8 mu g mL(-1)), (HeLa) HPV 18 (IC50 12.0 pg mL(-1)) and Caco-2 (IC50 40.0 mu g mL(-1)) and showed bacteriostatic action against Staphylococcus aureus (MIC 50 mu g mL(-1)). Piceatannol 8 isolated from EAF showed activity against the protozoan which causes leishmaniosis (IC50 58.4 mu g mL(-1)). For Ttypanosorna cruzi, the methanol fraction (EC50 15.5 mu g mL(-1)), CE (20.5 mu g(-1)), and HEF (43.8 mu g mL(-1)) were the most active, being highly selective for the protozoan and less toxic against Vero cells. The compound 8 was further tested against Zika virus MR 766 strain on MOI 2, however the assays showed no inhibition against virus infection109483492CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO ARAUCÁRIA DE APOIO AO DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO DO ESTADO DO PARANÁ - FAFUNDAÇÃO DE AMPARO À PESQUISA E INOVAÇÃO DO ESTADO DE SANTA CATARINA - FAPESCsem informaçãosem informaçãosem informaçãosem informaçã