Publications by authors named "José Luiz Guerra"

6 Publications

  • Page 1 of 1

Inhibitory Effects of a Reengineered Anthrax Toxin on Canine Oral Mucosal Melanomas.

Toxins (Basel) 2020 03 2;12(3). Epub 2020 Mar 2.

Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo 05508-270, SP, Brazil.

Canine oral mucosal melanomas (OMM) are the most common oral malignancy in dogs and few treatments are available. Thus, new treatment modalities are needed for this disease. (anthrax) toxin has been reengineered to target tumor cells that express urokinase plasminogen activator (uPA) and metalloproteinases (MMP-2), and has shown antineoplastic effects both, in vitro and in vivo. This study aimed to evaluate the effects of a reengineered anthrax toxin on canine OMM. Five dogs bearing OMM without lung metastasis were included in the clinical study. Tumor tissue was analyzed by immunohistochemistry for expression of uPA, uPA receptor, MMP-2, MT1-MMP and TIMP-2. Animals received either three or six intratumoral injections of the reengineered anthrax toxin prior to surgical tumor excision. OMM samples from the five dogs were positive for all antibodies. After intratumoral treatment, all dogs showed stable disease according to the canine Response Evaluation Criteria in Solid Tumors (cRECIST), and tumors had decreased bleeding. Histopathology has shown necrosis of tumor cells and blood vessel walls after treatment. No significant systemic side effects were noted. In conclusion, the reengineered anthrax toxin exerted inhibitory effects when administered intratumorally, and systemic administration of this toxin is a promising therapy for canine OMM.
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http://dx.doi.org/10.3390/toxins12030157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150776PMC
March 2020

Slc11a1 (Nramp-1) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice.

Inflamm Res 2017 Nov 1;66(11):969-980. Epub 2017 Jul 1.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503000, Brazil.

Objective And Design: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA.

Treatment: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days.

Results: AIRmax mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of HO, NO, IL-1β, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development.

Conclusion: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines.
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http://dx.doi.org/10.1007/s00011-017-1077-8DOI Listing
November 2017

Histological alterations in the livers of Cx43-deficient mice submitted to a cholestasis model.

Life Sci 2007 Jul 6;81(5):380-4. Epub 2007 Jun 6.

Laboratory of Experimental Oncology, Department of Pathology, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Brazil.

Gap junction intercellular communication capacity and connexin expression are reportedly involved in cell proliferation. To understand the participation of connexins in biliary duct hyperplasia, a cholestasis model was applied to mice with heterologous deletion of Gja 1, the connexin 43 (Cx43) gene. Heterozygous (Cx43+/-) knockout (KO) and wild-type mice (Cx43+/+) (WT) were submitted to bile duct ligation and euthanized at different time points (48 h, 7 days, and 14 days) after surgery. After euthanasia, the macroscopic and microscopic liver alterations were examined. A histomorphometric study of the livers was performed. For this purpose, a grid containing 100 points was applied to each liver section. The volumetric fraction of bile ducts, hepatocytes, arterioles, and terminal hepatic vein were quantified. Cell proliferation was also quantified by western blot PCNA. High mortality was observed in both genotypes. The heterologous deletion of Cx43 did not affect the biliary duct hyperplasia or most of the other parameters analyzed; however, the Cx43-deficient mice showed decrease in hepatic vein angiogenesis in comparison with the wild-type mice 48 h after surgery. In conclusion, our results indicate that the Cx43 gene heterologous deletion does not affect the biliary duct hyperplasia; on the other hand, connexin 43 deficiencies do affect the hepatic vein angiogenesis, although other studies to understand the details of this influence will be necessary.
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http://dx.doi.org/10.1016/j.lfs.2007.05.017DOI Listing
July 2007

Hepatic granulomas induced by Schistosoma mansoni in mice deficient for connexin 43 present lower cell proliferation and higher collagen content.

Life Sci 2007 Mar 18;80(13):1228-35. Epub 2007 Jan 18.

Laboratory of Experimental Oncology, Department of Pathology, School of Veterinary Medicine, University of São Paulo, Brazil.

Granuloma formation involves a coordinated interaction between monocytes and macrophages, epithelioid cells, lymphocytes, eosinophils, neutrophils and fibroblasts. It has been established that extracellular communication via cytokines is important for the assembly of granulomas. However, the importance of gap junctions and intercellular communication to granuloma formation and development had never been assessed. Connexins are proteins that form gap junctions, and connexin 43 (Cx43) is present in macrophages, lymphoid cells, myelogenous cells, fibroblasts and others. We analyzed the effect of heterologous deletion of Gja1 (Cx43 gene) on the formation and development of hepatic granulomas induced by Schistosoma mansoni eggs. Heterozygous (Cx43(+/-)) and wild-type (Cx43(+/+)) mice were infected subcutaneously with S. mansoni cercarie and evaluated after 6, 8 and 12 weeks. Granuloma cells express Cx43, as revealed by real-time PCR in isolated granulomas, and by immunohistochemistry. Cx43 expression was reduced in Cx43(+/-) mice, as expected. No differences in the average area of granulomas or number of cells per granuloma were observed between mice of different genotypes. However, granuloma cells from Cx43(+/-) mice displayed a reduced index of the proliferating cell nuclear antigen (PCNA) labeling at 8 and 12 weeks post-infection. Moreover, Cx43(+/-) granulomas unexpectedly presented a higher degree of fibrosis, quantified by morphometric analysis in Sirius Red-stained slides. Our results indicate that the deletion of one allele of the Cx43 gene, and possibly the reduced gap junction intercellular communication capacity (GJIC), may impair the interactions between granuloma cells, reducing their proliferation and increasing their collagen content, thereby modifying the characteristics of S. mansoni granuloma in mice.
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http://dx.doi.org/10.1016/j.lfs.2006.12.030DOI Listing
March 2007

Walker 256 tumor-bearing rats as a model to study cancer pain.

J Pain 2007 May 6;8(5):412-21. Epub 2007 Feb 6.

Laboratory of Pathophysiology, Butantan Institute, São Paulo, Brazil.

Unlabelled: An animal model of cancer pain induced by injection of Walker 256 carcinoma cells into the plantar surface of rat hind paw is described. Tumor growth and the occurrence of metastasis were investigated by histopathological analysis. Tumor cell growth was also analyzed plethysmographically by the increase in paw volume. For characterization of pain symptoms, hyperalgesia, allodynia, and spontaneous pain were evaluated 5 to 8 days after cell injection. The volume of the inoculated paw started to increase on day 2 after inoculation, being 40% higher on day 5 after injection. At this time, there was a marked proliferation of tumor cells, with the presence of anaplastic and pleomorphic cells, nucleoli, and atypical mitotic features. On days 7 and 8 after injection, histopathological analysis of popliteal lymph nodes showed the presence of tumor cells. The intraplantar injection of Walker 256 cells caused hyperalgesia at day 5 after cell inoculation. Low-threshold mechanical allodynia was significant 2 days after cell injection, being increased on day 5. In addition, inoculation of tumor cells induced gross behavior, characterized by a significant increase in licking and lifting of the injected paw 5 days after injection. The pain-enhancing effect caused by cell inoculation was partially inhibited by indomethacin on day 2 after cell injection, whereas morphine blocked allodynia on days 2 and 5. These results indicate that intraplantar injection of Walker 256 cells cause pain symptoms characteristic of cancer pain. This experimental model can then be used to investigate new analgesic or anti-tumor drugs.

Perspective: This article presents a new animal model for studying cancer pain and metastasis. This model could help in understanding the mechanisms involved in cancer pain symptoms and may be used for the investigation of new analgesic or anti-tumor drugs.
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http://dx.doi.org/10.1016/j.jpain.2006.11.006DOI Listing
May 2007

Effect of beta-Carotene on the development of the solid Ehrlich tumor in mice.

Life Sci 2002 Jun;71(6):717-24

Laboratory of Experimental Oncology, Department of Pathology, Faculty of Veterinary Medicine and Zootechny, University of São Paulo, Av. Prof Dr. Orlando Marques de Paiva, no. 87, CEP 05508-900, -SP, São Paulo, Brazil.

The effect of beta-Carotene on the development of the solid Ehrlich tumor in BALB/c mice was investigated. Male mice received orally, on alternate days, three different doses of beta-Carotene (1, 3.5 or 7 mg/100 g) or corn oil as the control. This protocol started 14 days before tumor inoculation (1.75 x 10(5) cells) into mouse footpad and lasted until 10 days after. The tumor growth was evaluated by daily measurement of the footpad thickness, and the tumor mass was evaluated morphometrically. The proliferation rate of tumor was investigated by counting PCNA (proliferating cell nuclear antigen) positive nuclei in the 10th day of the tumor development. Histopathological examination of the lymphoid tissue: thymus, spleen and popliteal lymph node were also performed. beta-Carotene treatment, at dose 3.5 mg/100 g, increased the tumor growth, proliferative rate and the relative weight of popliteal lymph nodes, showing up an adverse effect only when this intermediate dose was used. No effects were obtained when the smaller (1,0 mg/100 g) or the higher (7.0 mg/100 g) doses were used. These results suggest that depending on the dose, beta-Carotene may determine an undesirable effect upon the tumor growth. This should be taken into account in chemopreventive experiments and human applications.
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http://dx.doi.org/10.1016/s0024-3205(02)01730-7DOI Listing
June 2002