Pedunculagin and tellimagrandin-I stimulate inflammation and angiogenesis and upregulate vascular endothelial growth factor and tumor necrosis factor-alpha in vivo.

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.

Tellimagrandin-I and camptothin a exhibit chemopreventive effects in Salmonella enterica serovar Typhimurium strains and human lymphocytes.

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.

Chemopreventive effect and induction of DNA repair by oenothein B ellagitannin isolated from leaves of Eugenia uniflora in Swiss Webster treated mice.

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.

Novel sulfonamide-chalcone hybrid stimulates inflammation, angiogenesis and upregulates vascular endothelial growth factor (VEGF) in vivo.

Chalcones and sulfonamides are well-known chemical groups associated with several biological activities such as antibiotic, anti-inflammatory, and antitumor activities. Over the past few decades, a series of sulfonamide-chalcone hybrids have been synthesized and assessed to develop compounds with interesting biological properties for application in disease therapy. In the present study, a new sulfonamide-chalcone hybrid µ - (2,5-dichloro-N-{4-[(3E)-4-(3-nitrophenyl) buta-1,3-dien-2-yl] phenyl} benzene sulfonamide), or simply CL185, was synthesized, and its angiogenic activity was assessed using the chick embryo chorioallantoic membrane (CAM) assay at different concentrations (12.5, 25, and 50 µg/µL). To further investigate the role of CL185 in the angiogenic process, we evaluated the levels of vascular endothelial growth factor (VEGF) in all treated CAMs. The results showed that all concentrations of CL185 significantly increased tissue vascularization (p < 0.05) as well as the parameters associated with angiogenesis, in which inflammation was the most marked phenomenon observed. In all CAMs treated with CL185, VEGF levels were significantly higher than those in the negative control (p < 0.05), and at the highest concentration, VEGF levels were even higher than in the positive control (p < 0.05). The pronounced angiogenic activity displayed by CL185 may be related to the increase in VEGF levels that were stimulated by inflammatory processes observed in our study. Therefore, CL185 presents a favorable profile for the development of drugs that can be used in pro-angiogenic and tissue repair therapies.

Pedunculagin isolated from Plinia cauliflora seeds exhibits genotoxic, antigenotoxic and cytotoxic effects in bacteria and human lymphocytes.

Pedunculagin (PD), an ellagitannin found in different plant species, possesses several pharmaceutical properties, including antitumor, antioxidant, gastroprotective, hepatoprotective, and anti-inflammatory properties. However, the effects of PD alone on DNA remain to be determined. The aim of this study was to investigate the potential cytotoxic, genotoxic, and antigenotoxic activities of PD isolated from Plinia cauliflora seeds using in silico and in vitro assays. To elucidate the biological activities of PD, in silico tools indicative of antioxidant, antineoplastic, and chemopreventive activities of PD were used. Subsequently, the mutagenic/antimutagenic effects of PD were later assessed using bacteria with the Ames test, and the cytotoxic, genotoxic, and antigenotoxic effects utilizing human lymphocytes as evidenced by trypan blue exclusion test and CometChip assay. In silico analysis indicated potential antioxidant, chemopreventive, free radical scavenger, and cytostatic activities of PD. In the Ames test, PD was found to be not mutagenic; however, this plant component protected DNA against damage-mediated by mutagens 4-nitroquinoline-1-oxide and sodium azide. Regarding human lymphocytes, PD alone was cytotoxic and genotoxic; however, it also reduced DNA damage induced by doxorubicin at co- and post-treatment. In conclusion, PD showed genotoxic, antigenotoxic and cytotoxic effects in human lymphocytes and antimutagenic effects in bacteria.

Protective effects and DNA repair induction of a coumarin-chalcone hybrid against genotoxicity induced by mutagens.

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.

Anti-angiogenic activity of azathioprine.

Azathioprine (AZA) is the main drug used in immunomodulatory therapy in post-transplant patients or with autoimmune diseases. However, no study has evaluated the AZA angiogenic response. Therefore, this study investigated the effects of AZA on the angiogenic process through macroscopic, histological, and immunohistochemical analyses in chick embryo chorioallantoic membrane (CAM). Our results showed potent anti-angiogenic activity of AZA at the higher concentrations tested in the CAM assay. The histological analysis of CAM confirmed this effect, since AZA induced a significant reduction in all parameters evaluated. In addition, immunohistochemical evaluation of CAM revealed that AZA decreased TGF-ß and VEGF levels, important cytokines involved in the angiogenic process. Therefore, the AZA anti-angiogenic effect identified in our study provides new information for the possible application of this drug in anticancer treatment.

Predictive Model for Delivery Efficiency: Erythrocyte Membrane-Camouflaged Magnetofluorescent Nanocarriers Study.

Delivery efficiencies of theranostic nanoparticles (NPs) based on passive tumor targeting strongly depend either on their blood circulation time or on appropriate modulations of the tumor microenvironment. Therefore, predicting the NP delivery efficiency before and after a tumor microenvironment modulation is highly desirable. Here, we present a new erythrocyte membrane-camouflaged magnetofluorescent nanocarrier (MMFn) with long blood circulation time (92 h) and high delivery efficiency (10% ID for Ehrlich murine tumor model). MMFns owe their magnetic and fluorescent properties to the incorporation of manganese ferrite nanoparticles (MnFe2O4 NPs) and IR-780 (a lipophilic indocyanine fluorescent dye), respectively, to their erythrocyte membrane-derived camouflage. MMFn composition, morphology, and size, as well as optical absorption, zeta potential, and fluorescent, magnetic, and magnetothermal properties, are thoroughly examined in vitro. We then present an analytical pharmacokinetic (PK) model capable of predicting the delivery efficiency (DE) and the time of peak tumor uptake (tmax), as well as changes in DE and tmax due to modulations of the tumor microenvironment, for potentially any nanocarrier. Experimental PK data sets (blood and tumor amounts of MMFns) are simultaneously fit to the model equations using the PK modeling software Monolix. We then validate our model analytical solutions with the numerical solutions provided by Monolix. We also demonstrate how our a priori nonmechanistic model for passive targeting relates to a previously reported mechanistic model for active targeting. All in vivo PK studies, as well as in vivo and ex vivo biodistribution studies, were conducted using two noninvasive techniques, namely, fluorescence molecular tomography (FMT) and alternating current biosusceptometry (ACB). Finally, histopathology corroborates our PK and biodistribution results.

Noninvasive intratumoral thermal dose determination during in vivo magnetic nanoparticle hyperthermia: combining surface temperature measurements and computer simulations.

PURPOSE: Noninvasive thermometry during magnetic nanoparticle hyperthermia (MNH) remains a challenge. Our pilot study proposes a methodology to determine the noninvasive intratumoral thermal dose during MNH in the subcutaneous tumor model. METHODS: Two groups of Ehrlich bearing-mice with solid and subcutaneous carcinoma, a control group (n = 6), and a MNH treated group (n = 4) were investigated. Histopathology was used to evaluate the percentage of non-viable lesions in the tumor. MNH was performed at 301 kHz and 17.5 kA.m-1, using a multifunctional nanocarrier. Surface temperature measurements were obtained using an infrared camera, where an ROI with 750 pixels was used for comparison with computer simulations. Realistic simulations of the bioheat equation were obtained by combining histopathology intratumoral lesion information and surface temperature agreement of at least 50% of the pixel's temperature data calculated and measured at the surface. RESULTS: One animal of the MNH group showed tumor recurrence, while two others showed complete tumor remission (monitored for 585 days). Sensitivity analysis of the simulation parameters indicated low tumor blood perfusion. Numerical simulations indicated, for the animals with complete remission, an irreversible tissue injury of 91 ± 5% and 100%, while the one with recurrence had a lower value, 56 ± 7%. The computer simulations also revealed the in vivo heat efficiency of the nanocarrier. CONCLUSION: A new methodology for determining noninvasively the three-dimensional intratumoral thermal dose during MNH was developed. The method demonstrates the potential for predicting the long-term preclinical outcome of animals treated with MNH.

Physical exercise alters hepatic morphology of low-density lipoprotein receptor knockout ovariectomized mice.

To explore the effects of physical exercise on the liver of animals in menopause, we analyzed the histomorphometric parameters of the hepatic tissue in ovariectomized and dyslipidemic female mice. The animals were distributed in six groups (n = 5): sedentary control (SC), sedentary ovariectomized control (SOC), trained ovariectomized control (TOC), sedentary LDL knockout (LDL-S), sedentary ovariectomized LDL knockout (LDL-SO), and trained ovariectomized LDL knockout (LDL-TO). At the end of the experiment, the liver and the visceral adipose tissue (VAT) of animals were removed for morphometric and stereological studies. In the LDL-S and LDL-SO animals, both sedentary, results showed reduction in the area (µm2) and major and minor diameters (µm) of hepatocytes and reduction in the portions of large hepatocytes, and increase in the percentage of Kupffer cells. The trained group showed a tendency of increase in the area and diameter and in the percentage of hepatocytes, as well significant reduction in the percentage of Kupffer cells and interstitial tissue. We suggested that training can prevent cell and tissue damage caused by the process of increase in hepatic fat, lipoperoxidation, and tissue inflammation in animals with privation of estrogen and dyslipidemia, apparently reflecting a better metabolic response of the hepatic tissue in organisms undergoing training.

Effects of moderate exercise on biochemical, morphological, and physiological parameters of the pancreas of female mice with estrogen deprivation and dyslipidemia.

Menopausal women are at high risk of developing heart disease. However, physical exercise practice can reverse this scenario. We evaluated the biochemical, morphological, and physiological effects of moderate aerobic physical exercise on the pancreas of knockout mice for LDL receptor with estrogen deprivation by ovariectomy. Animals were divided into six groups (n = 5): sedentary non-ovariectomized control; sedentary ovariectomized control; trained ovariectomized control; sedentary non-ovariectomized LDL-R knockout; sedentary ovariectomized LDL-R knockout; and trained ovariectomized LDL-R knockout. Physical exercise practice promoted improvement in biometric and biochemical parameters analyzed, with reduction of visceral adipose tissue and VLDL, triglycerides, total cholesterol, and blood glucose levels. In addition, physical exercise practice altered the morphology of pancreatic islets and improved their response to the effects of menopause. Thus, physical exercise practice was fundamental to minimize the effects of dyslipidemia associated with ovariectomy in the pancreatic tissue of LDL-R knockout animals, contributing to reduce the risk of developing cardiac diseases in the menopause period.

Antitumor effectiveness and mechanism of action of Ru(II)/amino acid/diphosphine complexes in the peritoneal carcinomatosis progression.

Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF6(1) and the [Ru(l-Trp)(bipy)(dppb)]PF6(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg-1) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.

Antimutagenic, Antigenotoxic, and Anticytotoxic Activities of Silybum Marianum [L.] Gaertn Assessed by the Salmonella Mutagenicity Assay (Ames Test) and the Micronucleus Test in Mice Bone Marrow.

Silymarin (SM), a standardized extract from Silybum marianum (L.) Gaertn., is composed mainly of flavonolignans, and silibinin (SB) is its major active constituent. The present study aimed to evaluate the antimutagenic activities of SM and SB using the Ames mutagenicity test in Salmonella Typhimurium, as well as their anticytotoxic and antigenotoxic activities using the mouse bone marrow micronucleus test. To assess antimutagenicity, Salmonella Typhimurium strains were treated with different concentrations of SM or SB and the appropriate positive control for each strain. To assess antigenotoxicity and anticytotoxicity, Swiss mice were treated with different concentrations of SM or SB and mitomycin C (MMC). The results showed that SM was not significantly effective in reducing the number of frameshift mutations in strain TA98, while SB demonstrated significant protection at higher doses (P < 0.05). Regarding strain TA 100, SM and SB significantly decreased mutagenicity (point mutations) (P < 0.05). The results of the antigenotoxic evaluation demonstrated that SM and SB significantly reduced the frequency of micronucleated polychromatic erythrocytes (MNPCE) (P < 0.05). The results also indicated that SM and SB significantly attenuated MMC-induced cytotoxicity (P < 0.05). Based on these results, both SM and SB presented antimutagenic, antigenotoxic, and anticytotoxic actions.

Dioclea violacea lectin inhibits tumorigenesis and tumor angiogenesis in vivo.

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.

Immunogenic Cell Death Photothermally Mediated by Erythrocyte Membrane-Coated Magnetofluorescent Nanocarriers Improves Survival in Sarcoma Model.

Inducing immunogenic cell death (ICD) during cancer therapy is a major challenge that might significantly improve patient survival. The purpose of this study was to develop a theranostic nanocarrier, capable both of conveying a cytotoxic thermal dose when mediating photothermal therapy (PTT) after its intravenous delivery, and of consequently inducing ICD, improving survival. The nanocarrier consists of red blood cell membranes (RBCm) embedding the near-infrared dye IR-780 (IR) and camouflaging Mn-ferrite nanoparticles (RBCm-IR-Mn). The RBCm-IR-Mn nanocarriers were characterized by size, morphology, surface charge, magnetic, photophysical, and photothermal properties. Their photothermal conversion efficiency was found to be size- and concentration-dependent. Late apoptosis was observed as the cell death mechanism for PTT. Calreticulin and HMGB1 protein levels increased for in vitro PTT with temperature around 55 °C (ablative regime) but not for 44 °C (hyperthermia), suggesting ICD elicitation under ablation. RBCm-IR-Mn were then intravenously administered in sarcoma S180-bearing Swiss mice, and in vivo ablative PTT was performed five days later. Tumor volumes were monitored for the subsequent 120 days. RBCm-IR-Mn-mediated PTT promoted tumor regression in 11/12 animals, with an overall survival rate of 85% (11/13). Our results demonstrate that the RBCm-IR-Mn nanocarriers are great candidates for PTT-induced cancer immunotherapy.

Lactose-binding lectin from Vatairea macrocarpa seeds induces in vivo angiogenesis via VEGF and TNF-ɑ expression and modulates in vitro doxorubicin-induced genotoxicity.

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.

Prednisone is genotoxic in mice and Drosophila melanogaster.

Prednisone (PD) is one of the most commonly used corticosteroids in immunosuppressive therapy for patients with autoimmune diseases and transplants. Chronic use of corticosteroids is associated with several side effects and an increase in neoplasia. Since genotoxic effects are associated with an increased risk of cancer development, this study evaluated the genotoxic and cytotoxic activities of PD using the SMART/wing assay in Drosophila melanogaster and the micronucleus test and comet assay in mouse bone marrow cells. Further, the toxic effects of PD on mouse organ tissues were assessed using histopathological analyses. In the SMART/wing assay, PD showed a significant genotoxic activity at all concentrations tested (0.375, 0.75, 1.5, and 2.0 mg/mL) compared to the negative control (p < 0.05). The micronucleus test and comet assay also showed an elevated genotoxicity of PD at all treatment conditions (24, 48, and 120 h with doses ranging from 0.5 to 1.5 mg/kg) compared to the negative control (p < 0.05). The histopathological analyses did not show toxicity of PD in mouse cells and tissues. Therefore, our results demonstrate that PD is a potent genotoxic immunosuppressant in mice and D. melanogaster cells. Somatic recombination was the primary contributor (46%-82%) to the induced genotoxicity observed in the SMART test.

Molecular epidemiological investigation of Mayaro virus in febrile patients from Goiania City, 2017-2018.

Mayaro virus (MAYV) has historically been associated with sylvatic transmission; however, urban outbreaks have been reported in Brazil, including cases of co-detection with dengue virus (DENV). Therefore, we performed a molecular survey to investigate MAYV circulation and cocirculation with DENV within Goiania, a major city in Central-West Brazil. Among 375 subjects with arbovirus-like symptoms, 259 were positive for DENV and 26 for MAYV. Of these, 17 were coinfected with DENV-2, suggesting co-transmission of the viruses. The most common complaints at the time of inclusion were myalgia, headache, fever, arthralgia, retro-orbital pain, and skin rash. No specific symptoms were associated with MAYV when either detected alone or co-detected with DENV, compared to that when DENV was detected alone. Most MAYV-infected subjects were women with no recent travel history to rural/sylvatic areas. Phylogenetic reconstruction indicated that the MAYV identified in this study is closely related with a lineage observed in Peru, belonging to genotype D. Our results corroborate the growing circulation of MAYV in urban environments in Brazil and reinforce the need to implement laboratory diagnosis in the Unified Health System, considering that the clinical manifestations of Mayaro fever are similar to those of other arboviruses, particularly dengue. Furthermore, most cases occurred in association with DENV-2. Further phylogenetic studies are needed to evaluate MAYV, which has not been widely examined.

Effects of moderate aerobic exercise on thoracic aortic remodeling of female LDL-receptor knockout ovariectomized mice.

Menopause is a major factor involved in dyslipidemia increasing the risk of atherosclerosis which may be reversed by a routine of aerobic physical activity. Thus, this study aimed to analyze the effects of aerobic training on the thoracic aorta of female LDL-receptor knockout mice submitted to estrogen deprivation. Fifteen genetically modified female mice, knockout for the low-density lipoprotein receptor (LDL-Knockout group) were used as experimental groups and fifteen wild female mice (C57BL/6 J) were used as control groups. Animals were divided as (n = 5/per group): sedentary control (SC); sedentary control ovariectomized (SCO); trained control ovariectomized (TCO); LDL-Knockout sedentary (KS); LDL-Knockout sedentary ovariectomized (KOS); and LDL-Knockout trained ovariectomized (KOT). Immunohistochemical techniques for TIMP-1 and metalloproteinases 2 and 9 were used to evaluate thoracic aorta remodeling. Picrosirius stain was used to highlight the collagen fibers. Verhoff-Van Gienson was used for the quantitative analyses of elastic lamellae. Our results demonstrate a positive remodeling promoted by physical exercise in ovariectomized and dyslipidemic animals. However, further studies are needed including the evaluation of inflammatory markers present in dyslipidemia.

IR-780-Albumin-Based Nanocarriers Promote Tumor Regression Not Only from Phototherapy but Also by a Nonirradiation Mechanism.

IR-780 iodide is a fluorescent dye with optical properties in the near-infrared region that has applications in tumor detection and photothermal/photodynamic therapy. This multifunctional effect led to the development of theranostic nanoparticles with both IR-780 and chemotherapeutic drugs such as docetaxel, doxorubicin, and lonidamine. In this work, we developed two albumin-based nanoparticles containing near-infrared IR-780 iodide multifunctional dyes, one of them possessing a magnetic core. Molecular docking with AutoDock Vina studies showed that IR-780 binds to bovine serum albumin (BSA) with greater stability at a higher temperature, allowing the protein binding pocket to better fit this dye. The theoretical analysis corroborates the experimental protocols, where an enhancement of IR-780 was found coupled to BSA at 60 °C, even 30 days after preparation, in comparison to 30 °C. In vitro assays monitoring the viability of Ehrlich ascites carcinoma cells revealed the importance of the inorganic magnetic core on the nanocarrier photothermal-cytotoxic effect. Fluorescence molecular tomography measurements of Ehrlich tumor-bearing Swiss mice revealed the biodistribution of the nanocarriers, with marked accumulation in the tumor tissue (≈3% ID). The histopathological analysis demonstrated strong increase in tumoral necrosis areas after 24 and 72 h after treatment, indicating tumor regression. Tumor regression analysis of nonirradiated animals indicate a IR-780 dose-dependent antitumoral effect with survival rates higher than 70% (animals monitored up to 600 days). Furthermore, an in vivo photothermal therapy procedure was performed and tumor regression was also verified. These results show a novel insight for the biomedical application of IR-780-albumin-based nanocarriers, namely cancer therapy, not only by photoinduced therapy but also by a nonirradiation mechanism. Safety studies (acute oral toxicity, cardiovascular evaluation, and histopathological analysis) suggest potential for clinical translation.