Publications by authors named "Geovanni Dantas Cassali"

69 Publications

Diet-induced obesity leads to alterations in behavior and gut microbiota composition in mice.

J Nutr Biochem 2021 06 8;92:108622. Epub 2021 Mar 8.

Laboratório de Genética Animal e Humana, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address:

The high prevalence of obesity and associated metabolic disorders are one of the major public health problems worldwide. Among the main causal factors of obesity, excessive consumption of food rich in sugar and fat stands out due to its high energy density. The regulation of food intake relies on hypothalamic control by the action of several neuropeptides. Excessive consumption of hypercaloric diets has impact in the behavior and in the gut microbiota. In the present study, we used a high-sugar and fat (HSB) diet for 12 weeks to induce obesity in C57BL/6 mice and to investigate its effects on the gut microbiota, hypothalamic peptides, and behavior. We hypothesize that chronic consumption of HSB diet can change the behavior. Additionally, we also hypothesize that changes in gut microbiota can be associated with changes in the transcriptional regulation of hypothalamic peptides and behavior. To evaluate the gut microbiota, we performed the sequencing of 16S rRNA gene, which demonstrate that HSB diet modulates the gut microbiota with an increase in the Firmicutes and Actinobacteria phylum and a decrease of Bacteroidetes phylum. The real time qPCR revealed that HSB-fed mice presented changes in the transcriptional regulation of hypothalamic neuropeptides genes such as Npy, Gal and Galr1. The Marble-burying and Light/dark box tests also showed an alteration in anxiety and impulsive behaviors for the HSB-fed mice. Our data provides evidence that obesity induced by HSB diet consumption is associated with alterations in gut microbiota and behavior, highlighting the multifactorial characteristics of this disease.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108622DOI Listing
June 2021

Marine Seagrass Extract of Suppresses Colorectal Tumor Growth, Motility and Angiogenesis by Autophagic Stress and Immunogenic Cell Death Pathways.

Mar Drugs 2021 Jan 22;19(2). Epub 2021 Jan 22.

Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, Campus Drie Eiken, University of Antwerp, Building S, 4th Floor, Universiteitsplein 1, 2610 Wilrijk, Belgium.

Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC values of, respectively, 175, 115, and 60 μg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.
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http://dx.doi.org/10.3390/md19020052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912590PMC
January 2021

Neuroendocrine Carcinomas of the Canine Mammary Gland: Histopathological and Immunohistochemical Characteristics.

Front Vet Sci 2020 5;7:621714. Epub 2021 Jan 5.

Laboratory of Comparative Pathology, Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Invasive mammary carcinomas with neuroendocrine differentiation are rare in women and were reported only once in female dogs. For the present study, ten cases of solid mammary carcinoma positive for chromogramin A in immunohistochemistry were selected. Histopathological characteristics of these tumors were described and immunohistochemical evaluation was performed with chromogranin A, synaptophysin, CD56, NSE, PGP 9.5, pancitokeratin, Ki67, estrogen receptor (ER), and progesterone receptor (PR). The average animal age was 13.2 years old and the average tumor size was 4.8 cm. In total, 70% of the neoplasms were classified as grade III and 30% as grade II by the Nottingham histological grade system. High mitotic index was observed with a mean of 27.5 mitoses in 10 high magnification fields. Only one case showed typical carcinoid tumor characteristics. In addition, vascular invasion was shown in 3 tumors. All carcinomas were positive for chromogran A, while only two cases were reactive to synaptophysin. For PGP 9.2, NSE and CD56, we observed positivity of 100, 90, and 70%, respectively, in the samples, being that no tumor was positive for all the neuroendocrine markers. All neoplasms showed ER and PR in at least 10% of neoplastic cells, while Ki67 varied from 29 to 95%, with mean mitotic index of 67%. Four of the ten animals died within 1 year of the tumor diagnosis. Neuroendocrine neoplasms occur in the canine mammary gland and are propably underdiagnosed. This is due to their non-specific morphological characteristics and the low use of neuroendocrine immunohistochemistric markers the diagnostic routine. More studies are necessary to determine the prognosis of this new histological type.
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http://dx.doi.org/10.3389/fvets.2020.621714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813755PMC
January 2021

COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice.

Cancer Lett 2021 04 9;502:44-57. Epub 2021 Jan 9.

Laboratório de Farmacologia e Bioquímica do Câncer (LabCancer), Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, 88049-900, Brazil. Electronic address:

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.
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http://dx.doi.org/10.1016/j.canlet.2021.01.003DOI Listing
April 2021

Doxorubicin-loaded pH-sensitive micelles: A promising alternative to enhance antitumor activity and reduce toxicity.

Biomed Pharmacother 2021 Feb 16;134:111076. Epub 2020 Dec 16.

Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Doxorubicin (DOX) is an anthracycline antibiotic widely used in the treatment of cancer, however, it is associated with the occurrence of adverse reactions that limits its clinical use. In this context, the encapsulation of DOX in micelles responsive to pH variations has shown to be a strategy for tumor delivery of the drug, with the potential to increase therapeutic efficacy and to reduce the toxic effects. In addition, radiolabeling nanoparticles with a radioactive isotope is of great use in preclinical studies, since it allows the in vivo monitoring of the nanostructure through the acquisition of quantitative images. Therefore, this study aimed to develop, characterize, and evaluate the antitumor activity of a pH-sensitive micelle composed of DSPE-PEG, oleic acid, and DOX. The micelles had a diameter of 13 nm, zeta potential near to neutrality, and high encapsulation percentage. The critical micellar concentration (CMC) was 1.4 × 10 mol L. The pH-sensitivity was confirmed in vitro through a drug release assay. Cytotoxicity studies confirmed that the encapsulation of DOX into the micelles did not impair the drug cytotoxic activity. Moreover, the incorporation of DSPE-PEG-DTPA into the micelles allowed it radiolabeling with the technetium-99 m in high yield and stability, permitting its use to monitor antitumor therapy. In this sense, the pH-sensitive micelles were able to inhibit tumor growth significantly when compared to non-pH-sensitive micelles and the free drug. in vivo toxicity evaluation in the zebrafish model revealed significantly lower toxicity of pH-sensitive micelles compared to the free drug. These results indicate that the developed formulation presents itself as a promising alternative to potentiate the treatment of tumors.
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http://dx.doi.org/10.1016/j.biopha.2020.111076DOI Listing
February 2021

Encapsulating paclitaxel in polymeric nanomicelles increases antitumor activity and prevents peripheral neuropathy.

Biomed Pharmacother 2020 Dec 3;132:110864. Epub 2020 Nov 3.

Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.
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http://dx.doi.org/10.1016/j.biopha.2020.110864DOI Listing
December 2020

Prophylactic and therapeutic supplementation using fructo-oligosaccharide improves the intestinal homeostasis after mucositis induced by 5- fluorouracil.

Biomed Pharmacother 2021 Jan 27;133:111012. Epub 2020 Nov 27.

Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

The beneficial effects of prebiotic, such as fructo-oligosaccharides (FOS), in intestinal inflammation have been demonstrated in several studies. Herein, we evaluate whether joint treatment with FOS, both before and during mucositis, had additional beneficial effects and investigated the mechanisms underlying in the action of FOS on the intestinal barrier. BALB/c mice were randomly divided into five groups: CTR (without mucositis + saline solution), FOS (without mucositis + 6 % FOS), MUC (mucositis + saline solution), PT (mucositis + 6 % FOS supplementation before disease induction), and TT (mucositis + 6 % FOS supplementation before and during disease induction). Mucositis was induced by intraperitoneal injection (300 mg/kg) of 5-fluorouracil (5-FU). After 72 h, the animals were euthanized and intestinal permeability (IP), tight junction, bacterial translocation (BT), histology and morphometry, and immunoglobulin A secretory (sIgA), inflammatory infiltrate, and production of short-chain fatty acids (acetate, butyrate and propionate) were evaluated. The MUC group showed an increase in the IP, BT, and inflammatory infiltrate but a decrease in the tight junction expression and butyrate and propionate levels (P < 0.05). In the PT and TT groups, FOS supplementation maintained the IP, tight junction expression, and propionate concentration within physiologic levels, increased butyrate levels, and reduced BT and inflammatory infiltrate (P < 0.05). Total treatment with FOS (TT group) was more effective in maintaining histological score, morphometric parameters, and sIgA production. Thus, total treatment (prophylactic and therapeutic supplementation) with FOS was more effective than pretreatment alone, in reducing 5-FU-induced damage to the intestinal barrier.
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http://dx.doi.org/10.1016/j.biopha.2020.111012DOI Listing
January 2021

Enhanced antitumor efficacy of lapachol-loaded nanoemulsion in breast cancer tumor model.

Biomed Pharmacother 2021 Jan 27;133:110936. Epub 2020 Nov 27.

Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Lapachol (LAP) is a natural compound with various biological properties, including anticancer activity. However, its clinical application is limited due to the low aqueous solubility and potential adverse side effects. Nanoemulsions are drug delivery systems that can assist in the administration of hydrophobic drugs, increasing their bioavailability and protecting from degradation. Thus, this study aimed to prepare a LAP-loaded nanoemulsion (NE-LAP), and evaluate its antitumor activity. For this purpose, the nanoemulsion was prepared using a hot homogenization method and characterized morphologically by cryogenic transmission electron microscopy (cryo-TEM). Mean diameter, polydispersity index, and zeta potential was evaluated by DLS, encapsulation efficiency was measured by HPLC. Moreover, the short-term storage stability, the drug release and hemolysis in vitro was determined. Additionally, pharmacokinetic, toxicology and toxicity properties ofTc-NE-LAP were evaluated in a breast cancer (4T1) tumor model. The cryo-TEM showed spherical globules, and the physicochemical characterization of NE-LAP showed a homogeneous stable nanoemulsion with a mean diameter of ∼170 nm, zeta potential of around -20 mV, and encapsulation greater than 85 %. In vitro studies validated that encapsulation did not impair the cytotoxicity activity of LAP. The nanoemulsion was successfully radiolabeled and Tc-NE-LAP showed prolonged blood circulation and tumor affinity was confirmed by tumor-to-muscle ratio. Moreover, NE-LAP showed higher antitumor activity than the free drug and the treatment did not result in any signs of toxicity. Therefore, these findings suggest that NE-LAP can be considered an effective strategy for cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110936DOI Listing
January 2021

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice.

Front Immunol 2020 2;11:566953. Epub 2020 Oct 2.

Laboratory of Comparative Pathology, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Rationale: Increased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases.

Objective: To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component.

Findings: Ladarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival.

Conclusion: CXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.
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http://dx.doi.org/10.3389/fimmu.2020.566953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566412PMC
May 2021

Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity.

Biomed Pharmacother 2020 Dec 28;132:110876. Epub 2020 Oct 28.

Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

Doxorubicin (DOX) is widely used in cancer treatment, however, its use is often limited due to its side effects. To avoid these shortcomings, the encapsulation of DOX into nanocarriers has been suggested. Herein, we proposed a novel nanostructured lipid carrier (NLC) formulation loading DOX, docosahexaenoic acid (DHA), and α-tocopherol succinate (TS) for cancer treatment. DHA is an omega-3 fatty acid and TS is a vitamin E derivative. It has been proposed that these compounds can enhance the antitumor activity of chemotherapeutics. Thus, we hypothesized that the combination of DOX, DHA, and TS in NLC (NLC-DHA-DOX-TS) could increase antitumor efficacy and also reduce toxicity. NLC-DHA-DOX-TS was prepared using emulsification-ultrasound. DOX was incorporated after preparing the NLC, which prevented its degradation during manufacture. High DOX encapsulation efficiency was obtained due to the ion-pairing with TS. This ion-pairing increases lipophilicity of DOX and reduces its crystallinity, contributing to its encapsulation in the lipid matrix. Controlled DOX release from the NLC was observed in vitro, with increased drug release at the acidic environment. In vitro cell studies indicated that DOX, DHA, and TS have synergistic effects against 4T1 tumor cells. The in vivo study showed that NLC-DHA-DOX-TS exhibited the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice. In addition, this formulation reduced mice mortality, prevented lung metastasis, and decreased DOX-induced toxicity to the heart and liver, which was demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that NLC-DHA-DOX-TS may be a promising carrier for breast cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110876DOI Listing
December 2020

Clinical significance and prognostic role of tumor-associated macrophages infiltration according to histologic location in canine mammary carcinomas.

Res Vet Sci 2021 Mar 17;135:329-334. Epub 2020 Oct 17.

Laboratório de Patologia Comparada (LPC), Departamento de Patologia Geral, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais - UFMG, 31270-091 Belo Horizonte, Brazil. Electronic address:

Tumor-associated macrophages (TAMs) have been involved in growth and metastases of human and canine mammary tumors. However, the prognostic importance of TAM specific location in canine mammary tumors (CMT) was not evaluated. In this study, we evaluated the potential role of TAMs in specific histologic locations - intratumoral (iTAM) and stromal (sTAM), as well as total macrophage (tTAM) counts - as prognostic indicators in CMT. Clinicopathologic data from 66 animals with mammary carcinoma and their tumors were used in this study. Samples were stained with anti-macrophage antibody for subsequent TAM count. High levels of iTAM, sTAM, and tTAM were related with advanced clinical stage and vascular invasion. Additionally, tTAM revealed a relation with larger tumor size, while high levels of sTAM and tTAM were also correlated with node metastasis and a poor prognosis based on survival analysis. CMT with aggressive features can reveal higher TAM counts. TAMs are associated with vascular invasion and nodal metastasis, and sTAM and tTAM counts are correlated with overall survival, suggesting they could be used as prognostic indicators in canine mammary carcinomas.
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http://dx.doi.org/10.1016/j.rvsc.2020.10.010DOI Listing
March 2021

Correction to: A role for mast cells and mast cell tryptase in driving neutrophil recruitment in LPS-induced lung inflammation via protease-activated receptor 2 in mice.

Inflamm Res 2020 Oct;69(10):1071

Laboratory of Pain and Inflammation, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-010, Brazil.

The original article can be found online.
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http://dx.doi.org/10.1007/s00011-020-01386-2DOI Listing
October 2020

Erratum to "Mixed tumors of the canine mammary glands: Evaluation of prognostic factors, treatment, and overall survival" [7C (June 2019) 100039].

Vet Anim Sci 2020 Jun 21;9:100109. Epub 2020 Mar 21.

Laboratory of Comparative Pathology, Department of General Pathology, Biological Sciences Institute (ICB), Federal University of Minas Gerais (UFMG), Avenida Antônio Carlos 6627 Bloco C3 Sala 166 P.O. Box 31270-901, Pampulha, Belo Horizonte, Brazil.

[This corrects the article DOI: 10.1016/j.vas.2018.09.003.].
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http://dx.doi.org/10.1016/j.vas.2020.100109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386705PMC
June 2020

A role for mast cells and mast cell tryptase in driving neutrophil recruitment in LPS-induced lung inflammation via protease-activated receptor 2 in mice.

Inflamm Res 2020 Oct 6;69(10):1059-1070. Epub 2020 Jul 6.

Laboratory of Pain and Inflammation, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-010, Brazil.

Objective: This study aims to investigate the role of protease-activated receptor (PAR) 2 and mast cell (MC) tryptase in LPS-induced lung inflammation and neutrophil recruitment in the lungs of C57BL/6 mice.

Methods: C57BL/6 mice were pretreated with the PAR2 antagonist ENMD-1068, compound 48/80 or aprotinin prior to intranasal instillation of MC tryptase or LPS. Blood leukocytes, C-X-C motif chemokine ligand (CXCL) 1 production leukocytes recovered from bronchoalveolar lavage fluid (BALF), and histopathological analysis of the lung were evaluated 4 h later. Furthermore, we performed experiments to determine intracellular calcium signaling in RAW 264.7 cells stimulated with LPS in the presence or absence of a protease inhibitor cocktail or ENMD-1068 and evaluated PAR2 expression in the lungs of LPS-treated mice.

Results: Pharmacological blockade of PAR2 or inhibition of proteases reduced neutrophils recovered in BALF and LPS-induced calcium signaling. PAR2 blockade impaired LPS-induced lung inflammation, PAR2 expression in the lung and CXCL1 release in BALF, and increased circulating blood neutrophils. Intranasal instillation of MC tryptase increased the number of neutrophils recovered in BALF, and MC depletion with compound 48/80 impaired LPS-induced neutrophil migration.

Conclusion: Our study provides, for the first time, evidence of a pivotal role for MCs and MC tryptase in neutrophil migration, lung inflammation and macrophage activation triggered by LPS, by a mechanism dependent on PAR2 activation.
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http://dx.doi.org/10.1007/s00011-020-01376-4DOI Listing
October 2020

ZEB and Snail expression indicates epithelial-mesenchymal transition in canine melanoma.

Res Vet Sci 2020 Aug 6;131:7-14. Epub 2020 Apr 6.

Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, MG, Brazil. Electronic address:

Melanoma progression is associated with the epithelial-mesenchymal transition (EMT) when tumor cells reduce E-cadherin and increase N-cadherin expression resulting in an escape from the microenvironment via loss of cellular adhesion and gain of motility. Transcription factor proteins Snail and ZEB trigger EMT by repression of epithelial markers and activation of mesenchymal properties. This study evaluated E-cadherin, N-cadherin, Snail, ZEB1 and ZEB2 expression by IHC and investigated their relationship with morphological characteristics in cutaneous and oral canine melanoma. Results from melanoma cases demonstrated E-cadherin expression in 45% (9/20) of oral and 58% (22/38) of cutaneous tumors, while N-cadherin expression was observed in 95% (18/19) of oral and 92% (34/37) of cutaneous melanoma. Cytoplasmic and nuclear N-cadherin expression was positively correlated with ZEB1 expression, while the cell membrane N-cadherin expression was positively correlated with ZEB2. In addition, an increase in nuclear N-cadherin expression was associated with reduced Snail expression in cutaneous melanoma and an increase in Snail expression in oral melanoma, indicating that the correlation between N-cadherin and Snail expression is coincident with tumor location. Our data suggest that ZEB family protein is associated with N-cadherin translocation from cell membrane to the cytoplasm and nuclei, and may act as important transcription factors of EMT regulation in canine melanoma.
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http://dx.doi.org/10.1016/j.rvsc.2020.04.007DOI Listing
August 2020

Diverse roles of epidermal growth factors receptors in oral and cutaneous canine melanomas.

BMC Vet Res 2020 Jan 29;16(1):24. Epub 2020 Jan 29.

Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

Background: The epidermal growth factor receptors participate in the physiological processes such as regulation of morphogenesis, proliferation and cell migration, but when overexpressed or overactivated they may play an important role in neoplastic progression. Melanoma is the most aggressive skin neoplasm and is characterized by elevated invasion and low survival rates in both humans and dogs. In human melanomas the overexpression of EGFR, HER3 or HER4 is associated with poor prognosis. In canine melanomas the epidermal growth factor receptors expression has not been evaluated. Therefore, this study evaluated the expression of epidermal growth factor receptors by immunohistochemistry and investigated their relationship with morphological characteristics and proliferative indices in cutaneous and oral canine melanoma.

Results: In cutaneous melanoma an increased proliferative index was associated with increased cytoplasmic HER4 and reduced EGFR and HER3 protein expression. In oral melanomas, membranous HER2 protein expression correlated with occurrence of emboli, but ERBB2 gene amplification wasn't observed.

Conclusion: Thus, our work evidenced the relationship between HER4 and the stimulus to cell proliferation in cutaneous melanomas, in addition to the relationship between HER2 and the occurrence of emboli in oral melanomas.
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http://dx.doi.org/10.1186/s12917-020-2249-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988198PMC
January 2020

Milk Fermented by Lactobacillus paracasei NCC 2461 (ST11) Modulates the Immune Response and Microbiota to Exert its Protective Effects Against Salmonella typhimurium Infection in Mice.

Probiotics Antimicrob Proteins 2020 12;12(4):1398-1408

Department of Microbiology, Biological Science Institute (ICB), Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.

Probiotics form a promising strategy to maintain intestinal health. Milks fermented with probiotic strains, such as the Lactobacillus paracasei ST11, are largely commercialized in Brazil and form a low-cost alternative to probiotic pharmaceutical formulations. In this study, we assessed the probiotic effects of milk fermented by L. paracasei ST11 (administered through fermented milk) in a Salmonella typhimurium infection model in BALB/c mice. We observed in this murine model that the applied probiotic conferred protective effects against S. typhimurium infection, since its administration reduced mortality, weight loss, translocation to target organs (liver and spleen) and ileum injury. Moreover, a reduction in the mRNA expression of pro-inflammatory cytokines such as IFN-γ, IL-6, TNF-α and IL-17 in animals that received the probiotic before challenge was observed. Additionally, the ileum microbiota was better preserved in these animals. The present study highlights a multifactorial protective aspect of this commercial probiotic strain against a common gastrointestinal pathogen.
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http://dx.doi.org/10.1007/s12602-020-09634-xDOI Listing
December 2020

Phenotypic, structural, and ultrastructural analysis of triple-negative breast cancer cell lines and breast cancer stem cell subpopulation.

Eur Biophys J 2019 Oct 4;48(7):673-684. Epub 2019 Sep 4.

Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias, Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil.

Triple negative breast cancer (TNBC) is a highly heterogeneous disease, which influences the therapeutic response and makes difficult the discovery of effective targets. This heterogeneity is attributed to the presence of breast cancer stem cells (BCSCs), which determines resistance to chemotherapy and subsequently disease recurrence and metastasis. In this context, this work aimed to evaluate the morphological and phenotypic cellular heterogeneity of two TNBC cell lines cultured in monolayer and tumorsphere (TS) models by fluorescence and electron microscopy and flow cytometry. The BT-549 and Hs 578T analyses demonstrated large phenotypic and morphological heterogeneity between these cell lines, as well as between the cell subpopulations that compose them. BT-549 and Hs 578T are heterogeneous considering the cell surface marker CD44 and CD24 expression, characterizing BCSC mesenchymal-like cells (CD44/CD24), epithelial cells (CD44/CD24), hybrid cells with mesenchymal and epithelial features (CD44/CD24), and CD44/CD24 cells. BCSC epithelial-like cells (ALDH) were found in BT-549, BT-549 TS, and Hs 578T TS; however, only BT-549 TS showed a high ALDH activity. Ultrastructural characterization showed the heterogeneity within and among BT-549 and Hs 578T in monolayer and TS models being formed by more than one cellular type. Further, the mesenchymal characteristic of these cells is demonstrated by E-cadherin absence and filopodia. It is well known that tumor cell heterogeneity can influence survival, therapy responses, and the rate of tumor growth. Thus, molecular understanding of this heterogeneity is essential for the identification of potential therapeutic options and vulnerabilities of oncological patients.
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http://dx.doi.org/10.1007/s00249-019-01393-0DOI Listing
October 2019

Folate-coated, long-circulating and pH-sensitive liposomes enhance doxorubicin antitumor effect in a breast cancer animal model.

Biomed Pharmacother 2019 Oct 7;118:109323. Epub 2019 Aug 7.

Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Long circulating pH-sensitive liposomes have been shown to effectively deliver doxorubicin (DOX) to tumors and reduce its toxic effects. Folic acid receptors are upregulated in a wide variety of solid, epithelial tumors, including breast cancer. In order to improve liposomal endocytosis and antitumor activity, folic acid has been added to nanoparticles surfaces to exploit overexpression of folate receptors in tumor cells. The purpose of this study was to evaluate the antitumor activity in vitro and in vivo of long circulating pH-sensitive folate-coated DOX-loaded liposomes (SpHL-DOX-Fol) in a 4T1 breast cancer model system in vitro and in vivo. Biodistribution studies were performed and in vivo electrocardiographic parameters were evaluated. A higher tumor uptake for radiolabeled SpHL-Fol (Tc-SpHL-Fol) 4 h after intravenous administration was observed in comparision with non-folate-coated liposomes (Tc-SpHL). Antitumor activity showed that SpHL-DOX-Fol treatment led to a 68% growth arrest and drastically reduce pulmonary metastasis foci. Additionally, eletrocardiographic parameters analysis revealed no dispersion in the QT and QTc interval was observed in liposomal treated mice. In summary, this novel multifunctional nanoplatform deomonstrated higher tumor uptake and antitumor activity. SpHL-DOX-Fol represents a drug delivery platform to improve DOX tumor delivery and reduce dose-limiting toxicity.
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http://dx.doi.org/10.1016/j.biopha.2019.109323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104811PMC
October 2019

Sclareol is a potent enhancer of doxorubicin: Evaluation of the free combination and co-loaded nanostructured lipid carriers against breast cancer.

Life Sci 2019 Sep 22;232:116678. Epub 2019 Jul 22.

Department of Pharmaceutics, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Aims: In this work, it was sought to determine if there was synergism between doxorubicin (DOX), a well-known antineoplastic, and sclareol (SC), a diterpene from natural origin, in breast cancer treatment. Moreover, it was investigated if their co-loading in the same nanocarrier would result in a gain of activity and/or a toxicity diminishment.

Main Methods: The synergism of the DOX:SC combination was evaluated in MDA-MB-231 and 4T1 cells. A nanostructured lipid carrier (NLC) co-encapsulating DOX and SC in their synergistic molar ratio was prepared and characterised, in terms of mean diameter, zeta potential, DOX encapsulation efficiency, small angle X-ray scattering, differential scanning calorimetry, and polarised light microscopy for further intravenous administration. The anticancer activity of the combination, free and encapsulated, was evaluated in 4T1-tumour bearing mice.

Key Findings: It was determined that DOX:SC combination at the molar ratio 1:1.9 presents better synergistic anticancer activity than the molar ratio 1:7.5 in vitro. DOX:SC-loaded NLC (NLC-DOX-SC) improved in vitro cytotoxic and in vivo antitumour activity compared to free DOX. Although NLC-DOX-SC and free DOX:SC, at the synergistic molar ratio, showed similar activity in the in vivo study, the free combination provoked body weight loss, behaviour alterations and haematological toxicity in the animals, while this was not observed for NLC-DOX-SC.

Significance: This work shows that SC and DOX present synergistic anticancer activity for breast cancer treatment whereas NLC-DOX-SC was a feasible alternative to attain the benefits posed by DOX:SC combination but with none to fewer side effects.
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http://dx.doi.org/10.1016/j.lfs.2019.116678DOI Listing
September 2019

Versican and Tumor-Associated Macrophages Promotes Tumor Progression and Metastasis in Canine and Murine Models of Breast Carcinoma.

Front Oncol 2019 3;9:577. Epub 2019 Jul 3.

Department of General Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Versican and tumor-associated macrophages (TAMs) are involved in growth and metastases in several cancers. Here, we investigated the potential role of versican, a matrix proteoglycan, and its correlation with TAMs infiltrates in different stages of two different breast cancer models: spontaneous canine mammary gland carcinomas and the murine 4T1 breast cancer model. The stromal versican expression was correlated with TAMs accumulation in tumors with an advanced stage from spontaneous canine mammary carcinoma samples. Versican expression in mice, identified in late stages of tumor progression, was associated to a high number of peri-tumoral infiltrating TAMs. Indeed, TAMs were related to a pro-inflammatory and pro-angiogenic state in the primary tumor. Furthermore, TAMs accumulation was related to versican expression in the lungs and an increased number of pulmonary metastatic nodules with pulmonary mechanical dysfunction, which was due to leukocyte influx in the airways and elevated growth factor levels in the microenvironment. Thus, we suggest that versican and TAMs as attractive targets for breast cancer therapy.
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http://dx.doi.org/10.3389/fonc.2019.00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616078PMC
July 2019

Quantification of EGFR family in canine mammary ductal carcinomas in situ: implications on the histological graduation.

Vet Res Commun 2019 May 24;43(2):123-129. Epub 2019 Apr 24.

Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte, MG, 31270-901, Brazil.

The epithelial growth factor receptors are transmembrane proteins with an important role in the neoplastic progression of tumors, and in this context, DCIS is an important phase in the progression of canine mammary tumors. Studies on the molecular profile and its relationship to a progression of canine mammary tumors are important to improve the treatment of patients and for a better understanding of canine mammary carcinogenesis. The aim of this study was to determine, by immunohistochemistry, the relation between the expression of EGFR, ErbB-2, ErbB-3, and ErbB-4 in 52 canine mammary gland DCIS with high and low histological grade. A positive correlation between histological grade and expression of membrane ErbB-2 and cytoplasmic ErbB-4 was observed. Increased ErbB-4 membrane expression was correlated with increased ErbB-3 expression in low and high-grade DCIS. Our data suggest that increased expression of ErbB-2 and ErbB-4 may be related to more aggressive DCIS and probabily involved with canine mammary neoplastic progression.
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http://dx.doi.org/10.1007/s11259-019-09752-0DOI Listing
May 2019

The investigation of transcriptional repression mediated by ZEB2 in canine invasive micropapillary carcinoma in mammary gland.

PLoS One 2019 15;14(1):e0209497. Epub 2019 Jan 15.

Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

The E-cadherin loss has frequently been associated with transcriptional repression mediated by transcription factors, such as the Zinc Finger E-Box Binding Homeobox-2 (ZEB2). Invasive micropapillary carcinomas (IMPCs) of the breast are aggressive neoplasms frequently related to lymph node metastasis and poor overall survival. In the canine mammary gland, IMPCs has just been reported and, based on its behavioral similarity with the human IMPCs, appears to be a good spontaneous model to this human entity. This study aimed to evaluate the relationship between E-cadherin and ZEB2 in a spontaneous canine model of invasive micropapillary carcinoma of the mammary gland. The correlation among gene expression (ZEB2 and CDH1) and clinicopathological findings was also explored. Nineteen cases of IMPC of the canine mammary gland were obtained, protein and mRNA expression were investigated through immunohistochemistry and RNA In Situ Hybridization, respectively. To better understand the relationship between E-cadherin and ZEB2, immunofluorescence was performed in canine IMPCs. Immunohistochemically, most of IMPCs showed 1+ (14/19, 73.7%) for E-cadherin; and positivity for ZEB2 was diagnosed in 47.4% of the IMPCs. Regarding the RNA In Situ Hybridization (ISH), most of IMPCs showed 4+ and 0+ for E-cadherin (CDH1) and ZEB2 respectively. Through immunofluorescence, the first and second more frequent combinatorial group were E-cadherin+ZEB2- and E-cadherin+ZEB2+; neoplastic cells showing concomitantly weak expression for E-cadherin and positivity for ZEB2 were frequently observed. A negative correlation was observed between E-cadherin and progesterone receptor expression in IMPCs. Based on these results, canine mammary IMPCs show E-cadherin lost and, at times reveals nuclear positivity for the transcription factor ZEB2 that seems to exert transcriptional repression of the CDH1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209497PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333364PMC
September 2019

Investigation of the antitumor activity and toxicity of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in a murine breast cancer animal model.

Biomed Pharmacother 2019 Jan 21;109:1728-1739. Epub 2018 Nov 21.

Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for this combination, it presents a cardiotoxic synergism, attributed to pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol. One of the main strategies to minimize the cardiotoxicity of the combination is to extend the interval of time between DXR and PTX administration. However, it has been previously suggested that their co-administration leads to better efficacy compared to their sequential administration. In the present study, we investigated different molar ratio combinations of PTX:DXR (10:1; 1:1, and 1:10) against the 4T1 murine breast cancer cell line and concluded that there is no benefit of enhancing PTX concentration above that of DXR on the combination. Therefore, we obtained a long-circulating and fusogenic liposomal formulation co-encapsulating PTX and DXR (LCFL-PTX/DXR) at a molar ratio of 1:10, respectively, which maintained the in vitro biological activity of the combination. This formulation was investigated for its antitumor activity and toxicity in Balb/c mice bearing 4T1 breast tumor, and compared to treatments with free PTX, free DXR, and the mixture of free PTX:DXR at 1:10 molar ratio. The higher tumor inhibition ratios were observed for the treatments with free and co-encapsulated PTX:DXR in liposomes (66.87 and 66.52%, respectively, P>0.05) as compared to the control. The great advantage of the treatment with LCFL-PTX/DXR was its improved cardiac toxicity profile. While degeneration was observed in the hearts of all animals treated with the free PTX:DXR combination, no signs of cardiac toxicity were observed for animals treated with the LCFL-PTX/DXR. Thus, LCFL-PTX/DXR enables the co-administration of PTX and DXR, and might be considered valuable for breast cancer management.
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http://dx.doi.org/10.1016/j.biopha.2018.11.011DOI Listing
January 2019

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms.

In Vivo 2018 Nov-Dec;32(6):1659-1666

Laboratory of Comparative Pathology, Department of General Pathology, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil

Background/aim: The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC).

Materials And Methods: Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated.

Results: No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001).

Conclusion: The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages.
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http://dx.doi.org/10.21873/invivo.11429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365760PMC
January 2019

Mixed tumors of the canine mammary glands: Evaluation of prognostic factors, treatment, and overall survival.

Vet Anim Sci 2019 Jun 22;7:100039. Epub 2018 Sep 22.

Laboratory of Comparative Pathology, Department of General Pathology, Biological Sciences Institute (ICB), Department of General Pathology, Federal University of Minas Gerais (UFMG), Avenida Antônio Carlos 6627 Bloco C3 Sala 166 PO Box 31270-901, Pampulha, Belo Horizonte, Brazil.

Mixed tumors are the most frequent mammary gland neoplasms in bitches; however, studies that thoroughly describe their clinicopathological data, treatment approaches, and the survival of bitches with mixed tumors are scarce. This study evaluated the epidemiological and clinicopathological data, prognostic factors, and therapeutic approaches for bitches with mixed tumors. In all, 162 benign mixed tumors, 682 carcinomas in mixed tumors, and 60 carcinosarcomas were included. Regarding tumor size, T lesions were predominantly associated with carcinosarcomas, while T and T lesions occurred more frequently in benign mixed tumors and in carcinomas in mixed tumors. Based on clinical staging, most bitches with benign mixed tumors presented with stage I tumors; 92% of bitches with carcinomas in mixed tumors presented with stage I-III tumors, while 8% presented with stage IV-V tumors; and 70% of bitches with carcinosarcomas presented with stage I-III tumors, while 30% presented with stage IV-V tumors. Surgery was curative for bitches with benign mixed tumors and for those with stage I-III carcinomas in mixed tumors. Combination therapy in bitches with carcinomas in mixed tumors (IV-V) and carcinosarcomas resulted in a higher overall survival compared with bitches who underwent surgery only. Carcinosarcomas presented higher relapse rates and distant metastases than carcinomas in mixed tumors did.
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http://dx.doi.org/10.1016/j.vas.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386670PMC
June 2019

Relationship between the inflammatory tumor microenvironment and different histologic types of canine mammary tumors.

Res Vet Sci 2018 Aug 23;119:209-214. Epub 2018 Jun 23.

Laboratório de Patologia Comparada, Departamento de Patologia Geral, ICB/UFMG, Belo Horizonte, MG, Brazil. Electronic address:

Mammary neoplasms are the tumors with higher incidence in female dogs. Among the factors that contribute for the development of this and other neoplasms, the inflammatory tumor microenvironment plays a crucial role. Several studies reported important roles for lymphocytes, macrophages, plasma cells, neutrophils, eosinophils and mast cells in this context. In the present study, our aim was to evaluate the number of profile cells of inflammatory cells and area of tumor fibrosis and the relation of these features with canine mammary tumors of different histologic and clinical presentation (benign mixed tumor, carcinoma in mixed tumor, solid carcinoma and tubular carcinoma) Counting and staining of inflammatory cells and tumor fibrosis were performed through histochemistry, while counting and staining of CD4, TCD8 and FOXP3 lymphocytes were performed through immunohistochemistry. Statistical analysis of the association between densities of inflammatory cells, tumor fibrosis and histologic types revealed significant difference for plasma cells (p = .035), neutrophils (p = .0113), macrophages (p = .0047), and tumor fibrosis (p = .05). The found data suggest associations between high number of neutrophils and aggressive mammary tumors, between high densities of plasma cells, macrophages and CD8 cells and between low number of profile cells of CD4 cells and less aggressive tumors. Larger areas of tumor fibrosis showed relation to more aggressive canine mammary tumors.
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http://dx.doi.org/10.1016/j.rvsc.2018.06.012DOI Listing
August 2018

Conjugated linoleic acid prevents damage caused by intestinal mucositis induced by 5-fluorouracil in an experimental model.

Biomed Pharmacother 2018 Jul 7;103:1567-1576. Epub 2018 May 7.

Department of Clinical and Toxicological Analysis, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Background: Studies have showed the protective effects of conjugated linoleic acid (CLA) on intestinal epithelium, modulating host immune and inflammatory responses on intestinal diseases.

Objective: To evaluate the preventive effects of CLA on the intestinal mucositis induced by 5-FU in a murine model.

Methods: Sixty-four BALB/c mice were randomly divided into four groups: Control (CTL), fed a standard chow diet; CLAs, fed a diet supplemented with CLA; Mucositis (5-FU), fed a standard chow diet and underwent mucositis induction and CLAs 5-FU, fed a diet supplemented with CLA and underwent mucositis induction. Mucositis was induced by intraperitoneal injection of 300 mg/kg 5-FU. After 72 h, the animals were euthanized and intestinal permeability, bacterial translocation, inflammatory mediators, and intestinal histology were evaluated.

Results: Mice in the CLAs 5-FU group showed reduced weight loss compared to those in the 5-FU group (p < 0.005). Furthermore, the results also showed that the treatment with CLA reduced intestinal permeability, bacterial translocation, and biomarkers of inflammatory response besides minor damage to ZO-1 and occludin with maintenance of the integrity of the intestinal epithelium and a favorable balance between the inflammatory and regulatory cytokines.

Conclusion: This study suggests that CLA reduced the adverse effects from 5-FU administration on the intestinal mucosa.
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http://dx.doi.org/10.1016/j.biopha.2018.04.133DOI Listing
July 2018

Toxicological study of a new doxorubicin-loaded pH-sensitive liposome: A preclinical approach.

Toxicol Appl Pharmacol 2018 08 1;352:162-169. Epub 2018 Jun 1.

Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Doxorubicin (DOX) is widely used in cancer treatment, however, the use of this drug is often limited due to its cardiotoxic side effects. In order to avoid these adverse effects, the encapsulation of DOX into nanosystems has been used in the last decades. In this context, pH-sensitive liposomes have been shown promising for delivering cytotoxic agents into tumor cells, however, the lack of information about in vivo toxicity of this nanocarrier has impaired translational studies. Therefore, the aim of this work was to investigate the acute toxicity and cardiotoxicity of DOX-loading pH-sensitive liposomes (SpHL-DOX). To achieve this, female BALB/c mice, after intravenous administration, were monitored by means of clinical, laboratory, histopathological and electrocardiographic (ECG) analyses. Results indicate that SpHL was able to prevent renal toxicity and the hepatic injury was less extensive than free DOX. In addition, lower body weight loss was associated with less ECG QT interval prolongation to animals receiving SpHL-DOX (14.6 ± 5.2%) compared to animals receiving free DOX (35.7 ± 4.0%) or non-pH-sensitive liposomes (nSpHL-DOX) (47.0 ± 9.8%). These results corroborate with SpHL-DOX biodistribution studies published by our group. In conclusion, the SpHL-DOX showed less toxic effects on mice compared to free DOX or nSpHL-DOX indicating that SpHL-DOX is a promising strategy to reduce the serious cardiotoxic effects of DOX.
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http://dx.doi.org/10.1016/j.taap.2018.05.037DOI Listing
August 2018
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