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Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant‐induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) or fibrogenic parameters (collagen, TGF‐β, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7‐day‐old implants. However, AM was able to downregulate angiogenesis and FBR in 14‐day‐old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Peritoneal injury can result in a persistent fibroproliferative process in the abdominal cavity, causing pain and loss of function of internal organs. This study aimed to demonstrate the use of sodium butyrate (NaBu) as a potential agent to attenuate peritoneal fibrosis induced by a synthetic matrix.What is the main finding and its importance?Our findings provide the first evidence that NaBu attenuates the inflammatory, angiogenesis and fibrogenesis axes involved in the formation of peritoneal fibrovascular tissue, indicating the potential of this compound to ameliorate peritoneal fibrosis. The aim of this study was to identify the bio‐efficacy of sodium butyrate (NaBu) on preventing the development of peritoneal fibrovascular tissue induced by implantation of a synthetic matrix in the abdominal cavity. Polyether–polyurethane sponge discs were implanted in the peritoneal cavity of mice, which were treated daily with oral administration of NaBu (100 mg/kg). Control animals received water (100 μl). After 7 days, the implants were removed for assessment of inflammatory, angiogenic and fibrogenic markers. Compared with control values, NaBu treatment decreased mast cell recruitment/activation, inflammatory enzyme activities, levels of pro‐inflammatory cytokines, and the proteins p65 and p50 of the nuclear factor‐κB pathway. Angiogenesis, as determined by haemoglobin content, vascular endothelial growth factor levels and the number of blood vessels in the implant, was reduced by the treatment. In NaBu‐treated animals, the predominant collagen present in the abdominal fibrovascular tissue was thin collagen, whereas in control implants it was thick collagen. Transforming growth factor‐β1 levels were also lower in implants of treated animals. Sodium butyrate downregulated the inflammatory, angiogenesis and fibrogenesis axes of the fibroproliferative tissue induced by the intraperitoneal synthetic matrix. This compound has potential to control/regulate chronic inflammation and adverse healing processes in the abdominal cavity. [ABSTRACT FROM AUTHOR]

Thiamine is an important cofactor of metabolic enzymes, and its deficiency leads to cardiovascular dysfunction. First, we characterized the metabolic status measuring resting oxygen consumption rate and lactate blood concentration after 35 days of thiamine deficiency (TD). The results pointed to a decrease in resting oxygen consumption and a twofold increase in blood lactate. Confocal microscopy showed that intracellular superoxide (~40%) and [H.sub.2][O.sub.2] (2.5 times) contents had been increased. In addition, biochemical activities and protein expression of SOD, glutathione peroxidase, and catalase were evaluated in hearts isolated from rats submitted to thiamine deprivation. No difference in SOD activity was detected, but protein levels were found to be increased. Catalase activity increased 2.1 times in TD hearts. The observed gain in activity was attended by an increased catalase protein level. However, a marked decrease in glutathione peroxidase activity (control 435.3 [+ or -] 28.6 vs. TD 199.4 [+ or -] 30.2 nmol NADPH x [min.sup.-1] x [ml.sup.-l]) was paralleled by a diminution in the protein levels. Compared with control hearts, we did observe a greater proportion of apoptotic myocytes by TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 reactivity techniques. These results indicate that during TD, reactive oxygen species (ROS) production may be enhanced as a consequence of the installed acidosis. The perturbation in the cardiac myocytes redox balance was responsible for the increase in apoptosis. catalase; glutathione peroxidase; superoxide dismutase doi: 10.1152/ajpheart.00820.2009.

Objective: To assess the predictive abilities of serum and urinary cystatin C levels for glomerular lesions in pregnant women with pre-eclampsia.Methods: In this study, kidney function markers were compared between38 pregnant women with pre-eclampsia and 22 healthy pregnant women.Results: The serum and urine levels of cystatin C and urea were significantly higher in the pre-eclampsia group than in the control group. Receiver operating characteristic curve analysis demonstrated that the serum cystatin C level (91.7%) had a superior diagnostic accuracy for pre-eclampsia than the other markers.Conclusion: Serum cystatin C level maybe a significant marker of pre-eclampsia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Obesity is a highly prevalent multifactorial metabolic condition in which the need for functional bioengineered substitutes (e.g., scaffolds for tissue engineering) is likely to occur. However, the adverse foreign body response (FBR) that invariably takes place adjacent to implant devices impairing their function is poorly characterized in this condition. This study investigated the influence of obesity on the host response to a synthetic matrix implanted subcutaneously in high-fat-fed obese mice.Methods: Histological analysis of 14-day-old implants was performed to identify collagen deposition, capsule thickness, fibroblast-like cells, foreign body giant cells, and mast cells. In addition, transforming growth factor β1 (TGF-β1) levels in the implants and serum were determined.Results: All fibrogenic markers (and TGF-β1 levels) increased in the implants of obese mice compared with their nonobese counterparts. Particularly relevant was the fibrous capsule thickness in implants of obese mice (234.2 ± 22.1 µm vs. 109.2 ± 13.4 µm in implants of nonobese animals).Conclusions: The study results showing that obesity upregulates the main features of the FBR induced by subcutaneous implants in mice may be relevant in understanding biomaterial integration and performance in this condition. This is crucial to the development of strategies to maintain the integrity and function of implantable devices. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Arrabidaea chica (Bignoniacea) has been used in popular medicine in Brazil to treat inflammation, skin diseases and leukemia. This work aimed to investigate the anti-inflammatory and antitumoral activities of the A. chica aqueous (AE) and ethanol (EE) extracts. Materials and methods The murine sponge model was used to evaluate the anti-inflammatory and antiangiogenic activities of AE and EE. Accumulation of neutrophil and macrophage in the implants were determined by assaying myeloperoxidase and N-acetyl-glucosaminidase activities and the neovascularization evaluated by the amount of hemoglobin present in the implant using the Drabkin method. The antitumoral activity was evaluated using the MTT colorimetric method against Jurkat, HL60 and MCF-7 cells. Semi-purified fractions F1-F4 from the EE extract were obtained by a liquid–liquid solvent extraction method and their in vitro anti-proliferative effects were also investigated. Results Ethanol and aqueous extracts of A. chica decreased neutrophil accumulation and hemoglobin content in the sponge implants without altering the level of cytokines (IL-2, IL- 4, IL-5, IFN-γ, TNF-α and VEGF) and the albumin/globulin ratio in the serum of treated animals. There was no sign of toxicity (clinical, laboratory or histopathology). The ethanol extract presented antiproliferative activity (IC 50 21.5–36.3 µg/mL) against HL60 and Jurkat cell lineages and proapoptotic activity at 50 µg/mL in HL60 cells. The fraction F1 also demonstrated significant antiproliferative activity (IC 50 38.5 µg/mL) and proapoptotic activity against HL60 cells in a dose dependent manner. Conclusions Aqueous and ethanol extracts of A. chica attenuate the inflammatory and angiogenic components of the subcutaneous fibrovascular tissue induced by the synthetic matrix in mice. In addition, the ethanol extract from Arrabidaea chica and its fraction F1 presented in vitro antiproliferative activity and could be useful for developing potential chemopreventive substances. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the third most common cancer in the world. 5- Fluorouracil (5-FU) is a conventional and most effective drug used in the clinic for the treatment of CRC. However, the clinical use of 5-FU is limited due to the acquired resistance and systemic toxicity, such as hepatotoxicity and gastrointestinal toxicity., Objective: Recent advances in nanomedicine are being exploited to develop nanoparticle platforms to overcome resistance and therapeutic delivery of active molecules. Here, we developed 5-FU loaded sulfadiazine-poly(lactide-co-glycolide) nanoparticles (SUL-PLGA NPs) to be applied in the colorectal cancer model., Methods: We assessed the in vivo efficacy of the SUL-PLGA NPs to enhance the antitumor effect of 5-FU., Results: In vivo treatment with 5-FU-SUL-PLGA NPs significantly reduced tumor growth in a colon cancer xenograft model compared to free 5-FU and 5-FU loaded non-targeted NPs. Treatment with 5-FU-SUL-PLGA NPs also increased blood vessel diameters within tumors, which could act in conjunction to enhance antitumor efficacy. In addition, 5-FU-SUL-PLGA NPs significantly reduced liver mass and lung mass, which are the most common metastasis sites of CRC, and decreased liver hepatotoxicity compared to free 5-FU drug and 5-FU loaded non-targeted NPs., Conclusion: Our findings suggest that the use of 5-FU-SUL-PLGA NPs is a promising strategy to enhance 5-FU efficacy against CRC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To assess the action of pentoxifylline, administered by subcutaneous route, on skin flap tissue repair in rats, and to verify the histological aspects and biomarkers., Methods: Thirty-two male Wistar rats were divided into four groups: control (CT) and treated with pentoxifylline (P1, P3 and P5). Modified McFarlane technique flap was used. Ten days later, the animals were euthanized and the areas of viable and necrotic tissue were evaluated. Hematoxylin/eosin staining was used to assess the morphometric characteristics of the number of vessels and epithelial thickness. Picrosirius red was used to assess collagen density. VEGF and TGF-?1 levels on the skin flap and serum of the animals were measured by the ELISA method., Results: The macroscopic evaluation of the skin flap dimensions showed reduced necrotic tissue in the pentoxifylline (p < 0.05) treated groups. There was an increase in angiogenesis and reepithelization, demonstrated by analyses with an increased number of vessels (p < 0.05), VEGF and epithelial thickness. Fibrogenic effect showed decreased collagen density and TGF-β1 in the skin flap and serum., Conclusion: The benefits of pentoxifylline administered by subcutaneous route, at dose 100 mg/kg, which was effective to improve the survival of skin flap by acting on tissue repair components, stimulating angiogenesis and reepithelization, in addition to reducing fibrogenesis.

A crucial component of the integration between foreign implants and the host is angiogenesis. However, to date, none of the available techniques and/or endothelial markers employed to assess angiogenesis in the implant/host interface seems to be able to highlight vascular structures convincingly. In the present study we investigated and compared the expression of two endothelial cell markers: platelet endothelial cell adhesion molecule (PECAM-1) (CD31) and endoglin (CD105) using immunohistochemistry (IHC) and immunofluorescence (IF) to identify and quantify newly formed blood vessels in subcutaneous implants of polyether-polyurethane sponge of formalin-fixed paraffin-embedded tissue. At day 14 post implantation the discs of the synthetic matrix were removed and processed for histological and morphometric analysis. In IHC staining for CD31 antibody the number of vessels was 2.27±0.69 and 5.25±0.46 for CD105. In IF for CD31 the number of vessels was 15.36±1.295 and 10.54±0.8213 for CD105. The level of cross-reaction was lesser in IF images compared with IHC images. Co-localization of CD31/CD105 using confocal images showed positive correlation (Pearson's co-relation and Manders' equation). The double labeling for blood vessels using the IF technique for CD31/CD105 may be an important tool for evaluation of angiogenesis in biomaterial/host integration.

Based on the notion that inflammation favors tumorigenesis, our experiments comparatively assessed the influence of acute and chronic inflammation on the development of a murine mammary tumor (4T1). In addition, we characterized angiogenic and inflammatory markers in the tumor tissue and systemically. Subcutaneous implantation of polyether-polyurethane sponge discs in Balb/c mice was used to host 4T1 tumor cells (1x10(6)), which were inoculated intraimplant 24 h or 10 days post implantation. Flow cytometric analysis of enzyme-digested implants revealed that, after 24 hours, the population of leukocytes was primarily characterized by neutrophils (42.53% +/- 8.45) and monocytes (37.53% +/- 7.48), with some lymphocytes (16.27% +/- 4.0) and a few dendritic cells (1.82% +/- 0.36). At 10 days, macrophages were predominant (37.10% +/- 4.54), followed by lymphocytes (28.1% +/- 4.77), and monocytes (22.33% +/- 3.05), with some dendritic cells (13.60% +/- 0.55) and neutrophils (11.07% +/- 2.27). A mammary tumor grown in a chronic inflammatory environment was 2-fold when compared with one grown in acute inflammation and 5-fold when compared with tumor alone. The levels of pro-angiogenic cytokine (VEGF-Vascular Endothelial Growth Factor) were higher in implant-bearing tumor when 4T1 cells were grown in 10-day old implants as compared to the VEGF levels of the two other groups. Overall, the levels of the inflammatory markers evaluated (NAG -N-acetylglucosaminidase, TNF-α-Tumor Necrosis Factor-α) were higher in both groups of implant-bearing tumors and in serum from those animals when compared with the tumor alone levels. This inflammation-related difference in tumor growth may provide new insights into the contribution of different inflammatory cell populations to cancer progression.