Intraurethral injection with LPS: an effective experimental model of prostatic inflammation.

OBJECTIVE: Chronic inflammation has been recognized as having a prominent role pathogenesis of benign prostatic hyperplasia (BPH) and cancer. It is believed that chronic inflammation induces prostatic fibromuscular growth. This correlation has been clearly illustrated by both in vivo and in vitro studies; however, current experimental models of BPH require complex surgery or hormonal treatment. Therefore, the aim of the present study was to propose a new murine model of BPH/prostatitis induced by intraurethral injection of LPS. METHODS: Male Swiss and C57Bl/6 mice were then sacrificed 3, 7, 10, and 14 days after intraurethral injection of LPS. The prostates were quickly dissected and fixed for morphological and immunohistochemical analyses. RESULTS: The results showed that LPS played an important role in the cell proliferation of the prostate. Histological and ultrastructural analysis showed epithelial hyperplasia, clear stromal cells, little inflammatory infiltration, and heavy bleeding. Treatment with LPS also promoted the increase of growth factor (FGF-7 and TGF-ß), α-actin, and proinflammatory cytokines (IL-1, IL-6, IL-17), both in the stroma and epithelium. CONCLUSION: According to the present findings, it can be concluded that the intraurethral administration of LPS promotes tissue remodeling, as well as stimulating the pattern of pro-inflammatory cytokines, and therefore, constitutes an effective experimental model of BPH/inflammation.

Chronic LPSF/GQ-02 treatment attenuates inflammation and atherosclerosis development in LDLr-/- mice.

BACKGROUND: Atherosclerosis is a complex disorder with a multifactorial pathogenesis. We previously indicated that the new TZD LPSF/GQ-02 inhibits hepatic steatosis and inflammation, which are reported as risk factors for atherosclerosis development. Here, we explored the effects of LPSF/GQ-02 on atherosclerosis in LDLr-/- mice comparing two treatment periods. METHODS AND RESULTS: LDLr-/- mice were fed a high-fat diet for 10 and 12 weeks and received oral treatment with LPSF/GQ-02 (30mg/kg/day) or pioglitazone (20mg/kg/day) for 15 and 30 days, respectively. Both treatment protocols with LPSF/GQ-02 resulted in lower collagen density in the atherosclerotic lesions. In addition, the treatment for 15 days also decreased mRNA levels of CD40, MCP-1, ABCG1 and upregulated PPARα, whereas the 30-days treatment reduced the protein levels of LOX-1, p-IκBα and p-NFκB. CONCLUSION: This study provides evidence that LPSF/GQ-02 affects the composition and growth of atherosclerotic lesions in LDLr-/- mice. Moreover, our data also support previous findings showing anti-inflammatory properties of LPSF/GQ-02 and reinforce the therapeutic potential of this TZD for treating atherosclerosis and inflammation-related disorders.

Influence of fatty acids in maternal diet on atherogenesis in offspring of LDL receptor-deficient mice.

AIMS: The present study investigated the effect of a maternal diet rich in omega-6 (E6D) or omega-9 (E9D) on atherogenesis in the offspring of mice. MAIN METHODS: LDL receptor-deficient mice were fed a diet rich in either omega-6 (E6D) or omega-9 (E9D) for 45 days prior to mating and until the birth of the offspring, evaluating the effect on the offspring aorta in comparison to a standard diet (STD), by immunohistochemical analysis, morphometric analysis and electron microscopy. KEY FINDINGS: Hypercholesterolemic female mice fed E6D generated offspring with high levels of total cholesterol, triglycerides (TG) and CC-chemokine ligand 2/monocyte chemoattractant protein 1 (CCL2/ MCP-1) as well as a reduction in high-density lipoprotein. The ascending aorta of these animals exhibited an increase in arterial wall thickness as well as increased expression of CCL2/MCP-1 and vascular cell adhesion molecule 1. The ultrastructural analysis revealed severe alterations in endothelial cells. The offspring from mothers fed E9D exhibited a reduction in TG and an increase in low-density lipoprotein. The ultrastructural analysis revealed a well-preserved aortic endothelium in these animals. SIGNIFICANCE: The results suggest that hypercholesterolemic mothers feed a diet rich in omega-6 predispose their offspring to endothelial dysfunction.

Effect of maternal diet rich in omega-6 and omega-9 fatty acids on the liver of LDL receptor-deficient mouse offspring.

BACKGROUND: Omega-6 fatty acids are important to fetal development. However, during gestation/lactation, these fatty acids may contribute toward the development of fat tissue. Omega-9 fatty acids are associated with a reduction in serum lipids and protection from liver disease. OBJECTIVES: The present study investigated the effect of the maternal intake of omega-6 and omega-9 in hypercholesterolemic mothers on the liver of the offspring. METHODS: LDL receptor-deficient mice were fed a diet rich in either omega-6 (E6D) or omega-9 (E9D) for 45 days prior to mating and until the birth of the offspring, evaluating the effect on the offspring liver in comparison to a standard diet (STD). RESULTS: Mothers fed with the E6D experienced an increase in total cholesterol (TC) and the offspring exhibited an increase in TC, hepatic triglycerides (TG), and CC-chemokine ligand (CCL)2/monocyte chemoattractant protein (MCP)-1 as well as a reduction in HDL. Histological analysis on this group revealed steatosis, leukocyte infiltrate, and increased CCL2/MCP-1 expression. The ultrastructural analysis revealed hepatocytes with lipid droplets and myofibroblasts. The offspring of mothers fed the standard diet exhibited low serum TC, but microvesicular steatosis was observed. The offspring of mothers fed the E9D exhibited lower serum and hepatic TG as well as higher LDL in comparison to the other diets. The histological analyses revealed lower steatosis and leukocyte infiltrate. CONCLUSIONS: The findings suggest that hypercholesterolemic mothers with a diet rich in omega-6 fatty acids predispose their offspring to steatohepatitis, whereas a diet rich in omega-9 has a protective effect.

Chronic treatment with sildenafil stimulates Leydig cell and testosterone secretion.

The phosphodiesterase type 5 (PDE5) inhibitor, Sildenafil, is a novel, oral treatment approach for pulmonary hypertension. As Leydig cells present PDE5, this study was conducted to investigate the effects of the chronic treatment with Sildenafil (25 mg/kg) on male Swiss Webster mice steroidogenesis. After a 4-week long experimental design, Leydig cells were analysed by morphological and immunocytochemical procedures. Serum testosterone was assayed by radioimmunoassay. Leydig cells presented noteworthy ultrastructural alterations, such as a vesicular smooth endoplasmic reticulum, large vacuoles scattered through the cytoplasm, enlarged mitochondria with discontinue cristaes and whorle membranes with vesicles at the periphery, which are typical characteristics of an activated steroid-secreting cell. Important immunocytochemical labelling for steroidogenic acute regulatory protein, cytochrome P450 side-chain cleavage enzyme and testosterone were detected in isolated Leydig cells. In addition, Sildenafil-treated mice showed significant increased levels of total testosterone. The results obtained in the present study are consistent with the hypothesis that the accumulation of cyclic guanosine monophosphate by PDE5 inhibition could be involved in the androgen biosynthesis stimulation. Important clinical implications of hormonal disorders should be taken into account for patients with pulmonary hypertension.