Casiopeinas® third generation, with indomethacin: synthesis, characterization, DFT studies, antiproliferative activity, and nanoencapsulation.

Seven new Casiopeinas® were synthesized and properly characterized. These novel compounds have a general formula [Cu(N-N)(Indo)]NO3, where Indo is deprotonated indomethacin and N-N is either bipyridine or phenanthroline with some methyl-substituted derivatives, belonging to the third generation of Casiopeinas®. Spectroscopic characterization suggests a square-based pyramid geometry and voltammetry experiments indicate that the redox potential is strongly dependent on the N-N ligand. All the presented compounds show high cytotoxic efficiency, and most of them exhibit higher efficacy compared to the well-known cisplatin drug and acetylacetonate analogs of the first generation. Computational calculations show that antiproliferative behavior can be directly related to the volume of the molecules. Besides, a chitosan (CS)-polyacrylamide (PNIPAAm) nanogel was synthesized and characterized to examine the encapsulation and release properties of the [Cu(4,7-dimethyl-1,10-phenanthroline)(Indo)]NO3 compound. The results show good encapsulation performance in acidic conditions and a higher kinetic drug release in acidic media than at neutral pH. This result can be described by the Peppas-Sahlin model and indicates a release mechanism predominantly by Fick diffusion.

Calotropin and corotoxigenin 3-O-glucopyranoside from the desert milkweed Asclepias subulata inhibit the Na+/K+-ATPase activity.

Na+/K+-ATPase is an essential transmembrane enzyme found in all mammalian cells with critical functions for cell ion homeostasis. The inhibition of this enzyme by several cardiotonic steroids (CTS) has been associated with the cytotoxic effect on cancer cell lines of phytochemicals such as ouabain and digitoxin. This study evaluated the inhibitory capacity of cardenolides calotropin and corotoxigenin 3-O-glucopyranoside (C3OG) from Asclepias subulata over the Na+/K+-ATPase activity in vitro and silico. The inhibitory assays showed that calotropin and C3OG decreased the Na+/K+-ATPase activity with IC50 values of 0.27 and 0.87 µM, respectively. Furthermore, the molecules presented an uncompetitive inhibition on Na+/K+-ATPase activity, with Ki values of 0.2 µM to calotropin and 0.5 µM to C3OG. Furthermore, the molecular modeling indicated that calotropin and C3OG might interact with the Thr797 and Gln111 residues, considered essential to the interaction with the Na+/K+-ATPase. Besides, these cardenolides can interact with amino acid residues such as Phe783, Leu125, and Ala323, to establish hydrophobic interactions on the binding site. Considering the results, these provide novel evidence about the mechanism of action of cardenolides from A. subulata, proposing that C3OG is a novel cardenolide that deserves further consideration for in vitro cellular antiproliferative assays and in vivo studies as an anticancer molecule.

Antiproliferative activity of standardized herbal phytopreparation from Asclepias subulata.

Background: Several studies have shown that active compounds of Asclepias subulata (cardenolides) have antiproliferative effect on human cancer cells. Cardenolides isolated from A. subulata can be used as active chemical markers to elaborate phytopharmaceutical preparations. To evaluate the antiproliferative effect of a standardized extract of the aerial parts, based on Asclepias subulata cardenolides. Methods: Four standardized extracts were prepared by HPLC-DAD depending on the concentration of calotropin and the antiproliferative activity was measured for the MTT assay, on the A549, MCF-7, HeLa, PC3 and ARPE cell lines. The concentrations of calotropin used for the standardization of the extracts were 10, 7.6, 5 and 1 mg/dL. Results: Standardization of the A. subulata extract based on calotropin at 7.6 mg/g dry weight was achieved and the antiproliferative activity was evaluated over A549, HeLa and MCF-7 cell lines, obtaining proliferation percentages of 3.8 to 13.4% . Conclusions: The standardized extracts of A. subulata at different concentrations of calotropin showed antiproliferative activity against all the cell lines evaluated. The greatest effect was observed against the HeLa cell line.

Evaluation of Quality, Antioxidant Capacity, and Digestibility of Chickpea (Cicer arietinum L. cv Blanoro) Stored under N2 and CO2 Atmospheres.

The aim of this work was to monitor the quality, antioxidant capacity and digestibility of chickpea exposed to different modified atmospheres. Chickpea quality (proximal analysis, color, texture, and water absorption) and the antioxidant capacity of free, conjugated, and bound phenol fractions obtained from raw and cooked chickpea, were determined. Cooked chickpea was exposed to N2 and CO2 atmospheres for 0, 25, and 50 days, and the antioxidant capacity was analyzed by DPPH (2,2'-diphenyl-1-picrylhydrazyl), ABTS (2,2'-azino-bis-[3ethylbenzothiazoline-6-sulfonic acid]), and total phenols. After in vitro digestion, the antioxidant capacity was measured by DPPH, ABTS, FRAP (ferric reducing antioxidant power), and AAPH (2,2'-Azobis [2-methylpropionamidine]). Additionally, quantification of total phenols, and UPLC-MS profile were determined. The results indicated that this grain contain high quality and high protein (18.38%). Bound phenolic compounds showed the highest amount (105.6 mg GAE/100 g) and the highest antioxidant capacity in all techniques. Cooked chickpeas maintained their quality and antioxidant capacity during 50 days of storage at 4 and -20 °C under a nitrogen atmosphere. Free and conjugated phenolic compounds could be hydrolyzed by digestive enzymes, increasing their bioaccessibility and their antioxidant capacity during each step of digestion. The majority compound in all samples was enterodiol, prevailing the flavonoid type in the rest of the identified compounds. Chickpea contains biological interest compounds with antioxidant potential suggesting that this legume can be exploited for various technologies.

Antiproliferative activity of cardenolides on cell line A549: structure-activity relationship analysis.

Since the beginning, natural products have represented an important source of bioactive molecules for cancer treatment. Among them, cardenolides attract the attention of different research groups due to their cardiotonic and antitumor activity. The observed biological activity is closely related to their Na+/K+-ATPase inhibition potency. Currently, the discovery of new compounds against cancer is an urgent need in modern pharmaceutical research. Thus, the aim of this work is to determine the physicochemical properties and substituent effects that module the antiproliferative activity of cardenolides on the human lung cancer cell line A549. We build and curate a library with results obtained from literature; molecular descriptors were calculated in PaDEL software, and SAR/QSAR analysis was performed. The SAR results showed that cardenolides were sensitive to modifications in C and D steroidal ring and required substituent groups with the function of hydrogen bond acceptor at the C3 position. QSAR models to doubly linked-type cardenolides indicated that properties as lipoaffinity and atoms with the capacity to be hydrogen bond acceptors are involved in the increment of antiproliferative activity on A549 cell line. In contrast, the presence and position of very electro-negative atoms on the molecule decreased the antiproliferative effect on A549 cells. These results suggest that the antiproliferative capacity of cardenolides on the cell line A549 is strongly related to substituent groups on the C3 position, which must not be carbohydrate. Additionally, the steroidal rings C and D must remain without modifications.

Antiproliferative and Apoptotic Activities of the Medicinal Plant Ziziphus obtusifolia.

BACKGROUND: Ziziphus obtusifolia is a spiny shrub found in Northwest Mexico desert, with traditional medicinal use to treat several diseases including cancer. OBJECTIVE: The aims of the present study were to evaluate the antiproliferative and apoptotic activities of the aerial parts of this plant. MATERIALS AND METHODS: The methanol extract and its fractions were prepared using several solvents. The antiproliferative activity was evaluated by the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium) (MTT) assay on HeLa, A549, RAW 264.7, M12.C3.F6, and L-929 cell lines, and the apoptotic activity using Annexin V and (5,50,6,60-tetra-chloro-1,10,3,30-tetra-ethylbenzimidazol-carbocyanine iodide) staining. The most active fraction was further separated by column chromatography. RESULTS: The most active fraction was hexane with an IC50 of 90.4 µg/mL against RAW 264.7, 94 µg/mL against M12.C3.F6, 165.5 µg/mL against HeLa and 187.7 µg/mL against A549 cell lines. In apoptotic activity assays the methanol extract and its n-hexane fraction were found to induce mitochondrial depolarization in HeLa cells (83 and 87% respectively), and both induced the externalization of the phosphatidylserine increasing the percentage of cells in early apoptosis from 1.4% in untreated control cells, to 1.9% and 3.5% for methanol extract and n-hexane fraction-treated cells, respectively, statistically different for the total percentage of apoptotic cells (P < 0.05). CONCLUSIONS: These results show that Z. obtusifolia has antiproliferative and apoptotic activities in vitro and confirms its use in traditional medicine. SUMMARY: The methanol extract and its fractions using several solvents were evaluated in the antiproliferative activity by the MTT assay on HeLa, A549, RAW 264.7, M12.C3.F6, and L-929 cell lines, and the apoptotic activity using Annexin V and (5,50,6,60-tetra-chloro-1,10,3,30-tetra-ethylbenzimidazol-carbocyanine iodide) staining. The most active fraction against cell lines was hexane. In apoptotic activity assays, the methanol extract and its n-hexane fraction were found to induce mitochondrial depolarization. This results we showed that Ziziphus obtusifolia has antiproliferative and apoptotic activities in vitro.Abbreviations Used: DMEM: Dulbecco's modified eagle's medium, DMSO: Dimethyl sulfoxide, MTT: (3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium), JC-1: (5,50,6,60-tetra-chloro-1,10,3,30-tetra-ethylbenzimidazol-carbocyanine iodide), FBS: Fetal bovine serum, CAPE: Caffeic acid phenethyl ester, PBS: Phosphate-buffered saline.

Two new lignans from the resin of Bursera microphylla A. gray and their cytotoxic activity.

Two new lignans, namely 7-O-podophyllotoxinyl butyrate (1) and dihydroclusin 9-acetate (2), were isolated from the dichloromethane fraction of a methanol extract of Bursera microphylla (Burseraceae), along with eight known lignans (3-10). Their structures were determined by means of comprehensive spectroscopic analysis. Lignans 2-6 were tested for their anti-proliferative activity on the cancer cell lines LS180, A549 and HeLa, and on a non-cancer cell line, ARPE-19. Only compounds 4 and 5 showed an interesting activity on HeLa cells.

Abordaje quirúrgico de las lesiones de plexo braquial en el departamento de Cirugía Plástica del Hospital Dr Salvador B Gautier, Santo Domingo, República Dominicana: estudio retrospectivo de 5 años / Surgical management of braquial plexus injuries at Plastic Surgery Unit Dr Salvador B Gautier Hospital, Santo Domingo, Dominican Republic: a 5 year retrospective study

Introducción y Objetivo. El tratamiento de las lesiones de plexo braquial es demandante y dificultoso, no solo por su complejidad y variabilidad anatómica sino también por las habilidades requeridas para el diagnóstico y abordaje de las mismas. Están descritas gran cantidad de técnicas y modificaciones en busca de readquirir la capacidad funcional de un miembro paralizado. En el presente trabajo revisamos la experiencia de nuestro servicio en el abordaje y tratamiento de estos pacientes, para, en una segunda fase, poder evaluar los resultados de estas intervenciones y establecer políticas de atención para el futuro. Material y Método. Presentamos un estudio de revisión retrospectiva de la experiencia de 5 años y 49 pacientes con tratamiento de lesiones del plexo braquial en el Hospital Dr. Salvador B. Gautier de la República Dominicana. Resultados. La mayoría de los afectados fueron adultos jóvenes (53%), sexo masculino (93%). La causa más frecuente de la lesión fue accidente relacionado con motocicleta (86%). La lesión fue cerrada en el 86%. Por lo general, los pacientes llegaron tardíamente al centro para recibir atención. Las raíces más afectadas fueron las superiores C5, C6, y la avulsión fue la lesión más frecuente. De los 49 pacientes intervenidos, 48 lo fueron directamente en el plexo braquial realizándose neurolisis en el 100%; transferencias e injertos nerviosos en el 41%; y transferencia extraplexual en 7 casos. Conclusiones. Tras los datos recogidos y una vez determinado el perfil del paciente más frecuentemente afectado en nuestro entorno, procede realizar un estudio de seguimiento de los pacientes para determinar el grado de recuperación alcanzado, su autonomía y retorno al trabajo productivo (AU)

Background and Objective. Treatment of braquial plexus injuries is highly demand and difficult, not only because of its complexity and anatomical variability, but because it needs of special abilities for diagnosis and management. Many surgical techniques and its modifications are described looking for recovering of functional capacity of a palsy extremity. In this paper we review the experience of our Unit in management and treatment of these patients, looking for, in a second phase, to get an evaluation of results in order to archive rules for future attention to these patients. Methods. A5 years and 49 patients series about management of brachial plexus injuries is presented. Cases were treated at Dr. Salvador B. Gautier Hospital in the Dominican Republic and evaluated retrospectively. Results. Most of the patients were young adults between 21 and 29 years old (53%).Male patients predominance of 93%.Motorcycle accidents caused 86% of injuries. Closed lesion was present in 86%.Most of the patients were referred late to the hospital. The most common affected roots were C5, C6. Avulsion was the most common injury and 48 out of 49 patients had a direct braquial plexus surgery with a 100% of neurolisis; 41% nerve grafts and nerve transfers; and 7 cases with out of the plexus nerve transfers. Conclusions. With all our recovered data and once determined the most frequent type of patient with braquial plexus injury in our area, we may conduct a follow-up study of the patients in order to know their recover level, their autonomy and their back to a productive job (AU)

Diterpenoids and Triterpenoids from the Resin of Bursera microphylla and Their Cytotoxic Activity.

A chemical study of the nonpolar fraction of a methanol-soluble extract of Bursera microphylla resin yielded a variety of di- and triterpenoids. In total, 15 compounds were isolated, of which three are new, namely, malabaricatrienone (1), malabaricatrienol (2), and microphyllanin (3). The antiproliferative activity of the major compounds was evaluated in different murine cancer cell lines (M12.C3.F6 and RAW264.7) and human cancer cells (A549, HeLa, and PC-3). The new compounds (1-3) did not show significant antiproliferative activity. The known compounds ariensin (4), burseran (5), and dihydroclusin diacetate (6) were effective against the RAW264.7 cell line, with IC50 values in the micromolar range.

Antiproliferative and apoptotic activities of extracts of Asclepias subulata.

CONTEXT: Asclepias subulata Decne. (Apocynaceae) is a shrub used in the Mexican traditional medicine for the treatment of cancer. OBJECTIVE: The objective of this study was to evaluate the antiproliferative activity of methanol extract of aerial parts of A. subulata and its fractions against different cancer cell lines. Additionally, we analyzed the mechanism of action of the active fractions. MATERIALS AND METHODS: Methanol extract fractions were prepared by serial extraction with n-hexane, ethyl acetate, and ethanol. The antiproliferative activity of methanol extract and its fractions was evaluated, against several murine (M12.C3.F6, RAW 264.7, and L929) and human (HeLa, A549, PC-3, LS 180, and ARPE-19) cell lines by the MTT assay, using concentrations of 0.4-400 µg/mL for 48 h. Ethanol and residual fractions were separated using silica gel column. Apoptosis induction of cancer cells was evaluated by Annexin and JC-1 staining using flow cytometry. RESULTS: Methanol extract and its fractions showed antiproliferative activity against all human cancer cell lines tested. Methanol extract had the highest antiproliferative activity on A549 and HeLa cells (IC50 values < 0.4 and 8.7 µg/mL, respectively). Ethanol and residual fractions exerted significant antiproliferative effect on A549 (IC50 < 0.4 µg/mL) and PC3 cells (IC50 1.4 and 5.1 µg/mL). Apoptotic assays showed that CEF7, CEF9, CRF6, and CRF5 fractions induced mitochondrial depolarization in A549 cells, 70, 73, 77, and 80%, respectively. Those fractions triggered the apoptosis mitochondrial pathway. CONCLUSION: Our data show that A. subulata extracts have potent antiproliferative properties on human cancer cell lines. This plant should be considered an important source of potent anticancer compounds.