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Oenothein B (OeB), a dimeric ellagitannin with a macrocyclic structure, is reported to have beneficial effects, including antioxidant, antitumor, antiviral, and antimutagenic effects, on human health. Despite the remarkable properties of OeB, its role in neovascularization process has not yet been evaluated. Thus, this study aimed to evaluate the angiogenic activity of OeB using a chorioallantoic membrane (CAM) assay at different concentrations (6.25, 12.5, and 25 µg/µL), employing digital imaging and histological analysis. Furthermore, to elucidate the mechanisms by which OeB influences angiogenesis, we assessed the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) in CAM using immunohistochemical analysis. All concentrations of OeB significantly increased (p < 0.05) the percentage of vascularization as well as the levels of all the angiogenesis-associated parameters evaluated, indicating the pronounced pro-angiogenic activity of OeB. Our results showed that inflammation was one of the most relevant phenomena observed in CAM histology along with angiogenesis. In addition, a significant increase in VEGF and TNF-α levels was observed in all the CAMs compared to the negative control (p < 0.05). We suggest that OeB may induce the presence of inflammatory cells in CAM, leading to increased VEGF and TNF-α levels that result in the induction of angiogenesis. Therefore, OeB presents a favorable profile that could be further explored for the development of drugs for pro-angiogenic and tissue repair therapies.

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Although the last pandemic created an urgency for development of vaccines, there was a continuous and concerted effort to search for therapeutic medications among existing drugs with different indications. One of the medications of interest that underwent this change was infliximab (IFM). This drug is used as an anti-inflammatory, predominantly in patients with Crohn 's disease, colitis ulcerative, and rheumatoid arthritis. In addition to these patients, individuals infected with Coronavirus Disease (COVID-19) were administered this chimeric monoclonal antibody (IMF) to act as an immunomodulator for patients in the absence of comprehensive research. Consequently, the present study aimed to examine the genotoxic effects attributed to IFM treatment employing different assays in vivo using mouse Mus musculus. Therefore, IFM was found to induce genotoxic effects as evidenced by the comet assay but did not demonstrate genotoxic potential utilizing mouse bone marrow MN test. The results of evaluating the expression of the P53 and BCL-2 genes using RT-qPCR showed stimulation of expression of these genes at 24 hr followed by a decline at 48 hr. Although the comet assay provided positive results, it is noteworthy that based upon negative findings in the micronucleus test, the data did not demonstrate significant changes in the genetic material that might affect the therapeutic use of IFM. The stimulation of expression of P53 and BCL-2 genes at 24 hr followed by a decline at 48 hr suggest a transient, if any, effect on genetic material. However, there is still a need for more research to more comprehensively understand the genotoxic profile of this medication.

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Dioclea violacea seed mannose-binding lectin (DvL) has attracted considerable attention because of its interesting biological activities, including antitumor, antioxidant, and anti-inflammatory activities. This study evaluated the cytotoxic effect of DvL on tumor and normal cells using the mitochondrial activity reduction (MTT) assay, the carcinogenic and anti-carcinogenic activity by the epithelial tumor test (ETT) in Drosophila melanogaster, and the anti-angiogenic effect by the chick embryo chorioallantoic membrane (CAM) assay. Data demonstrated that DvL promoted strong selective cytotoxicity against tumor cell lines, especially A549 and S180 cells, whereas normal cell lines were weakly affected. Furthermore, DvL did not promote carcinogenesis in D. melanogaster at any concentration tested, but modulated DXR-induced carcinogenesis at the highest concentrations tested. In the CAM and immunohistochemical assays, DvL inhibited sarcoma 180-induced angiogenesis and promoted the reduction of VEGF and TGF-ß levels at all concentrations tested. Therefore, our results demonstrated that DvL is a potent anticancer, anti-angiogenic, and selective cytotoxic agent for tumor cells, suggesting its potential application as a prototype molecule for the development of new drugs with chemoprotective and/or antitumor effects.

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Tellimagrandin-I (TL) and camptothin A (CA) are ellagitannins widely found in diverse plant species. Numerous studies demonstrated their significant biological activities, which include antitumor, antioxidant, and hepatoprotective properties. Despite this protective profile, the effects of TL and CA on DNA have not been comprehensively investigated. Thus, the aim of this study was to determine the mutagenic and antimutagenic effects attributed to TL and CA exposure on Salmonella enterica serovar Typhimurium strains using the Ames test. In addition, the cytotoxic and genotoxic effects were examined on human lymphocytes, employing both trypan blue exclusion and CometChip assay. The antigenotoxic effect was determined following TL and CA exposure in the presence of co-treatment with doxorubicin (DXR). Our results from the Ames test indicated that TL or CA did not display marked mutagenic activity. However, TL or CA demonstrated an ability to protect DNA against the damaging effects of the mutagens 4-nitroquinoline-1-oxide and sodium azide, thereby exhibiting antimutagenic properties. In relation to human lymphocytes, TL or CA did not induce significant cytotoxic or genotoxic actions on these cells. Further, these ellagitannins exhibited an ability to protect DNA from damage induced by DOX during co-treatment, indicating their potential beneficial usefulness as antigenotoxic agents. In conclusion, the protective effects of TL or CA against mutagens, coupled with their absence of genotoxic and cytotoxic effects on human lymphocytes, emphasize their potential therapeutic value in chemopreventive strategies.

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Pedunculagin (PD) and tellimagrandin-I (TL), isolated from Myrciaria cauliflora seeds and Eucaliptus microcorys leaves, respectively, have attracted great attention owing to their relevant biological activities, such as antitumor, antioxidant, and hepatoprotective activities. This study investigated the angiogenic potential of PD and TL using a chick embryo chorioallantoic membrane (CAM) assay. Using the CAM assay, our results showed that both PD and TL promoted a significant increase in the number and caliber of blood vessels, the thickness of the CAM, and the presence of fibroblasts and inflammatory cells. Moreover, an increase of tumor necrosis factor-α and vascular endothelial growth factor was observed in the CAM treated with PD and TL, indicating the induction of angiogenic factors. Thus, the remarkable profile of PD and TL in inducing angiogenesis opens up new perspectives for their potential utilization in different therapeutic approaches involving neovascularization.

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Oenothein B (OeB) is a dimeric ellagitannin with potent antioxidative, antitumor, immunomodulatory, and anti-inflammatory properties. Despite the promising activities of OeB, studies examining the genotoxic or protective effects of this ellagitannin on DNA are scarce. Therefore, to further comprehensively elucidate the chemopreventive profile of OeB, the aim of this study was to evaluate the mutagenic and antimutagenic actions of OeB using Salmonella typhimurium strains with the Ames test. The micronucleus (MN) test and comet assay were used to assess the anticytotoxic and antigenotoxic effects of OeB on mouse bone marrow cells following differing treatments (pre-, co-, and post-treatment) in response to cyclophosphamide (CPA)-induced DNA damage. In addition, histopathological analyses were performed to assess liver and kidney tissues of Swiss Webster treated mice. Our results did not detect mutagenic or antimutagenic activity attributed to OeB at any concentration in the Ames test. Regarding the MN test, data showed that this ellagitannin exerted antigenotoxic and anticytotoxic effects against CPA-induced DNA damage under all treatment conditions. However, no anticytotoxic action was observed in MN test after pre-treatment with the highest doses of OeB. In addition, OeB demonstrated antigenotoxic effects in the comet assay for all treatments. Histopathological analyses indicated that OeB attenuated the toxic effects of CPA in mouse liver and kidneys. These findings suggest that OeB exerted a chemoprotective effect following pre- and co-treatments and a DNA repair action in post-treatment experiments. Our findings indicate that OeB protects DNA against CPA-induced damaging agents and induces post-damage DNA repair.

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Coumarins and chalcones are compounds widely found in plants or obtained by synthetic methods which possess several biological properties including antioxidant, anti-inflammatory, and antitumor effects. A series of coumarin-chalcone hybrids were synthesized to improve their biological actions and reduce potential adverse effects. Considering the applications of these molecules, a coumarin-chalcone hybrid [7-methoxy-3-(E)-3-(3,4,5-trimethoxyphenyl) acryloyl-2 H-chromen-2-one] (4-MET) was synthesized and the genotoxic, cytotoxic, and protective effects assessed against damage induced by different mutagens. First, in silico tools were used to predict biological activity of 4-MET which indicated a chemopreventive potential. Subsequently, the genotoxic/antigenotoxic activities of 4-MET were determined both in vitro (Ames test) and in vivo (micronucleus (MN) test and comet assay). In addition, molecular docking simulations were performed between 4-MET and glutathione reductase, an important cellular detoxifying enzyme. Our results indicated that 4-MET was not mutagenic in the Ames test; however, when co-treated with sodium azide or 4-nitroquinoline 1-oxide (4-NQO), 4-MET significantly reduced the harmful actions of these mutagens. Except for a cytotoxic effect after 120 hr treatment, 4-MET alone did not produce cytotoxicity or genotoxicity in the MN test and comet assay. Nonetheless, all treatments of 4-MET with cyclophosphamide (CPA) showed a chemoprotective effect against DNA damage induced by CPA. Further, molecular docking analysis indicated a strong interaction between 4-MET and the catalytic site of glutathione reductase. These effects may be related to (1) damage prevention, (2) interaction with detoxifying enzymes, and (3) DNA-repair induction. Therefore, data demonstrated that 4-MET presents a favorable profile to be used in chemopreventive therapies.

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Vernonanthura polyanthes (Spreng.) A.J. Vega & Dematt. (syn.: Vernonia polyanthes Less) is popularly known as "assa-peixe" and its leaves are used in folk medicine mainly to treat respiratory diseases. In this study, we evaluated the cytogenotoxic and anticytogenotoxic potential of the V. polyanthes leaf aqueous extract (VpLAE) and its n-butanol fraction (n-BF) in the presence or absence of doxorubicin (DXR) (pre-, co-, and post-treatments) on a murine model for 24 h or 120 h. The micronucleus test (MN) and the comet assay were used to assess the cytogenotoxic and anticytogenotoxic potential of VpLAE and n-BF (250, 500, and 1000 mg/kg) administered via gavage to Swiss Webster mice. The chemical profiles of VpLAE and n-BF were assessed by liquid chromatography coupled to mass spectrometry, and their metabolites were putatively identified. Lastly, the possible biological activities related to the (anti) cytogenotoxicity of the compounds were predicted using the PASS online webserver. The in vivo results showed that different doses of VpLAE and n-BF did not present cytotoxic activity; however, the MN test revealed a slight mutagenic activity for the 24 h treatments. Moderate genotoxic effects were demonstrated for all treatments in the comet assay. Regarding anticytotoxicity and antimutagenicity, VpLAE and n-BF presented a high cytoprotective potential against DXR toxic effects. In the co-treatment, VpLAE reduced the DXR genotoxicity by ~27%, and n-BF did not demonstrate antigenotoxic potential. In contrast, an antigenotoxic effect was observed for both VpLAE and n-BF in the pre- and post-treatments, reducing DXR genotoxicity by ~41% and ~47%, respectively. Chemical analysis of VpLAE and n-BF showed the presence of eight phenolic compounds, including seven chlorogenic acids and a flavonoid. The PASS online tool predicted antimutagenic, anticancer, antineoplastic, chemoprotective, antioxidant, and radical scavenging activities for all constituents identified in VpLAE and n-BF. V. polyanthes leaves presented a protective effect against DXR cytogenotoxicity. In general, VpLAE and n-BF showed a greater antigenotoxic potential in the pre- and post-treatments. The metabolites putatively identified in VpLAE and n-BF exhibited antioxidant and chemoprotective potential according to computational prediction analysis. Altogether, our results highlight the potential application of V. polyanthes to protect against toxic manifestations induced by DXR.

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Cerrado has many compounds that have been used as biopesticides, herbicides, medicines, and others due to their highly toxic potential. Thus, this review aims to present information about the toxicity of Cerrado plants. For this purpose, a review was performed using PubMed, Science Direct, and Web Of Science databases. After applying exclusion criteria, 187 articles published in the last 20 years were selected and analyzed. Detailed information about the extract preparation, part of the plant used, dose/concentration tested, model system, and employed assay was provided for different toxic activities described in the literature, namely cytotoxic, genotoxic, mutagenic, antibacterial, antifungal, antiviral, insecticidal, antiparasitic, and molluscicidal activities. In addition, the steps to execute research on plant toxicity and the more common methods employed were discussed. This review synthesized and organized the available research on the toxic effects of Cerrado plants, which could contribute to the future design of new environmentally safe products.

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Lactose-binding lectin from Vatairea macrocarpa seeds (VML) has attracted great attention due to its interesting biological activities, such as pro-inflammatory effects and macrophage activation. This study evaluated the cytotoxicity and genotoxicity/antigenotoxicity of VML in human lymphocytes using the CometChip assay, and angiogenic activity by the chick embryo chorioallantoic membrane (CAM) assay. In genotoxicity, lymphocytes were treated with different concentrations of VML (0.5, 2 and 8 µM). In antigenotoxicity, lymphocytes were treated with the same concentrations of VML concomitant doxorubicin (90 µM DXR). To evaluate angiogenesis, all CAM were treated with different concentrations of VML (0.5, 2 and 8 µM) alone or co-treated with lactose (0.1 M). Furthermore, the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) in CAM were assessed by immunohistochemistry. The results showed that VML was cytotoxic to lymphocytes, genotoxic at the highest concentration (8 µM) and antigenotoxic at low concentrations (0.5, and 2 µM). Regarding the CAM assay and immunohistochemistry, VML was angiogenic and significantly increased VEGF and TNF-α levels. In contrast, co-treatment with lactose significantly reduced the angiogenic effect and VEGF levels. We propose that protein-carbohydrate interactions between VML and glycans in the cell membrane are probably the major events involved in these activities. It seems likely that VML elicits a pro-inflammatory response through VEGF and TNF-α expression, resulting in increased vascularization at the site of inflammation. Therefore, our results show novel information on the effects of VML on DNA, as well as provide data regarded the neovascularization process involving this lectin.

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