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Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (E)-1′-((4-bromobenzylidene)amino)-5′-oxo-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins’ activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19′s in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways.

The characterization and cytotoxicity of the essential oil from Conyza bonariensis (L.) aerial parts (CBEO) were previously conducted. The major compound was (Z)-2-lachnophyllum ester (EZ), and CBEO exhibited significant ROS-dependent cytotoxicity in the melanoma cell line SK-MEL-28. Herein, we employed the Molegro Virtual Docker v.6.0.1 software to investigate the interactions between the EZ and Mitogen-Activated Protein Kinases (MAPKs), the Nuclear Factor kappa B (NF-κB), and the Protein Kinase B (PKB/AKT). Additionally, in vitro assays were performed in SK-MEL-28 cells to assess the effect of CBEO on the cell cycle, apoptosis, and these signaling pathways by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using MAPKs inhibitors. CBEO induced a significant increase in the sub-G1 peak, as well as biochemical and morphological changes characteristic of apoptosis. The in-silico results indicated that EZ interacts with Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), p38α MAPK, NF-κB, and PKB/AKT. Moreover, CBEO modulated the ERK1/2, JNK, p38 MAPK, NF-κB, and PKB/AKT activities in SK-MEL-28 cells. Furthermore, CBEO’s cytotoxicity against SK-MEL-28 cells was significantly altered in the presence of MAPKs inhibitors. These findings support the in vitro antimelanoma effect of CBEO through apoptosis induction, and the modulation of ERK, JNK, p38 MAPK, NF-κB, and PKB/AKT activities.

The essential oil from Conyza bonariensis (Asteraceae) aerial parts (CBEO) was extracted by hydrodistillation in a Clevenger-type apparatus and was characterized by gas chromatography–mass spectrometry. The antitumor potential was evaluated against human tumor cell lines (melanoma, cervical, colorectal, and leukemias), as well as non-tumor keratinocyte lines using the MTT assay. The effect of CBEO on the production of Reactive Oxygen Species (ROS) was evaluated by DCFH-DA assay, and a protection assay using the antioxidant N-acetyl-L-cysteine (NAC) was also performed. Moreover, the CBEO toxicity in the zebrafish model was assessed. The majority of the CBEO compound was (Z)-2-lachnophyllum ester (57.24%). The CBEO exhibited selectivity towards SK-MEL-28 melanoma cells (half maximal inhibitory concentration, IC50 = 18.65 ± 1.16 µg/mL), and induced a significant increase in ROS production. In addition, the CBEO’s cytotoxicity against SK-MEL-28 cells was reduced after pretreatment with NAC. Furthermore, after 96 h of exposure, 1.5 µg/mL CBEO induced death of all zebrafish embryos. Non-lethal effects were observed after exposure to 0.50–1.25 µg/mL CBEO. Additionally, significant alterations in the activity of enzymes associated with oxidative stress in zebrafish larvae were observed. These results provide evidence that CBEO has a significant in vitro antimelanoma effect by increasing ROS production and moderate embryotoxicity in zebrafish.

Context: The essential oil (EO) from Thymus capitatus Hoff. et Link. (Lamiaceae) has been traditionally used for its medicinal properties, such as anti-inflammatory, analgesic, antioxidant and antimicrobial properties.Objective: Characterize the constituents from T. capitatus EO and further evaluate the antinociceptive activity by in vivo and in vitro procedures.Materials and methods: Gas chromatography–mass spectrometry was used to identify and quantify the constituents of the T. capitatus EO. The antinociceptive activity was evaluated in vivo by the glutamate-induced nociception model in male Swiss mice (25 g), at doses of 3, 6 and 12 mg/kg, 1 h before evaluation of the licking time response (0–15 min). The mechanism of T. capitatus EO (1–500 μg/mL) on the isolated nerve excitability of Wistar rat (300 g) was assessed by the single sucrose technique.Results and discussion: The EO of T. capitatus presented 33 components, mainly monoterpenes and sesquiterpenes, carvacrol (ca. 80%) was its major constituent. T. capitatus EO induced antinociception in orally treated mice (3, 6, and 12 mg/kg) reducing the licking time from control (100.3 ± 11.9 s) to 84.8 ± 12.2, 62.7.6 ± 9.9, and 41.5 ± 12.7 s, respectively (n = 8; p < 0.05). Additionally, we have demonstrated that T. capitatus EO (500 μg/mL) decreased the compound action potential amplitude (VCAP) of about 80.0 ± 4.3% from control recordings (n = 4; p < 0.05). Such activity was presumably mediated through a voltage-gated Na+ channels.Conclusions: The present study demonstrated the antinociceptive activity of Thymus capitatus essential oil, which acts via peripheral nervous excitability blockade.

Background Among the food additives used in the food industry, food dyes are considered the most toxic. For instance, tartrazine (TRZ) is a food colorant commercially available with conflicting data regarding its cytotoxic, genotoxic, and mutagenic effects. Therefore, this study aimed to evaluate the cytotoxic and mutagenic potential of TRZ using different eukaryotic cells ( in vitro ). Methods This study employed 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), brine shrimp lethality, Allium cepa and Saccharomyces cerevisiae tests. Different concentrations of TRZ and different exposure times were used in this study. Results The results demonstrate that TRZ induced a concentration-dependent toxic effect on the test systems. It also exerted cytotoxicity in fibroblasts and human gastric cells. In addition, TRZ showed mutagenic effects on the A. cepa test system. However, its toxicogenic effects may not relate to the oxidizing activity, which was confirmed by the S. cerevisiae test model. Conclusion Taken together, TRZ exerted toxicogenic effects on the test systems. Therefore, it may be harmful to health, especially its prolonged use may trigger carcinogenesis.

Background/Aim: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1’-((4-chlorobenzylidene)amino)-5’-oxo-1’,5’-dihydro-10H-spiro[acridine-9,2’-pyrrole]-4’-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. Materials and Methods: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. Results: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1β and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. Conclusion: AMTAC-06 has low toxicity and a significant antitumor activity.

Background/Aim: Despite being a rare disease, melanoma is considered the most dangerous skin cancer due to its highly invasive and aggressive nature, and still requires for more effective treatments. The aim of this study was to evaluate the in vitro anti-melanoma potential of Ephedranthus pisocarpus R.E.Fr. (Annonaceae), a popular Brazilian plant with medicinal properties. Materials and Methods: Initially, the ethanolic extract (EtOH) was obtained from E. pisocarpus leaves and later partitioned using increasing polarity solvents. The anti-melanoma potential of E. pisocarpus was assessed by spectrophotometry and its cytotoxicity determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. Results: We demonstrated that the EtOH extract and fractions from E. pisocarpus had a moderate photoprotective action (FPS 3.0-5.0) against UVA radiation. Interestingly, the dichloromethane fraction presented higher anti-melanoma activity against B16-F10 (IC50=46.8 μg/ml) and SK-MEL-28 cells (IC50=40.1 μg/ml) and lesser toxicity on normal cells. Additionally, our study reported that spathulenol, one of the major constituents from E. pisocarpus, acts through an apoptosis-dependent mechanism in SK-MEL-28 cells. Conclusion: The present study demonstrated, for the first time, the in vitro anti-melanoma potential of E. pisocarpus against melanoma cells.

Leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from Leishmania genus. Conventional treatments are high costly, and promote a sort of side effects. Besides, protozoan resistance to treatments has been reported. Natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC 50 ) values 16.4 and 9.8 μg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC 50 values 126.6 and 23.8 μg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC 50 values 5.0 and 0.9 μg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca 2+ i ] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis.

Nanoparticles represent an innovative class of drug delivery systems that have gained increasing interest in nanotechnology applied to medicine. This study focused on the development of two Polyglycerol/PolyCaprolactone Nanocopolymers to be able to carry pharmaceuticals. The copolymers were characterized by FTIR, NMR, TG, DSC, MALDI, SEM, and DLS techniques. Two monomer initiators (glycerol and 1,1,1-tris(hydroxymethyl)propane) have been used, and the polymerization was obtained by anionic ring-opening polymerization of the glycerol carbonate, with CO 2 liberation leading to a branched polyether. The hyperbranched polymer was employed as a macroinitiator to initiate the ring-opening polymerization of ε-caprolactone, resulting in the multiarm star copolymers. The structures for the nanocopolymers were proposed based on nuclear magnetic resonance results. Hemolytic studies revealed that the copolymers do not have hemolytic activity. The copolymers were tested for safety against human cells and toxicity in cancer cells. The tests indicated that they are safe for in vivo applications and do not have anti-cancer efficiency, corroborating their purpose as a polymeric support for drug delivery.