3-Heptylidene-4,6-Dimethoxy-3H-Isobenzofuran-1-One Is Genotoxic, Increases the Frequency of Cell Death, and Potentiates the Effects of Cyclophosphamide and Cisplatin.

3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. As a result of the above, 1 has potential chemotherapeutic application and may be a candidate for developing a new generation of chemotherapeutics. In addition, it has characteristics to be used as a chemotherapy adjuvant in association with cyclophosphamide and cisplatin since it increases the frequency of cell death induced by chemotherapy. We also reported that the chemopreventive effect of 1, in association with cyclophosphamide and cisplatin, can prevent adverse effects (induction of DNA damage in non-tumor cells) without interfering with the mode of action of chemotherapy drugs and, therefore, without reducing the induction of cell death.

Determination of preclinical safety of oil obtained from Pachira aquatica Aublet (Malvaceae) seeds: histopathological, biochemical, hematological, and genetic toxicity studies in rats.

Pachira aquatica is a species used for medicinal and food purposes and has numerous phytochemicals that may have systemic toxic effects and damage to genetic material. This study aimed to evaluate acute and short-term oral toxicity, as well as genotoxic and clastogenic effects of oil extracted from P. aquatica (PASO) seeds in rats and Drosophila melanogaster. The results obtained with biochemical and hematological analyses did not show significant changes in any evaluated parameters when compared with reference values for the species used in the study. Data from the histopathological analysis corroborated results found in this study. These findings indicate low acute and short-term toxicity following oral PASO exposure in rats under the experimental conditions tested. Tests performed in rats showed that PASO did not present significant genotoxic or clastogenic effects on the cells analyzed with the three doses tested. Treatment with PASO in the offspring of HB crossing, which showed high cytochrome P450 levels, did not exhibit genotoxic activity, as demonstrated by the SMART test. These results suggest that products from the hepatic oil metabolism did not show genotoxicity under the conditions tested. Together, the results indicate that, under the experimental conditions tested, PASO is safe for repeated intake. As PASO exhibited low potential to cause harmful effects on living organisms, our study encourages further research aimed at assessing its pharmacological activity, since it is a widely consumed plant.

Cytotoxic, genotoxic and mutagenic evaluation of Alibertia edulis (rich.) a. Rich. ex DC: an indigenous species from Brazil.

Tea leaves of Alibertia edulis is popularly used in folk medicine. However, studies on the genotoxicity of this plant are not available. We aimed to investigate the in vivo and in vitro cytotoxic, genotoxic and mutagenic potentials of the aqueous extract of A. edulis leaves (AEAE). Antioxidant assays, the Artemia salina test, MTT in human platelets, micronucleus in bone marrow and comet in peripheral blood were performed. Animals received four different doses of the AEAE by oral gavage for 30 days. Saline and cyclophosphamide were used as controls. The AEAE exhibited a maximal inhibition at 100 and 250 µg/mL, according to the ABTS and DPPH methods, respectively. The A. salina assay showed that the AEAE presented some toxicity at doses of 100, 250 and 500 µg/mL. Through the MTT assay, the AEAE showed no toxic effects on human platelets during the incubation period. The alkaline comet assay showed that all doses of the AEAE were statistically similar to the negative control group since they did not induce any significant increase of the overall number of damaged cells nor the severity of the cell damage. In the micronucleous assay, results demonstrate that the AEAE did not increase the production of micronucleated polychromatic erythrocytes and was statistically similar to the negative control. The four doses of the plant extract did not affect the production of new erythrocytes and were statistically similar to the negative control groups. Furthermore, the AEAE demonstrated no cytotoxicity, genotoxicity and mutagenicity at the doses tested in rats.

Assessment of genetic integrity, splenic phagocytosis and cell death potential of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid and its effect when combined with commercial chemotherapeutics.

The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation.

Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

Evaluation of the toxicokinetics and apoptotic potential of ethanol extract from Echinodorus macrophyllus leaves in vivo.

This study evaluates the toxicological, genotoxic, mutagenic and apoptotic potential of an in vivo assay from Echinodorus macrophyllus extract (EEM). The acute toxicity test used 02 groups (n = 5) of female Wistar rats: negative control group (saline) and experimental group (2000 mg/kg b.w. EEM), both orally administered (gavage) at single doses and monitored for 14 days. To assess the genotoxic, mutagenic and apoptotic potential, 50 male Swiss mice were divided into 5 groups (n = 10): Group I: negative control (saline solution 0.1 ml/10 g b.w.); Group II: positive control (cyclophosphamide 100 mg/kg b.w.) intraperitoneally administered; groups III-V received EEM at 500, 1000 and 2000 mg/kg b.w., respectively. Groups I, III-V received oral administrations (gavage). The results showed that there was no acute lethality or any signs of acute toxicity, indicating that LD50 is greater than 2000 mg/kg b.w. The groups treated with EEM showed no genotoxic or mutagenic activity and did not induce apoptosis in the liver and kidney. Therefore, EEM showed no acute toxicity and at doses of 500, 1000 and 2000 mg/kg b.w. absence of genotoxicity, mutagenicity and no apoptotic events were observed.

Toxicological analysis and anti-inflammatory effects of essential oil from Piper vicosanum leaves.

This study assessed the anti-inflammatory effects of the essential oil from Piper vicosanum leaves (OPV) and evaluated the toxicological potential of this oil through acute toxicity, genotoxicity and mutagenicity tests. The acute toxicity of OPV was evaluated following oral administration to female rats at a single dose of 2 g/kg b.w. To evaluate the genotoxic and mutagenic potential, male mice were divided into five groups: I: negative control; II: positive control; III: 500 mg/kg of OPV; IV: 1000 mg/kg of OPV; V: 2000 mg/kg of OPV. The anti-inflammatory activity of OPV was evaluated in carrageenan-induced pleurisy and paw edema models in rats. No signs of acute toxicity were observed, indicating that the LD50 of this oil is greater than 2000 mg/kg. In the comet assay, OPV did not increase the frequency or rate of DNA damage in groups treated with any of the doses assessed compared to that in the negative control group. In the micronucleus test, the animals treated did not exhibit any cytotoxic or genotoxic changes in peripheral blood erythrocytes. OPV (100 and 300 mg/kg) significantly reduced edema formation and inhibited leukocyte migration analyzed in the carrageenan-induced edema and pleurisy models. These results show that OPV has anti-inflammatory potential without causing acute toxicity or genotoxicity.

Anti-hyperglycemic potential and chemical constituents of Aristolochia triangularis Cham. leaves - A medicinal species native to Brazilian forests.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochia triangularis Cham. has been used in Brazilian traditional medicine for various therapeutic purposes, including as a leaf-based infusion for diabetes management. AIM OF THE STUDY: This study was designed to chemically characterize an infusion of in natura A. triangularis leaves and evaluate the in vivo anti-hyperglycemic properties of this infusion. MATERIALS AND METHODS: Chemical composition was examined using liquid-liquid extraction procedure, chromatographic methods, NMR, and LC-MS/MS. The in vivo anti-hyperglycemic activity of the freeze-dried infusion of A. triangularis leaves (Inf-L-At) was assessed using oral glucose tolerance test (OGTT). Initially, normoglycemic male rats were pre-treated with orally administered Inf-L-At at doses of 62.5, 125, and 250 mg/kg for two consecutive days. On the day of the OGTT, fasting animals received a glucose load (4 g/kg) 30 min after treatment with Inf-L-At, and the blood glucose levels were verified at 15, 30, 60, and 180 min. Intestinal maltase, lactase, and sucrase activities and muscle and liver glycogen contents were also assessed after the OGTT. RESULTS: Inf-L-At extract led to glycemic reduction with no dose-response at 15, 30, and 60 min comparable to that of the antidiabetic drug glibenclamide and was accompanied by an increase in hepatic and muscle glycogen contents. Additionally, there was a significant statistically decrease in the in vitro activity of disaccharidases. Maltase and sucrase activities were inhibited at all doses, whereas lactase activity was inhibited only at 62.5 and 250 mg/kg. In total, 75 compounds were found in the infusion, including seven new ones, (7S*,8S*,7ꞌS*,8ꞌR*)-4,4ꞌ-dihydroxy-3,3ꞌ-dimethoxy-7,9ꞌ-epoxylignan-7ꞌ-ol; 4ꞌ-hydroxy-3ꞌ-methoxy-3,4-methylenedioxy-7,9ꞌ-epoxylignan-9,7ꞌ-diol; triangularisines A, B, and C; N-ethyl-N-methyl-affineine; and N-methyl pachyconfine, and one previously not described as a natural product, epi-secoisolariciresinol monomethyl ether. CONCLUSION: The results demonstrated the anti-hyperglycemic activity of the infusion from A. triangularis leaves and showed that it is a rich source of lignoids, alkaloids, and glycosylated flavonoids, which are known to exhibit antidiabetic effects and other biological properties that can be beneficial for patients with chronic hyperglycemia, thus certifying the popular use of this herbal drink.

General and genetic toxicology studies of Aleurites moluccana (L.) Willd. seeds in vitro and in vivo assays.

ETHNOPHARMACOLOGY RELEVANCE: Aleurites moluccana is popularly used for the diseases like ulcers, fever, headache, asthma, conjunctivitis, gonorrhea, inflammation, hepatitis, and rheumatism. The seed, also known as "noz da Índia", has been popularly consumed for weight loss purposes but reports of toxicity have been associated with its ingestion. In the literature, there are not enough studies to elucidate its toxicology, so evaluating the general and genetic toxicological of A. moluccana seeds can provide data to ensure their intake. AIM OF THE STUDY: The objective of the present study was to elucidate the oral toxicity, mutagenicity, genotoxicity and cytotoxicity of A. moluccana seeds in vitro and in vivo assays. MATERIALS AND METHODS: The chemical composition of the aqueous extract of A. moluccana seeds (AEAMS) was analyzed in relation to phenolic compounds, tannins, flavonoids and fatty acid. For the in vitro assays, the cytotoxic potential was assessed by the MTS assay whereas the mutagenic potential was assessed by the Ames test. For in vivo assays, was conducted an acute oral toxicity study, with "Up-and-Down Procedure" and repeated dose toxicity with "Repeated Dose 28-Day Oral Toxicity". To assess genetic damage, mutagenic potential was assessed by the micronucleus test whereas the polychromatic erythrocyte/normochromatic erythrocyte ratio was obtained with bone marrow cells to determine the cytotoxic potential and genotoxic potential was assessed by the comet assay using peripheral blood cells. RESULTS: AEAMS did not show cytotoxic and mutagenic potential in vitro. No clinical signs of toxicity were observed in animals after the acute oral toxicity test, suggesting that the LD50 of aqueous extract of A. moluccana seeds > 2000 mg/kg in a single dose by intragastric route. However, in toxicity at repeated doses for 28 days, the doses initially established (250; 500 and 750 mg/kg/day by intragastric route) caused mortality in the animals and the reestablished doses (25, 50 and 100 mg/kg/day by intragastric route) showed no changes in parameters or clinical signs attributed to toxicity. Furthermore, AEAMS also did not show mutagenic, genotoxic and cytotoxic potential in vivo. CONCLUSIONS: AEAMS did not show cytotoxic, genotoxic and mutagenic potential in vitro and in vivo. And although the AEAMS has an LD50 > 2000 mg/kg, and does not have physiological, biochemical, hematological, histopathological changes or clinical signs related to toxicity when administered in low concentrations and for a short period, in high concentrations and continued use caused toxicity and mortality in Wistar rats. In order to obtain complementary results, is recommended highly that further mid and long-term toxicological studies are investigated, and in no-rodent specie.

From general toxicology to DNA disruption: A safety assessment of Plinia cauliflora (Mart.) Kausel.

ETHNOPHARMACOLOGICAL RELEVANCE: Plinia cauliflora (Mart.) Kausel (Myrtaceae) is popularly known as "jaboticaba" or "jaboticaba". The fruit is appreciated for both fresh consumption and the manufacture of jelly, juice, ice cream, fermented beverages, and liqueurs. The more widespread traditional use of the plant involves the treatment of diarrhea, which utilizes all parts of the plant, including the fruit peels. AIM OF THE STUDY: We sought to elucidate possible risks of the administration of an ethanol-soluble fraction that was obtained from an infusion of P. cauliflora fruit peels (SEIPC). We performed a series of experiments to evaluate possible toxicity, in which we administered SEIPC orally both acutely and repeatedly for 28 days. We also evaluated possible endocrine-disruptive and genotoxic effects in eukaryotic cells. The possible mutagenic activity of SEIPC was evaluated using reverse mutation (Ames) assays. MATERIALS AND METHODS: SEIPC was produced and chemically characterized by LC-DAD-MS. Acute toxicity and behavioral and physiological alterations were evaluated in the modified Irwin test. Respiratory rate, arterial blood gas, electrocardiography, respiratory rate, heart rate, and blood pressure were evaluated, and hematological, biochemical, and histopathological analyses were performed after 28 days of oral treatment. The comet assay, mammalian erythrocyte micronucleus test, uterotrophic test, Hershberger bioassay, and AMES test were performed using appropriate protocols. RESULTS: From SEIPC, ellagic acid and derivatives, flavonols and anthocyanidins, as well as citric acid and gallic acid, were annotated by LC-DAD-MS. We did not observed any significant toxic effects after acute or prolonged SEIPC treatment. No endocrine-disruptive or mutagenic effects were observed. CONCLUSIONS: The present study found that SEIPC did not cause any significant alterations of various corporeal systems, including cardiac electrical activity, body temperature, respiratory rate, and arterial pressure. No alterations of biochemical, hematological, or blood gas parameters were observed. SEIPC did not cause any perturbations of the endocrine system or mutagenic, cytotoxic, or genotoxic effects. These findings substantiate the safe clinical use of P. cauliflora.

Comparative Meta-Analysis of the Effect of Concentrated, Hydrolyzed, and Isolated Whey Protein Supplementation on Body Composition of Physical Activity Practitioners.

Whey protein (WP) is a dairy food supplement and, due to its effects on fat-free mass (FFM) gain and fat mass (FM) loss, it has been widely consumed by resistance training practitioners. This review analyzed the impact of WP supplementation in its concentrated (WPC), hydrolyzed (WPH) and isolated (WPI) forms, comparing it exclusively to isocaloric placebos. Random effect meta-analyses were performed from the final and initial body composition values of 246 healthy athletes undergoing 64.5 ± 15.3 days of training in eight randomized clinical trials (RCT) collected systematically from five scientific databases. The weighted mean difference (WMD) was statistically significant for FM loss (WMD = -0.96, 95% CI = -1.37, -0.55, p < 0.001) and, in the analysis of subgroups, this effect was maintained for the WPC (WMD = -0.63, 95% CI = -1.19, -0.06, p = 0.030), with protein content between 51% and 80% (WMD = -1.53; 95% CI = -2.13, -0.93, p < 0.001), and only for regular physical activity practitioners (WMD = -0.95; 95% CI = -1.70, -0.19, p = 0.014). There was no significant effect on FFM in any of the scenarios investigated (p > 0.05). Due to several and important limitations, more detailed analyses are required regarding FFM gain.

Preclinical safety evaluation of the ethanolic extract from Campomanesia pubescens (Mart. ex DC.) O.BERG (guavira) fruits: analysis of genotoxicity and clastogenic effects.

Genotoxicity studies of plants with medicinal and nutritional properties are recommended by international regulatory agencies as part of the risk assessment. Due to their consumption as food, nutraceutical use and ethnopharmacological relevance, Campomanesia pubescens represents one of these plants to be studied. The aim of the present study was to evaluate the genotoxic, cytotoxic potential and clathogenic effects of the ethanolic extract obtained from the pulp of C. pubescens (EEFCP) fruits on rats submitted to experimental genotoxicity models and through the SMART test performed in Drosophila melanogaster. The comet assay and the micronucleus test were performed on peripheral and bone marrow blood, respectively, of Wistar rats orally treated with EEFCP at doses of 125, 250, 500 and 1000 mg per kg per bw for 28 days. In the SMART test, the standard cross between three mutant D. melanogaster strains was used. Larvae were treated with EEFCP at different concentrations and the wings of adult flies were evaluated for the presence/frequency of mutant spots and compared to the negative control group. Phytochemical analysis of EEFCP indicated high levels of flavonoids. The tests performed in rats showed that EEFCP did not present significant genotoxic or clastogenic effects. The biotransformation metabolites of EEFCP did not present genotoxic activity, as demonstrated by the SMART test. Together, all results indicate that, under the experimental conditions used, EEFCP did not reveal any preclinical genetic toxicity. Therefore, the safe consumption can be fomented increasing, consequently, the economic liquidity in the industrial market from the fruits of guavira.

Preclinical safety evaluation of the ethanolic extract from guavira fruits (Campomanesia pubescens (D.C.) O. BERG) in experimental models of acute and short-term toxicity in rats.

Campomanesia pubescens is a fruit plant widely distributed in South America and used by the population for medicinal and nutritional purposes, with important economic and cultural value. This study evaluated the toxic potential of the ethanolic extract from C. pubescens (EEFCP) fruits through acute and short-term toxicity tests. For the acute toxicity test, female rats received a single oral dose of 2000 mg/kg body weight of EEFCP and were observed for 14 days. In the short-term toxicity test, male and female rats received repeated oral doses of 125, 250, 500 or 1000 mg/kg of EEFCP, being treated and observed for 28 days, and after the treatment period, a satellite and satellite control group remained under observation for another 14 days. No mortality, clinical and organ weight alterations were observed, indicating that LD50 is greater than 2000 mg/kg body weight. In addition, the doses tested did not produce significant changes in the behavioral, physiological, hematological or histopathological parameters of animals. These results demonstrate the low acute and short-term toxicity of EEFCP in rats. The data obtained are of great relevance since they provide important information about a plant species of great economic, nutritional and ethnopharmacological value.

Safety Assessment of Oil from Pequi (Caryocar brasiliense Camb.): Evaluation of the Potential Genotoxic and Clastogenic Effects.

Genotoxic data of medicinal plants and functional foods are required as part of the risk assessment by international regulatory agencies. Due to its food consumption and ethnopharmacological relevance, pequi oil (Caryocar brasiliense Camb.) is one of these compounds to be studied. The aim of this study was to evaluate the cytotoxic, genotoxic, and clastogenic effects of the oil from the pulp of C. brasiliense (OPCB) in vivo and in vitro. Initially, the Artemia salina in vitro assay was conducted to determine the cells viability rate of different doses of the OPCB. Subsequently, comet assay (Organization for Economic Cooperation and Development, OECD 489) and micronucleus test (OECD 474) were performed in blood and bone marrow of Wistar rats treated orally with a 125, 250, 500, or 1000 mg/kg/bw of the OPCB for 4 weeks. The chemical analysis indicated the presence of ß-carotene and lycopene in the oil. In the A. salina test, all OPCB doses maintained cell viability rates statistically similar to the negative control. The in vivo tests performed showed that OPCB did not show significant genotoxic or clastogenic effects in cells analyzed with the four doses tested. Altogether, these results indicate that, under our experimental conditions, C. brasiliense fruit oil did not reveal genetic toxicity in rat cells.

Study on the Cytotoxic, Genotoxic and Clastogenic Potential of Attalea phalerata Mart. ex Spreng. Oil Pulp In Vitro and In Vivo Experimental Models.

Attalea phalerata Mart. ex Spreng. (Arecaceae), popularly known as "bacuri", is used in Brazilian folk medicine. Its oil is used orally to relieve pulmonary congestion and joint pain. In topical applications, it is applied as an effective hair tonic and anti-dandruff. The in natura pulp and its nuts are used as food because of its nutritional value. Despite its use in folk medicine, there is a lack of data regarding its in vivo/in vitro cytotoxic/genotoxic and clastogenic effects. Therefore, in this study, we evaluated the cytotoxic, genotoxic and clastogenic effects of Attalea phalerata Mart. ex Spreng. oil (APMO) in vitro and in vivo. For the analysis of cytotoxic potential, the Artemia salina and MTT (3-(4,5-dimethizzol-zyl)-2,5-diphenyltetrazolium bromide) assays were performed. Possible cytotoxic, genotoxic and clastogenic effects of APMO intake were determined by performing the comet and micronucleus assays. Male and female Wistar rats were orally treated with doses of 125, 250, 500 or 1000 mg.kg-1 of the APMO daily for 28 consecutive days (four weeks). The results showed that the APMO did not induce cell death in the experiments of Artemia salina and MTT, indicating that it has no cytotoxicity. The APMO did not cause significant damage to the DNA of the rats in the four doses used when compared to the negative control group (saline + Tween® 80). The APMO did not present any significant increase in micronucleated polychromatic erythrocytes (MNPCEs) for the four tested doses. When compared to the positive control group, all groups (comet and micronucleus tests) were statistically different. These data suggest that the administration of Attalea phalerata Mart oil. ex Spreng does not cause cytotoxicity, genotoxicity and clastogenicity in experimental models in vitro and in vivo following oral administration in this study.

Assessment of genetic integrity, splenic phagocytosis and cell death potential of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid and its effect when combined with commercial chemotherapeutics

Abstract The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation

Abstract Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

Uma abordagem influenciada por pré-processamento para aprendizagem do processo de regulação médica / Un approach influenced to pre-processing for learning medical claim process / Un enfoque influenciado por pre-procesamiento para aprender el proceso de regulación médica

Apresentar uma metodologia que utiliza técnicas de pré-processamento para melhorar a qualidade dos dados presentes na base de dados de uma Operadora de Plano de Saúde para, em seguida, utilizar técnicas de aprendizado de máquina objetivando aprender o processo de regulação médica. Métodos: Foram utilizadas as métricas de: precisão, recall, acurácia, f-measure, área sob a curva ROC e índice kappa para a comparação dos algoritmos de classificação C4.5, Naive Bayes e Multi Layer Perceptron. Resultados: Para a validação dos resultados foi utilizado o cross-validation 10-fold. O melhor classificador foi o C4.5, com taxa de acerto superior a 91%. Conclusão: Demonstrou-se que o processo de regulação pode ser aprendido por algoritmos de aprendizagem de máquina, porém faz-se necessário utilizar técnicas de pré-processamento para melhorar a qualidade dos dados...

Present a methodology that uses preprocessing techniques to improve the quality of the data present in Database of a health insurance company to learn the medical claim process. Methods: We use: precision, recall, f-measure, area under the ROC and kappa to compare classification algorithms C4.5, Naive Bayes and Multi-Layer Perceptron. Results: In order to validate the results we used cross-validation 10-fold. The best classification algorithm was the C4.5 with accuracy higher than 91%. Conclusion: We demonstrate that the medical claim process can be learned by machine learning algorithms; however it is need to use preprocessing techniques to improve quality of the data...

Presentar una metodología que utiliza técnicas de pre-procesamiento para mejorar la calidad de los datos presentes en la Base de datos de un Proveedor plan de salud para aprender el proceso de la regulación médica. Métodos: Precisión, recall, acurácia, f-measure, área bajo la ROC y índice kappa se utilizaron comparar diferentes algoritmos de clasificación: C4.5, Naive Bayes y Multi-Layer Perceptron. Resultados: Con el fin de validar los resultados que hemos utilizado la validación cruzada 10 fold. C4.5 algoritmo obtenido mejor desempeño con una precisión superior al 91%. Conclusión: Se demuestra que el proceso de regulación médica puede ser aprendido por los algoritmos de aprendizaje de máquina, pero primero tienes que utilizar técnicas de pre-procesamiento para mejorar la calidad de los...

Detecção de exsudatos em imagens de retina por técnicas de morfologia matemática e agrupamento nebuloso / Exudate detection in retina images by mathematical morphology techniques and fuzzy clustering

A retinopatia diabética (RD) é uma das principais complicações do diabetes mellitus, pois causa sérios danos à retina e consequentemente à visão, podendo inclusive resultar em cegueira. O diagnóstico da RD é realizado através da análise visual de imagens de retina, sendo os exsudatos (depósitos de gordura) os principais padrões rastreados pelo médico especialista. Vale destacar que o diagnóstico precoce, realizado através do monitoramento regular, associado ao tratamento adequado apresenta inúmeros benefícios na prevenção da deficiência visual. Neste trabalho, é proposto um algoritmo de detecção de exsudatos em imagens de retina, cuja validação experimental é realizada na base pública DIARETDB1. A escolha desta base se deve à disponibilidade da localização dos exsudatos na retina, o que constitui o padrão ouro para a validação dos algoritmos. A metodologia proposta combina agrupamento nebuloso e técnicas de morfologia matemática, além de prover a detecção do disco óptico considerando que o mesmo é um ponto de convergência dos vasos. Os resultados mostraram que o método de detecção de exsudatos apresentou taxas de acerto na avaliação por imagens e por regiões na ordem de 73,03% e 99,41%, respectivamente. Estes resultados confirmam que houve uma melhoria no desempenho na detecção, quando comparados, aos resultados de métodos disponíveis na literatura.

Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus and, furthermore it causes severe damage to the retina and consequently to the vision. DR may lead to blindness and therefore it is important to prevent it or early detect and treat it. The diagnosis of DR is performed by visual analysis of retinal images being exudates (fat deposits) the main patterns traced by a specialist doctor. It is noteworthy that early diagnosis, through regular monitoring when coupled with proper treatment, results in numerous benefits in the prevention of visual impairment. Thus, this paper proposes an algorithm for exudate detection in retinal images, whose experimental validation is performed on retina images of the publicly available DIARETDB1 database. The reason for choosing this database is that it provides spatial coordinates of exudates in retina images which constitute ground truths for the algorithm validation. The proposed methodology combines fuzzy clustering and mathematical morphology techniques, and thus it provides a method for optic disk detection considering that it is as the convergent point of vessels. The exudate detection method presented successful rates of 73.03% and 99.41% concerning the use of the whole image and only partial regions, respectively. These results confirm the performance improvement provided by the proposed methodology, when comparing it to other methods available in the literature.