Publications by authors named "Sérgio Luis Felisbino"

39 Publications

Exposure to Bacteriophages T4 and M13 Increases Integrin Gene Expression and Impairs Migration of Human PC-3 Prostate Cancer Cells.

Antibiotics (Basel) 2021 Oct 3;10(10). Epub 2021 Oct 3.

Laboratory of Extracellular Matrix Biology, Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil.

The interaction between bacteriophages and integrins has been reported in different cancer cell lines, and efforts have been undertaken to understand these interactions in tumor cells along with their possible role in gene alterations, with the aim to develop new cancer therapies. Here, we report that the non-specific interaction of T4 and M13 bacteriophages with human PC-3 cells results in differential migration and varied expression of different integrins. PC-3 tumor cells (at 70% confluence) were exposed to 1 × 10 pfu/mL of either lytic T4 bacteriophage or filamentous M13 bacteriophage. After 24 h of exposure, cells were processed for a histochemical analysis, wound-healing migration assay, and gene expression profile using quantitative real-time PCR (qPCR). qPCR was performed to analyze the expression profiles of integrins , , , , and . Our findings revealed that PC-3 cells interacted with T4 and M13 bacteriophages, with significant upregulation of , , , genes after phage exposure. PC-3 cells also exhibited reduced migration activity when exposed to either T4 or M13 phages. These results suggest that wildtype bacteriophages interact non-specifically with PC-3 cells, thereby modulating the expression of integrin genes and affecting cell migration. Therefore, bacteriophages have future potential applications in anticancer therapies.
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http://dx.doi.org/10.3390/antibiotics10101202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532711PMC
October 2021

Bacteriophages M13 and T4 Increase the Expression of Anchorage-Dependent Survival Pathway Genes and Down Regulate Androgen Receptor Expression in LNCaP Prostate Cell Line.

Viruses 2021 Sep 2;13(9). Epub 2021 Sep 2.

Laboratory of Extracellular Matrix Biology, Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil.

Wild-type or engineered bacteriophages have been reported as therapeutic agents in the treatment of several types of diseases, including cancer. They might be used either as naked phages or as carriers of antitumor molecules. Here, we evaluate the role of bacteriophages M13 and T4 in modulating the expression of genes related to cell adhesion, growth, and survival in the androgen-responsive LNCaP prostatic adenocarcinoma-derived epithelial cell line. LNCaP cells were exposed to either bacteriophage M13 or T4 at a concentration of 1 × 10 pfu/mL, 1 × 10 pfu/mL, and 1 × 10 pfu/mL for 24, 48, and 72 h. After exposure, cells were processed for general morphology, cell viability assay, and gene expression analyses. Neither M13 nor T4 exposure altered cellular morphology, but both decreased the MTT reduction capacity of LNCaP cells at different times of treatment. In addition, genes , , , , , , and were significantly up-regulated, whilst the genes , , , and were down-regulated. Our results show that bacteriophage M13 and T4 interact with LNCaP cells and effectively promote gene expression changes related to anchorage-dependent survival and androgen signaling. In conclusion, phage therapy may increase the response of PCa treatment with pathway inhibitors.
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http://dx.doi.org/10.3390/v13091754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473360PMC
September 2021

Syndecan Family Gene and Protein Expression and Their Prognostic Values for Prostate Cancer.

Int J Mol Sci 2021 Aug 12;22(16). Epub 2021 Aug 12.

Department of Structural and Functional BIology, Institute of Bioscience of Botucatu (IBB), São Paulo State University, Botucatu 18618-689, SP, Brazil.

Prostate cancer (PCa) is the leading cause of cancer-associated mortality in men, and new biomarkers are still needed. The expression pattern and protein tissue localization of proteoglycans of the syndecan family (SDC 1-4) and syntenin-1 (SDCBP) were determined in normal and prostatic tumor tissue from two genetically engineered mouse models and human prostate tumors. Studies were validated using SDC 1-4 and SDCBP mRNA levels and patient survival data from The Cancer Genome Atlas and CamCAP databases. RNAseq showed increased expression of in mouse Pca and upregulation of expression and downregulation of and when compared to the normal prostatic tissue in mouse tumors. These changes were confirmed by immunohistochemistry. In human PCa, SDC 1-4 and SDCBP immunostaining showed variable localization. Furthermore, Kaplan-Meier analysis showed that patients expressing SDC3 had shorter prostate-specific survival than those without SDC3 expression (log-rank test, = 0.0047). Analysis of the MSKCC-derived expression showed that and overexpression is predictive of decreased biochemical recurrence-free survival ( = 0.0099 and = 0.045, respectively), and overexpression is predictive of increased biochemical recurrence-free survival ( = 0.035). SDC4 overexpression was associated with a better prognosis, while SDC1 and SDC3 were associated with more aggressive tumors and a worse prognosis.
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http://dx.doi.org/10.3390/ijms22168669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395474PMC
August 2021

Telocytes contribute to aging-related modifications in the prostate.

Sci Rep 2020 12 7;10(1):21392. Epub 2020 Dec 7.

Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Bertrand Russel Av., Campinas, São Paulo, Brazil.

Telocytes are interstitial cells present in the stroma of several organs, including the prostate. There is evidence that these cells are present during prostate alveologenesis, in which these cells play a relevant role, but there is no information about the presence of and possible changes in telocytes during prostate aging. Throughout aging, the prostate undergoes several spontaneous changes in the stroma that are pro-pathogenic. Our study used histochemistry, 3D reconstructions, ultrastructure and immunofluorescence to compare the adult prostate with the senile prostate of the Mongolian gerbil, in order to investigate possible changes in telocytes with senescence and a possible role for these cells in the age-associated alterations. It was found that the layers of perialveolar smooth muscle become thinner as the prostatic alveoli become more dilated during aging, and that telocytes form a network that involves smooth muscle cells, which could possibly indicate a role for telocytes in maintaining the integrity of perialveolar smooth muscles. On the other hand, with senescence, VEGF+ telocytes are seen in stroma possibly contributing to angiogenesis, together with TNFR1+ telocytes, which are associated with a pro-inflammatory microenvironment in the prostate. Together, these data indicate that telocytes are important both in understanding the aging-related changes that are seen in the prostate and also in the search for new therapeutic targets for pathologies whose frequency increases with age.
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http://dx.doi.org/10.1038/s41598-020-78532-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721742PMC
December 2020

Identification of potential molecular pathways involved in prostate carcinogenesis in offspring exposed to maternal malnutrition.

Aging (Albany NY) 2020 10 13;12(20):19954-19978. Epub 2020 Oct 13.

Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil.

The developmental origins of health and disease concept links adult diseases with early-life exposure to inappropriate environmental conditions. Intrauterine and postnatal malnutrition may lead to an increased incidence of type 2 diabetes, obesity, and cardiovascular diseases. Maternal malnutrition (MM) has also been associated with prostate carcinogenesis. However, the molecular mechanisms associated with this condition remain poorly understood. Using a proteomic analysis, we demonstrated that MM changed the levels of proteins associated with growth factors, estrogen signaling, detoxification, and energy metabolism in the prostate of both young and old rats. These animals also showed increased levels of molecular markers of endoplasmic reticulum function and histones. We further performed an analysis that identified commonly deregulated proteins in the ventral prostate of old rats submitted to MM with a mouse model and patients with prostate cancer. In conclusion, our results demonstrated that estrogenic signaling pathways, endoplasmic reticulum functions, energy metabolism, and molecular sensors of protein folding and Ca2+ homeostasis, besides histone, and RAS-GTPase family appear to be involved in this process. Knowledge of these factors may raise discussions regarding the role of maternal dietary intervention as a public policy for the lifelong prevention of chronic diseases.
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http://dx.doi.org/10.18632/aging.104093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655221PMC
October 2020

Xenotransplantation of human dental pulp stem cells in platelet-rich plasma for the treatment of full-thickness articular cartilage defects in a rabbit model.

Exp Ther Med 2019 Jun 17;17(6):4344-4356. Epub 2019 Apr 17.

Department of Genetics, Blood Center, Faculdade de Medicina de Marília (FAMEMA), Marília, SP 17519-050, Brazil.

Stem cells in platelet-rich plasma (PRP) scaffolds may be a promising treatment for cartilage repair. Human dental pulp stem cell (hDPSC) subpopulations have been identified to have substantial angiogenic, neurogenic and regenerative potential when compared with other stem cell sources. The present study evaluated the potential of hDPSCs in a PRP scaffold to regenerate full-thickness cartilage defects in rabbits. Full-thickness articular cartilage defects were created in the patellar groove of the femur of 30 rabbits allocated into three experimental groups: Those with an untreated critical defect (CTL), those treated with PRP (PRP) and those treated with stem cells in a PRP scaffold (PRP+SC). The patellar grooves of the femurs from the experimental groups were evaluated macroscopically and histologically at 6 and 12 weeks post-surgery. The synovial membranes were also collected and evaluated for histopathological analysis. The synovial lining cell layer was enlarged in the CTL group compared with the PRP group at 6 weeks (P=0.037) but not with the PRP+SC group. All groups exhibited low-grade synovitis at 6 weeks and no synovitis at 12 weeks. Notably, macroscopic grades for the area of articular cartilage repair for the PRP+SC group were significantly improved compared with those in the CTL (P=0.001) and PRP (P=0.049) groups at 12 weeks. Furthermore, histological scores (modified O'Driscoll scoring system) of the patellar groove articular cartilage in the PRP+SC and PRP groups, in which the articular cartilage was primarily hyaline-like, were significantly higher compared with those in the CTL group at 12 weeks (P=0.002 and P=0.007, respectively). The present results support the therapeutic use of hDPSCs for the treatment of full-thickness articular cartilage defects.
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http://dx.doi.org/10.3892/etm.2019.7499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507499PMC
June 2019

"Prostate telocytes change their phenotype in response to castration or testosterone replacement".

Sci Rep 2019 03 6;9(1):3761. Epub 2019 Mar 6.

Sao Paulo State University - UNESP, Institute of Biosciences, Laboratory of Extracellular Matrix, Prof. Dr. Antônio Celso Wagner Zanin St., 250, Rubião Júnior District, Botucatu, São Paulo, 18618-689, Brazil.

Telocytes are CD34-positive cells with a fusiform cell body and long, thin cytoplasmic projections called telopodes. These cells were detected in the stroma of various organs, including the prostate. The prostate is a complex gland capable of undergoing involution due to low testosterone levels; and this condition can be reversed with testosterone replacement. Telocyte function in the mature prostate remains to be dermined, and it is not known whether telocytes can take place in tissue remodeling during prostate involution and regrowth. The present study employed structural, ultrastructural and immunohistochemical methods to investigate the telocyte's phenotypes in the ventral prostate (VP) from control (CT), castrated (CS) and testosterone replacement (TR) groups of adult male Wistar rats. Telocytes were found in the subepithelial, perimuscular and interstitical regions around glandular acini. Telocytes from CT animals have condensed chromatin and long and thin telopodes. In CS group, telocytes appeared quiescent and exhibited layers of folded up telopodes. After TR, telocytes presented loose chromatin, abundant rough endoplasmic reticulum and enlarged telopodes, closely associated with bundles of collagen fibrils. We called these cells "telocytes with a synthetic phenotype". As testosterone levels and glandular morphology returned toward to the CT group parameters, after 10 days of TR, these telocytes progressively switched to the normal phenotype. Our results demonstrate that telocytes exhibit phenotypic plasticity upon androgen manipulation and interact with fibroblast and smooth muscle cells to maintain glandular architecture in control animals and during tissue remodeling after hormonal manipulation.
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http://dx.doi.org/10.1038/s41598-019-40465-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403354PMC
March 2019

Development of pipette tip gap closure migration assay (s-ARU method) for studying semi-adherent cell lines.

Cytotechnology 2018 Dec 1;70(6):1685-1695. Epub 2018 Aug 1.

Department of Morphology, Institute of Biosciences of Botucatu, Universidade Estadual Paulista "Júlio de Mesquita Filho" -UNESP, Rua Antonio Celso Wagner Zanin, 250, Botucatu, Sao Paulo, 18618-689, Brazil.

This work presents a pipette tip gap closure migration assay prototype tool (semi-adherent relative upsurge-s-ARU-method) to study cell migration or wound healing in semi-adherent cell lines, such as lymph node carcinoma of the prostate (LNCaP). Basically, it consists of a 6-well cover plate modification, where pipette tips with the filter are shortened and fixed vertically to the inner surface of the cover plate, with their heights adjusted to touch the bottom of the well center. This provides a barrier for the inoculated cells to grow on, creating a cell-free gap. Such a uniform gap formed can be used to study migration assay for both adherent as well as semi-adherent cells. After performing time studies, effective measurement of gap area can be carried out conveniently through image analysis software. Here, the prototype was tested for LNCaP cells, treated with testosterone and flutamide as well as with bacteriophages T4 and M13. A scratch assay using PC3 adherent cells was also performed for comparison. It was observed that s-ARU method is suitable for studying LNCaP cells migration assay, as observed from our results with testosterone, flutamide, and bacteriophages (T4 and M13). Our method is a low-cost handmade prototype, which can be an alternative to the other migration assay protocol(s) for both adherent and semi-adherent cell cultures in oncological research along with other biological research applications.
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http://dx.doi.org/10.1007/s10616-018-0245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269371PMC
December 2018

Basement membrane extract attenuates the more malignant gene expression profile accentuated by fibronectin in prostate cancer cells.

Mol Cell Biochem 2019 Jan 30;451(1-2):131-138. Epub 2018 Jun 30.

Department of Morphology, Institute of Biosciences of Botucatu - Univ Estadual Paulista (Unesp), Botucatu, Sao Paulo, Brazil.

Prostate cancer (PCa) has high mortality rates, with most of the deaths resulting from the development of metastasis. Fibronectin (FN) plays key roles in cell adhesion and affects the migratory behavior of cells. In the tumor microenvironment and also in the blood plasma during metastasis, FN displays increased expression, however its role in prostate cancer remains poorly understood. This study aimed to unveil the specific roles of FN as a soluble component, alone or in combination with a complex basement membrane. To investigate the impact of FN in neoplastic prostate cells, we evaluated the gene expression of LNCaP cells by RT-qPCR after exposure to soluble FN (25 µg/mL) either alone or in combination with a basement membrane. When FN was the predominant matrix element, such as in blood plasma, PCa tumor cells increased their expression of genes related to an invasive behavior and resistance to apoptosis, including CDH2, ITGA5, AKT1, and BCL2. However, the combined presence of FN and a complex basement membrane had the opposite effect on LNCaP cells, in which the expression levels of CDH2, ITGA5, AKT1, and BCL2 were reduced. Hierarchical clustering analysis with LNCaP and RWPE-1 cells showed that LNCaP cells exposed to an enriched extracellular matrix displayed an expression pattern more similar to that shown by RWPE-1 cells, a cell line that illustrates characteristics of the normal prostate epithelium. These findings provide the groundwork for future studies addressing the role of FN in tumor growth, particularly in the context of cancer evolution/progression from a solid primary tumor to a transitory circulating state.
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http://dx.doi.org/10.1007/s11010-018-3399-4DOI Listing
January 2019

Immunohistochemical panel to characterize canine prostate carcinomas according to aberrant p63 expression.

PLoS One 2018 12;13(6):e0199173. Epub 2018 Jun 12.

Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, SP, Brazil.

An unusual variant of prostate adenocarcinoma (PC) expressing nuclear p63 in secretory cells instead of the typical basal expression has been reported in men. Nevertheless, the biological behavior and clinical significance of this phenomenon is unknown. In dogs, this unusual PC subtype has not been described. In this study, p63 immunoexpression was investigated in 90 canine PCs and 20 normal prostate tissues (NT). The p63 expression pattern in luminal or basal cells was confirmed in a selected group of 26 PCs and 20 NT by immunohistochemistry and/or Western blotting assays. Eleven canine PC samples aberrantly expressing p63 (p63+) in secretory cells were compared with 15 p63 negative (p63-) cases in the context of several molecular markers (high molecular weight cytokeratin-HMWC, CK8/18, CK5, AR, PSA, chromogranin, NKX3.1, PTEN, AKT and C-MYC). P63+ samples were positive for CK5, HMWC and CK8/18 and negative for PSA, NKX3.1, PTEN and chromogranin. Five p63+ PCs were negative for AR, and the remaining six samples had low AR expression. In contrast, p63- PC showed AR and PSA positive expression in all 15 samples. Only five p63- PCs were positive for CK5. Both p63+ and p63- PC samples showed higher cytoplasmic AKT expression and nuclear C-MYC staining in comparison with normal tissues. Metastatic (N = 12) and non-metastatic (N = 14) PCs showed similar immunoexpression for all markers tested. In contrast to human PC, canine PC aberrantly expressing p63 showed higher expression levels of HMWC and CK5 and lower levels of NKX3.1. Canine p63+ PC is a very rare PC group showing a distinct phenotype compared to typical canine PC, including AR and PSA negative expression. Although in a limited number of cases, p63 expression was not associated with metastasis in canine PC, and cytoplasmic p63 expression was observed in animals with shorter survival time, similar to human PC cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997330PMC
January 2019

Bisphenol a and mesenchymal stem cells: Recent insights.

Life Sci 2018 08 18;206:22-28. Epub 2018 May 18.

Department of Morphology, Institute of Biosciences, Univ Estadual Paulista - UNESP, Botucatu, Sao Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2018.05.023DOI Listing
August 2018

Hyperglycemic condition during puberty increases collagen fibers deposition in the prostatic stroma and reduces MMP-2 activity.

Biochem Biophys Res Commun 2017 12 6;493(4):1581-1586. Epub 2017 Oct 6.

Department of Morphology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil. Electronic address:

Puberty is an important period for the growth and maturation of the male reproductive system, and is also a critical window for endocrine or environmental interference. The physiological levels of circulating insulin and hyperglycemic control are important factors for a normal prostate growth. Hyperglycemia during puberty is reported to retard the growth of the prostate gland, with remarkable effects on the epithelial compartment. Here, we investigated the impact of hyperglycemia along with a simultaneous or late insulin replacement on the ventral prostate growth in rats during puberty, paying special attention to the deposition of collagen fibers and activities of gelatinase, matrix metalloproteinase-2 (MMP-2), and -9 (MMP-9). Hyperglycemia was induced by streptozotocin (STZ) administration in 40-day-old male Wistar rats. A subset of hyperglycemic rats underwent an early insulin replacement (three days after the STZ administration), and another subset underwent a late insulin replacement (twenty days after the STZ administration). Animals were euthanized at 60 and/or 80 days of age. The ventral prostatic lobe was processed for picrosirius red staining, type I and III collagen immunohistochemistry, and gelatin zymography. Hyperglycemic animals showed an increased area of collagen fibers in the prostate, which was composed both types of collagens. MMP-2 activity was significantly reduced in the hyperglycemic animals, while MMP-9 activity was very low and showed no alteration. The simultaneous and late insulin administration restored collagen content and MMP-2 activity. In conclusion, puberty is a critical window for prostate maturation and type-1 diabetes-induced hyperglycemia affects the ratio of the prostatic parenchymal and stromal growth, leading to fibrotic tissues by also MMP-2 down regulation.
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http://dx.doi.org/10.1016/j.bbrc.2017.10.022DOI Listing
December 2017

Prostate epithelium basement membrane and prostate cell biology: 20 years.

Cell Biol Int 2017 11 17;41(11):1170-1173. Epub 2017 Sep 17.

Department of Histology, Embryology, and Cell Biology, Institute of Biological Sciences, Federal University of Goiás, Goiania, GO, Brazil.

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http://dx.doi.org/10.1002/cbin.10831DOI Listing
November 2017

Enhanced immunization techniques to obtain highly specific monoclonal antibodies.

MAbs 2018 01 6;10(1):46-54. Epub 2017 Oct 6.

a Universidade Estadual Paulista (Unesp), Faculdade de Ciências Farmacêuticas, Araraquara, Proteomics Center, Monoclonal Antibody Lab. , Araraquara , Brazil.

Despite fast advances in genomics and proteomics, monoclonal antibodies (mAbs) are still a valuable tool for areas such as the evolution of basic research in stem cells and cancer, for immunophenotyping cell populations, diagnosing and prognosis of diseases, and for immunotherapy. To summarize different subtractive immunization approaches successfully used for the production of highly specific antibodies, we identified scientific articles in NCBI PubMed using the following search terms: subtractive immunization, monoclonal antibody, tolerization, neonatal, high-zone tolerance, masking immunization. Patent records were also consulted. From the list of results, we included all available reports, from 1985 to present, that used any enhanced immunization technique to produce either polyclonal or monoclonal antibodies. Our examination yielded direct evidence that these enhanced immunization techniques are efficient in obtaining specific antibodies to rare epitopes, with different applications, such as to identify food contaminants or tumor cells.
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http://dx.doi.org/10.1080/19420862.2017.1331804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800380PMC
January 2018

Fibrillar collagen genes are not coordinately upregulated with TGF β1 expression in finasteride-treated prostate.

Cell Biol Int 2017 Nov 31;41(11):1214-1222. Epub 2017 May 31.

Department of Morphology, Institute of Biosciences-Sao Paulo State University (Unesp), Botucatu, Sao Paulo, Brazil.

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in older men. In this regard, recent studies have attempted to define the relationships between prostatic fibrosis, LUTS, and increased expression of transforming growth factor β1 (TGF β1) in BHP. Therapeutic approaches for BPH such as 5-α-reductase inhibitors and alpha-adrenergic blocking agents increase TGF β1 expression in the prostatic tissue. Here, we investigated the effects of the 5-α-reductase inhibitor-finasteride-on rat ventral prostate tissue, especially with regard to the tissue distribution and gene expression of fibrillar collagens. Adult Wistar rats (n = 15) were treated with finasteride (25 mg/kg/day) by subcutaneous injection for 7 and 30 days. Age-matched, vehicle-treated (n = 15) adult Wistar rats were used as control. Finasteride treatment reduced prostate size and increased the area of types I and III collagen fibers in the prostatic stroma. As expected, TGF β1 mRNA expression was upregulated by finasteride treatment. However, COL1A1 and COL3A1 mRNA expressions decreased after both 7 and 30 days of finasteride treatment, suggesting that finasteride treatment promotes prostate parenchyma and stroma changes, which lead to the observed types I and III collagen remodeling without de novo collagen synthesis. The upregulation of TGF β1 mRNA and protein associated with the 5-α-reductase inhibitor is more closely related to epithelial and stromal cell death pathways than to prostatic fibrosis.
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http://dx.doi.org/10.1002/cbin.10787DOI Listing
November 2017

MMP-2 and MMP-9 activities and TIMP-1 and TIMP-2 expression in the prostatic tissue of two ethanol-preferring rat models.

Anal Cell Pathol (Amst) 2015 15;2015:954548. Epub 2015 Jul 15.

Department of Anatomy, Institute of Biosciences, Universidade Estadual Paulista (UNESP), 18618-970 Botucatu, SP, Brazil.

We investigated whether chronic ethanol intake is capable of altering the MMP-2 and MMP-9 activities and TIMP-2 and TIMP-1 expression in the dorsal and lateral prostatic lobes of low (UChA) and high (UChB) ethanol-preferring rats. MMP-2 and MMP-9 activities and TIMP-1 and TIMP-2 expression were significantly reduced in the lateral prostatic lobe of the ethanol drinking animals. Dorsal prostatic lobe was less affected showing no significant alterations in these proteins, except for a reduction in the TIMP-1 expression in UChA rats. These important findings demonstrate that chronic ethanol intake impairs the physiological balance of the prostate extracellular matrix turnover, through downregulation of MMPs, which may contribute to the development of prostatic diseases. Furthermore, since these proteins are also components of prostate secretion, the negative impact of chronic ethanol intake on fertility may also involve reduction of MMPs and TIMPs in the seminal fluid.
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http://dx.doi.org/10.1155/2015/954548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518171PMC
March 2016

The Anti-Inflammatory Effects of the Methanolic Extract and Fractions from Davilla elliptica St. Hil. (Dilleniaceae) on Bothrops jararaca Envenomation.

Int J Mol Sci 2015 Jun 2;16(6):12454-66. Epub 2015 Jun 2.

Departamento de Fisiologia, Instituto de Biociências, Universidade Estadual Paulista-UNESP, CEP 18618-970 Botucatu, São Paulo, Brazil.

Inflammation and haemorrhage are the main characteristics of tissue injury in botropic envenomation. Although some studies have shown that anti-venom prevents systemic reactions, it is not efficient in preventing tissue injury at the site of the bite. Therefore, this work was undertaken to investigate the anti-inflammatory effects of the methanolic extract and fractions from D. elliptica and to evaluate the role of matrix metalloproteinases (MMPs) in this process. Effects of the extract and fractions from D. elliptica were evaluated using a carrageenan-induced paw oedema model in rats, and leukocyte rolling was visualized by intravital. The quantification of MMPs activities (MMP-2 and MMP-9) extracted from the dermis of mice treated with extract and fractions alone or incubated with venom was determined by zymographic analyses. Our results show that intraperitoneal (i.p.) injection of fractions significantly reduced paw oedema after the carrageenan challenge. Treatment with the tannins fraction also resulted in considerable inhibition of the rolling of leukocytes and this fraction was able to decrease the activation of MMP-9. These results confirmed the anti-inflammatory activity of the methanolic extract and tannins fraction of D. elliptica and showed that the dermonecrosis properties of B. jararaca venom might be mediated through the inhibition of MMP-9 activity.
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http://dx.doi.org/10.3390/ijms160612454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490454PMC
June 2015

Ethanol modulates the synthesis and catabolism of retinoic acid in the rat prostate.

Reprod Toxicol 2015 Jun 25;53:1-9. Epub 2015 Feb 25.

Department of Anatomy, Institute of Biosciences, UNESP-Univ Estadual Paulista, Botucatu, SP, Brazil.

All-trans retinoic acid (atRA) maintains physiological stability of the prostate, and we reported that ethanol intake increases atRA in the rat prostate; however the mechanisms underlying these changes are unknown. We evaluated the impact of a low- and high-dose ethanol intake (UChA and UChB strains) on atRA metabolism in the dorsal and lateral prostate. Aldehyde dehydrogenase (ALDH) subtype 1A3 was increased in the dorsal prostate of UChA animals while ALDH1A1 and ALDH1A2 decreased in the lateral prostate. In UChB animals, ALDH1A1, ALDH1A2, and ALDH1A3 increased in the dorsal prostate, and ALDH1A3 decreased in the lateral prostate. atRA levels increased with the low activity of CYP2E1 and decreased with high CYP26 activity in the UChB dorsal prostate. Conversely, atRA was found to decrease when the activity of total CYP was increased in the UChA lateral prostate. Ethanol modulates the synthesis and catabolism of atRA in the prostate in a concentration-dependent manner.
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http://dx.doi.org/10.1016/j.reprotox.2015.02.010DOI Listing
June 2015

Terminalia catappa L.: a medicinal plant from the Caribbean pharmacopeia with anti-Helicobacter pylori and antiulcer action in experimental rodent models.

J Ethnopharmacol 2015 Jan 24;159:285-95. Epub 2014 Nov 24.

Univ. Estadual Paulista-UNESP - Departamento de Fisiologia, Instituto de Biociências, CEP 18618-970 Botucatu, SP, Brazil. Electronic address:

Ethnopharmacological Relevance: Terminalia catappa L. (Combretaceae) is a medicinal plant listed as a pharmacopeia vegetable from Caribbean to treat gastritis. The objective of this study was to evaluate the gastroprotective and healing effect of the aqueous fraction (FrAq) obtained from the leaves of Terminalia catappa and to determine the antiulcer mechanism of action in experimental rodent models and its activity to Helicobacter pylori.

Material And Methods: In rodents, the FrAq was challenged by different necrotizing agents, such as absolute ethanol and ischemia-reperfusion injury. The antiulcer mechanism of action of FrAq was assessed and the healing effects of the fraction after seven and 14 days of treatment was evaluated by matrix metalloproteinase activity (MMP-2 and MMP-9). The toxicological effect of subacute treatment with FrAq during 14 days of treatment was also analyzed. The anti-Helicobacter pylori activity was determined by microdilution. The phytochemical study of the fraction was analyzed by experiments with FIA-ESI-IT-MS(n) (Direct Flow Analysis-ionization Electrospray Ion Trap Tandem Mass Spectrometry) and high performance liquid chromatography (HPLC) coupled to a photodiode array (PDA).

Results: Oral treatment with FrAq (25mg/kg) significantly decreased the number of ulcerative lesions induced by ethanol and ischemia/reperfusion injury. The action of FrAq was mediated by the activation of defensive mucosa-protective factors, such as increases in mucus production, the nitric oxide (NO) pathway and endogenous prostaglandins. Oral treatment with FrAq for seven and 14 days significantly reduced the lesion area (80% and 37%, respectively) compared to the negative control group. Analyses of MMP-9 and MMP-2 activity from gastric mucosa confirmed the accelerated gastric healing effect of FrAq. This extract also presented considerable activity against Helicobacter pylori. The mass spectrum and MS/MS of the aqueous fraction indicates the existence of many different phenolic compounds, including punicalagin, punicalin, and gallagic acid, among others.

Conclusions: We concluded that FrAq from Terminalia catappa leaves has excellent preventive and curative effects on acute and chronic induced gastric ulcers and showed an important profile against Helicobacter pylori.
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http://dx.doi.org/10.1016/j.jep.2014.11.025DOI Listing
January 2015

Cytoxicity and apoptotic mechanism of ruthenium(II) amino acid complexes in sarcoma-180 tumor cells.

PLoS One 2014 17;9(10):e105865. Epub 2014 Oct 17.

Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, University Federal of Goiás-UFG, Goiânia, Goiás, Brazil.

Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201456PMC
July 2015

Light-emitting diode effects on combined decellularization of tracheae. A novel approach to obtain biological scaffolds.

Acta Cir Bras 2014 Aug;29(8):485-92

Department of Urology, Medical School, UNESP, Botucatu, SP, Brazil.

Purpose: To obtain a decellularized tracheal scaffold associating traditional approaches with the novel light-emitting diode (LED) proposal.

Methods: This study was performed with New Zealand adult rabbits weighing 3.0 - 4.0 kg. Different protocols (22) were used combining physical (agitation and LED irradiation), chemical (SDS and Triton X-100 detergents), and enzymatic methods (DNase and RNase).

Results: Generally, the cells surrounding soft tissues were successfully removed, but none protocol removed cells from the tracheal cartilage. However, longer protocols were more effective. The cost-benefits relation of the enzymatic processes was not favorable. It was possible to find out that the cartilaginous tissue submitted to the irradiation with LED 630nm and 475 nm showed an increased number of gaps without cells, but several cells were observed to be still present.

Conclusion: The light-emitting diode is a promising tool for decellularization of soft tissues.
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http://dx.doi.org/10.1590/s0102-86502014000800002DOI Listing
August 2014

[Changes in the extracellular matrix due to diabetes and their impact on urinary continence].

Rev Bras Ginecol Obstet 2014 Jul;36(7):328-33

Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Julio de Mesquita Filho, Botucatu, SP, Brasil.

The prevalence of urinary incontinence in diabetic pregnant women is significantly high two years after cesarean section. Incontinence can be the most common consequence of hyperglycemia compared to other complications. Thus, identifying the risk factors for the development of urinary incontinence in diabetes is the major aim in the prevention of this very common condition. Recent surveys have shown that not only muscle but also the urethral extracellular matrix play an important role in the mechanism of urinary continence. Translational work on rats by our research group showed that diabetes during pregnancy damages the extracellular matrix and urethral striated muscle, a fact that may explain the high prevalence of urinary incontinence and pelvic floor dysfunction in women with gestational diabetes mellitus. Diabetes affects the expression, organization and change in extracellular matrix components in different organs, and tissue remodeling and fibrosis appear to be a direct consequence of it. Therefore, understanding the impact of modifiable risk factors, such as diabetes, which involves using preventive strategies, can reduce the rates of urinary incontinence and the health care costs, and improve the quality of life of women, especially during pregnancy and postpartum.
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http://dx.doi.org/10.1590/so100-720320140005014DOI Listing
July 2014

Indole-3-carbinol attenuates the deleterious gestational effects of bisphenol A exposure on the prostate gland of male F1 rats.

Reprod Toxicol 2014 Jan 17;43:56-66. Epub 2013 Nov 17.

Department of Morphology, Institute of Biosciences, Sao Paulo State University - UNESP, Botucatu, SP 18618-970, Brazil. Electronic address:

Bisphenol A (BPA) is a chemical that has been investigated for it potential to cause prostate diseases. In this study, pregnant Sprague-Dawley rats were treated with 25 or 250 μg/kg BPA from gestational day (GD) 10 to GD21 with or without concurrent indole-3-carbinol (I3C) feeding. I3C is a phytochemical, and it affords chemoprotection against many types of neoplasia. Male F1 rats from different litters were euthanized on post-natal day (PND) 21 and PND180. BPA-treated groups showed a significant increase in histopathological lesions, but I3C feeding reversed many of these changes, mainly at PND180. Maternal I3C feeding increased prostate epithelial apoptosis in the BPA-treated groups and across age groups. Furthermore, I3C induced partial normalization of the prostate histoarchitecture. The results pointed to a protective effect of maternal I3C feeding during pregnancy in the BPA-exposed male offspring, thereby indicating reduction in the harmful effects of gestational BPA imprinting on the prostate.
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http://dx.doi.org/10.1016/j.reprotox.2013.11.001DOI Listing
January 2014

Time-course morphological and functional disorders of the kidney induced by long-term high-fat diet intake in female rats.

Nephrol Dial Transplant 2013 Oct;28(10):2464-76

Renal Function Laboratory, Campinas State University, UNICAMP, Campinas, São Paulo, Brazil.

Background: Evidence is emerging that highlights the far-reaching consequences of a high-fat diet (HFD) on kidney morphology and function disorders.

Methods: The present study was performed on 3-, 5-, 7- and 9-week-old HFD female rats compared with the appropriate gender and age-matched animals. We evaluated the kidney expression of angiotensin type II receptor and fibrotic and epithelial-to-mesenchymal transition (EMT) markers, by immunoblotting and immunohistochemical and histological techniques, in parallel with kidney function.

Results: In the current study, the time-course HFD-treated group showed, by immunoblotting and immunohistochemical analysis, an early time-course increase in the expression of transforming growth factor β-1 (TGFβ-1) in the entire kidney of HFD-treated rats, compared with that observed in the control group. Simultaneously, the study shows a transient increase in the expression of ZEB2 in the HFD whole kidney accompanied by a fall in the E-cadherin expression and increased collagen and fibronectin deposition. A pronounced decrease in fractional urinary sodium excretion was also demonstrated in the long-term HFD-treated rats. The decreased FENa(+) was accompanied by a fall in FEPNa(+) and FEPPNa(+), which occurred in association with significantly decreased CCr and, certainly on the sodium-filtered load. The reduction in the glomerular filtration rate (GFR) occurred in parallel to proteinuria and glomerular desmin overexpression.

Conclusions: The results of the current study suggest that podocyte injury in parallel with observed proteinuria and evidence of EMT transformation are associated with long-term loss of kidney function and renal sodium and water retention.
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http://dx.doi.org/10.1093/ndt/gft304DOI Listing
October 2013

Urethral striated muscle and extracellular matrix morphological characteristics among mildly diabetic pregnant rats: translational approach.

Int Urogynecol J 2014 Mar 17;25(3):403-15. Epub 2013 Sep 17.

Laboratory of Experimental Research on Gynecology and Obstetrics, Department of Gynecology and Obstetrics, Botucatu Medical School, Universidade Estadual Paulista-UNESP, Botucatu, São Paulo, Brazil.

Introduction And Hypothesis: Diabetes mellitus (DM) during pregnancy is associated with high levels of urinary incontinence (UI) and pelvic floor muscle dysfunction. Mild DM can lead to changes in urethral striated muscle and extracellular matrix (ECM) in pregnant rats considering both structures as an entire system responsible for urinary continence.

Methods: Ninety-two female Wistar rats were distributed in four experimental groups: virgin, pregnant, diabetic, and diabetic pregnant. In adult life, parental nondiabetic female rats were mated with nondiabetic male rats to obtain newborns. At the first day of birth, newborns received citrate buffer (nondiabetic group) or streptozotocin 100 mg/kg body weight, subcutaneous route (mild DM group). At day 21 of the pregnancy, the rats were lethally anesthetized and the urethra and vagina were extracted as a unit. Urethral and vaginal sections were cut and analyzed by: (a) cytochemical staining for ECM and muscle structural components, (b) immunohistochemistry to identify fast- and slow-muscle fibers, and (c) transmission electron microscopy for ultrastructural analysis of urethral striated muscle.

Results: In comparison with the three control groups, variations in the urethral striated muscle and ECM from diabetic pregnant rats were observed including thinning, atrophy, fibrosis, increased area of blood vessels, mitochondria accumulation, increased lipid droplets, glycogen granules associated with colocalization of fast and slow fibers, and a steady decrease in the proportion of fast to slow fibers.

Conclusions: Mild DM and pregnancy can lead to a time-dependent disorder and tissue remodeling in which the urethral striated muscle and ECM has a fundamental function.
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http://dx.doi.org/10.1007/s00192-013-2218-4DOI Listing
March 2014

Platelet lysate 3D scaffold supports mesenchymal stem cell chondrogenesis: an improved approach in cartilage tissue engineering.

Platelets 2013 30;24(3):219-25. Epub 2012 May 30.

Extracellular Matrix Laboratory, Department of Morphology, Institute of Biosciences, Universidade Estadual Paulista-UNESP, District of Rubião Júnior S/N, 18618-970, Botucatu, SP, Brazil.

Articular lesions are still a major challenge in orthopedics because of cartilage's poor healing properties. A major improvement in therapeutics was the development of autologous chondrocytes implantation (ACI), a biotechnology-derived technique that delivers healthy autologous chondrocytes after in vitro expansion. To obtain cartilage-like tissue, 3D scaffolds are essential to maintain chondrocyte differentiated status. Currently, bioactive 3D scaffolds are promising as they can deliver growth factors, cytokines, and hormones to the cells, giving them a boost to attach, proliferate, induce protein synthesis, and differentiate. Using mesenchymal stem cells (MSCs) differentiated into chondrocytes, one can avoid cartilage harvesting. Thus, we investigated the potential use of a platelet-lysate-based 3D bioactive scaffold to support chondrogenic differentiation and maintenance of MSCs. The MSCs from adult rabbit bone marrow (n = 5) were cultivated and characterized using three antibodies by flow cytometry. MSCs (1 × 10(5)) were than encapsulated inside 60 µl of a rabbit platelet-lysate clot scaffold and maintained in Dulbecco's Modified Eagle Medium Nutrient Mixture F-12 supplemented with chondrogenic inductors. After 21 days, the MSCs-seeded scaffolds were processed for histological analysis and stained with toluidine blue. This scaffold was able to maintain round-shaped cells, typical chondrocyte metachromatic extracellular matrix deposition, and isogenous group formation. Cells accumulated inside lacunae and cytoplasm lipid droplets were other observed typical chondrocyte features. In conclusion, the usage of a platelet-lysate bioactive scaffold, associated with a suitable chondrogenic culture medium, supports MSCs chondrogenesis. As such, it offers an alternative tool for cartilage engineering research and ACI.
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http://dx.doi.org/10.3109/09537104.2012.686255DOI Listing
September 2013

Lobe variation effects of experimental diabetes and insulin replacement on rat prostate.

Microsc Res Tech 2011 Nov 20;74(11):1040-8. Epub 2011 Apr 20.

Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

We investigated the impact of diabetes with simultaneous and late insulin replacement on rat prostate growth during puberty, paying special attention to different prostatic lobes. Diabetes was induced by administration of streptozotocin (STZ) in 40-day-old male Wistar rats. A subset of diabetic rats underwent simultaneous insulin replacement (3 days after STZ administration), and another subset underwent a late insulin replacement (20 days after STZ administration). The ventral, dorsolateral, and anterior prostatic lobes were weighed and processed for histological, immunohistochemical, and morphometric analyses. Both diabetic and insulin-treated animals maintained low plasma testosterone (T) concentrations, whereas dihydrotestostenore (DHT) levels were normal. Diabetic animals had a decreased gain in absolute prostatic weight when compared to age-matched controls and insulin replacement animals. However, prostatic lobe weight in the diabetic animals was ∼100% higher, even at the beginning of the experiment. Among the lobes, the anterior lobe showed the highest weight gain in diabetic and insulin replacement conditions. Epithelial cell proliferation in all lobes was significantly reduced in diabetic animals and significantly increased in insulin replacement animals, although apoptosis was unaltered. In conclusion, diabetes diminishes, but does not abolish, prostate growth during puberty. Even late insulin administration reduces the adverse effects of this disease on the prostate. In a scenario with both low insulin and T levels, DHT and other factors may play an important role in pubertal prostate growth. The adverse effects of diabetes on the rat prostate show a variation in lobe response, suggesting that diabetes may affect human prostate zones differently.
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http://dx.doi.org/10.1002/jemt.20991DOI Listing
November 2011

Doxazosin treatment alters stromal cell behavior and increases elastic system fibers deposition in rat prostate.

Microsc Res Tech 2010 Oct;73(11):1036-44

Department of Cell Biology, Institute of Biology, UNICAMP-University of Campinas, Campinas, Sao Paulo, Brazil.

Doxazosin (DOX), an α-adrenoceptor antagonist, induces the relaxation of smooth muscle cell tonus and reduces the clinical symptoms of benign prostatic hyperplasia (BPH). However, the effects of DOX in the prostate stromal microenvironment are not fully known. In a previous study, we showed that DOX treatment for 30 days increased deposition of collagen fibers in the three rat prostatic lobes. Herein, we investigated the effects of DOX on stromal cell ultrastructure and elastic fiber deposition. Adult Wistar rats were treated with DOX (25 mg/kg/day); and the ventral, dorsal, and anterior prostates were excised at 30 days of treatment. The prostatic lobes were submitted to histochemical and stereological-morphometric analyze and transmission electron microscopy (TEM). Histochemical staining plus stereological analysis of the elastic fiber system showed that DOX-treated prostatic lobes presented more elaunin and elastic fibers than controls, mainly in the ventral lobe. Ultrastructural analysis showed that fibroblasts and smooth muscle cells from DOX-treated prostates presented active synthetic phenotypes, evidenced by enlarged rough endoplasmic reticulum and Golgi apparatus cisterns, and confirmed the observation of thickened elaunin fibers. Our findings suggest that, under α-adrenergic blockade by DOX, the fibroblasts become more active and smooth muscle cells shift from a predominantly contractile to a more synthetic phenotype. The deposition of collagen and elastic system fibers in the prostatic stroma may counterbalance the absence of smooth muscle tone during α-blockers treatment.
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http://dx.doi.org/10.1002/jemt.20828DOI Listing
October 2010

Calcaneal tendon regions exhibit different MMP-2 activation after vertical jumping and treadmill running.

Anat Rec (Hoboken) 2009 Oct;292(10):1656-62

São Paulo State University (UNESP), School of Science and Technology, Department of Physical Education, Presidente Prudente, SP, Brazil.

Increased activity of matrix metalloproteinases (MMPs) -2 and -9 was found in calcaneal tendon after physical training. However, little attention has been given to the distinct biomechanical and tissue structure of the calcaneal tendon's proximal and distal regions. Herein, we evaluated the effect of two types of physical activities on tendon morphology and matrix metalloproteinase activities in the proximal and distal regions of rat calcaneal tendon, separately. Adult male Wistar rats from control, water-adapted, vertical-jumping, and treadmill-running groups were sacrificed after 1 or 4 days of physical exercise, 6 hr after the end of that day's exercise session. Tendons were processed for histology, morphometry, and gelatin zymography. Tendons from adapted and trained animals showed active secretory cells and increased thickness, cellularity, and blood vessel volume fraction of peritendinous sheath, but without inflammatory process. In the proximal region, both pro- and active MMP-2 were increased after vertical jumping, but only pro-MMP-2 was increased after treadmill running. In contrast, in the distal region, both exercise types increased the activity of pro- and active MMP-2, especially treadmill running, which increased the active MMP-2 by about 11- and eightfold, respectively, after 1 and 4 days of training. No activity of MMP-9 was observed in either tendon region in this study. In conclusion, distal and proximal regions of calcaneal tendon exhibit differential intensities of tissue remodeling after treadmill running or vertical jumping and MMP-2, in the absence of inflammation, plays a major role in this adaptive response.
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http://dx.doi.org/10.1002/ar.20953DOI Listing
October 2009

Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: proliferative and inflammatory disorders and a possible role of androgens.

Toxicology 2009 Aug 21;262(3):215-23. Epub 2009 Jun 21.

Department of Morphology, Institute of Biosciences, UNESP, Botucatu, SP, 18618-000, Brazil.

In the present study we evaluated the toxic effects on the male adult rat prostate of DBP exposure during fetal and lactational periods, because although many studies have addressed the influence of phthalates on the male reproductive system, only a few have discussed their possible effects on prostate development. Pregnant females were distributed into two experimental groups: Control (C) and Treated (T). The females of the T group received DBP (100mg/kg, by gavage) from gestation day 12 to postnatal day 21, while C rats received the vehicle (corn oil). In adulthood (90 days old), the animals were euthanized. The serum and testicular testosterone levels were measured. Ventral prostate was removed and weighed. Distal segment fragments of the ventral prostate were fixed and processed for histochemistry and immunohistochemistry to detect androgen receptor (AR) and Ki67 antigens. Protein extraction from ventral prostate fragments was performed for AR immunoblotting and Gelatin zymography for MMP-2 and MMP-9 (MMP, metalloproteinase). Stereological and histopathological analyses were also performed. Serum and testicular testosterone levels and prostate weight were comparable between groups. In the T group the relative proportions (%) of epithelial (C=32.86; T=42.04*) and stromal (C=21.61; T=27.88*) compartments were increased, while the luminal compartment was decreased (C=45.54; T=30.08*), *p<0.05. InT, disseminated inflammatory infiltrate in the stroma, associated or not with epithelial dysplasia and PIN (Prostatic Intraepithelial Neoplasia), was observed. Increases in AR expression, proliferation index and metalloproteinase 9 (MMP-9) activity were noted in T animals. In some T animals, collagen fibrils accumulated adjacent to the epithelium. As far as we are aware, this is the first report in the literature showing that phthalates could play a role in proliferative and inflammatory disorders of the rat prostate.
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http://dx.doi.org/10.1016/j.tox.2009.06.011DOI Listing
August 2009
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