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Hypercholesterolemia is one of the most important risk factors for cardiovascular diseases. However, it is mostly associated with vascular dysfunction and atherosclerotic lesions, while evidence of direct effects of hypercholesterolemia on cardiomyocytes and heart function is still incomplete and controversial. In this study, we assessed the direct effects of hypercholesterolemia on heart function and the electro-contractile properties of isolated cardiomyocytes. After 5 weeks, male Swiss mice fed with AIN-93 diet added with 1.25% cholesterol (CHO), developed an increase in total serum cholesterol levels and cardiomyocytes cholesterol content. These changes led to altered electrocardiographic records, with a shortening of the QT interval. Isolated cardiomyocytes displayed a shortening of the action potential duration with increased rate of depolarization, which was explained by increased IK, reduced ICa.L and altered INa voltage-dependent inactivation. Also, reduced diastolic [Ca2+]i was found with preserved adrenergic response and cellular contraction function. However, contraction of isolated hearts is impaired in isolated CHO hearts, before and after ischemia/reperfusion, although CHO heart was less susceptible to arrhythmic contractions. Overall, our results demonstrate that early hypercholesterolemia-driven increase in cellular cholesterol content is associated with direct modulation of the heart and cardiomyocytes' excitability, Ca2+ handling, and contraction. [ABSTRACT FROM AUTHOR]

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation and hepatocyte injury. Preclinical studies have shown exacerbated weight gain associated with an obesogenic gluten-containing diet. However, whether gluten affects obesity-induced hepatic lipid accumulation still remains unclear. We hypothesized that gluten intake could affect fatty liver development in high-fat diet (HFD)-induced obese mice. Thus, we aimed to investigate the impact of gluten intake on NAFLD in HFD-induced obese mice. Male apolipoprotein E-deficient (Apoe-/-) mice were fed with a HFD containing (GD) or not (GFD) vital wheat gluten (4.5%) for 10 weeks. Blood and liver were collected for further analysis. We found that gluten exacerbated weight gain, hepatic fat deposition, and hyperglycemia without affecting the serum lipid profile. Livers of the GD group showed a larger area of fibrosis, associated with the expression of collagen and MMP9, and higher expression of apoptosis-related factors, p53, p21, and caspase-3. The expression of lipogenic factors, such as PPARγ and Acc1, was more elevated and factors related to beta-oxidation, such as PPARα and Cpt1, were lower in the GD group compared to the GFD. Further, gluten intake induced a more significant expression of Cd36, suggesting higher uptake of free fatty acids. Finally, we found lower protein expression of PGC1α followed by lower activation of AMPK. Our data show that gluten-containing high-fat diet exacerbated NAFLD by affecting lipogenesis and fatty acid oxidation in obese Apoe-/- mice through a mechanism involving lower activation of AMPK. [ABSTRACT FROM AUTHOR]

Mucositis is a high-incidence side effect in cancer patients undergoing chemotherapy. Next-generation probiotics are emerging as new therapeutic tools for managing various disorders. Studies have demonstrated the potential of Akkermansia muciniphila to increase the efficiency of anticancer treatment and to mitigate mucositis. Due to the beneficial effect of A. muciniphila on the host, we evaluated the dose–response, the microorganism viability, and the treatment protocol of A. muciniphila BAA-835 in a murine model of chemotherapy-induced mucositis. Female Balb/c mice were divided into groups that received either sterile 0.9% saline or A. muciniphila by gavage. Mucositis was induced using a single intraperitoneal injection of 5-fluorouracil. The animals were euthanized three days after the induction of mucositis, and tissue and blood were collected for analysis. Prevention of weight loss and small intestine shortening and reduction of neutrophil and eosinophil influx were observed when animals were pretreated with viable A. muciniphila at 1010 colony-forming units per mL (CFU/mL). The A. muciniphila improved mucosal damage by preserving tissue architecture and increasing villus height and goblet cell number. It also improved the integrity of the epithelial barrier, decreasing intestinal permeability and bacterial translocation. In addition, the treatment prevented the expansion of Enterobacteriaceae. The immunological parameters were also improved by decreasing the expression of pro-inflammatory cytokines (IL6, IL1β, and TNF) and increasing IL10. In conclusion, pretreatment with 1010 CFU/mL of viable A. muciniphila effectively controlled inflammation, protected the intestinal mucosa and the epithelial barrier, and prevented Enterobacteriaceae expansion in treated mice. [ABSTRACT FROM AUTHOR]

Although it is well established that platelet-activated receptor (PAF) and protease-activated receptor 2 (PAR2) play a pivotal role in the pathophysiology of lung and airway inflammatory diseases, a role for a PAR2-PAFR cooperation in lung inflammation has not been investigated. Here, we investigated the role of PAR2 in PAF-induced lung inflammation and neutrophil recruitment in lungs of BALB/c mice. Mice were pretreated with the PAR2 antagonist ENMD1068, PAF receptor (PAFR) antagonist WEB2086, or aprotinin prior to intranasal instillation of carbamyl-PAF (C-PAF) or the PAR2 agonist peptide SLIGRL-NH2 (PAR2-AP). Leukocyte infiltration in bronchoalveolar lavage fluid (BALF), C-X-C motif ligand 1 (CXCL)1 and CXCL2 chemokines, myeloperoxidase (MPO), and N-acetyl-glycosaminidase (NAG) levels in BALF, or lung inflammation were evaluated. Intracellular calcium signaling, PAFR/PAR2 physical interaction, and the expression of PAR2 and nuclear factor-kappa B (NF-КB, p65) transcription factor were investigated in RAW 264.7 cells stimulated with C-PAF in the presence or absence of ENMD1068. C-PAF- or PAR2-AP-induced neutrophil recruitment into lungs was inhibited in mice pretreated with ENMD1068 and aprotinin or WEB2086, respectively. PAR2 blockade impaired C-PAF-induced neutrophil rolling and adhesion, lung inflammation, and production of MPO, NAG, CXCL1, and CXCL2 production in lungs of mice. PAFR activation reduced PAR2 expression and physical interaction of PAR2 and PAFR; co-activation is required for PAFR/PAR2 physical interaction. PAR2 blockade impaired C-PAF-induced calcium signal and NF-κB p65 translocation in RAW 264.7 murine macrophages. This study provides the first evidence for a cooperation between PAFR and PAR2 mediating neutrophil recruitment, lung inflammation, and macrophage activation. [ABSTRACT FROM AUTHOR]

Purpose: Gastrointestinal mucositis is a major problem associated with cancer therapy. To minimize these deleterious effects, simultaneous administration of antioxidant components, such as selenium, can be considered. There is a growing interest in the use of yeasts because they are able to convert inorganic selenium into selenomethionine. In the present study, oral administration of Saccharomyces cerevisiae UFMG A-905 enriched with selenium was evaluated as an alternative in minimizing the side effects of 5FU-induced mucositis in mice.Methods: Mice body weight, food consumption, faeces consistency and the presence of blood in faeces were assessed daily during experimental mucositis induced by 5-fluorouracil (5FU). Blood was used for intestinal permeability determination, and small intestine for oxidative stress, immunological and histopathological examination.Results: The increased intestinal permeability observed with mucositis induction was partially reverted by S. cerevisiae and selenium-enriched yeast. Both treatments were able to reduce myeloperoxidase activity, but only selenium-enriched yeast reduced eosinophil peroxidase activity. CXCL1/KC levels, histopathological tissue damage and oxidative stress (lipid peroxidation and nitrite production) in the small intestine were reduced by both treatments; however, this reduction was always higher when treatment with selenium-enriched yeast was evaluated.Conclusions: Results of the present study showed that the oral administration of S. cerevisiae UFMG A-905 protected mice against mucositis induced by 5-FU, and that this effect was potentiated when the yeast was enriched with selenium. [ABSTRACT FROM AUTHOR]

Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation. [ABSTRACT FROM AUTHOR]