Electrocontractile remodeling of isolated cardiomyocytes induced during early-stage hypercholesterolemia.

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.

The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques.

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.

Gluten worsens non-alcoholic fatty liver disease by affecting lipogenesis and fatty acid oxidation in diet-induced obese apolipoprotein E-deficient mice.

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.

Hair mercury is associated with dyslipidemia and cardiovascular risk: An anthropometric, biochemical and genetic cross-sectional study of Amazonian vulnerable populations.

This cross-sectional study evaluated the association between human exposure to mercury and cardiovascular risk using lipid profile (including apolipoproteins) and genetic analysis of Amazonian riverine population. Anthropometric data (gender, age, height, weight, blood pressure, and neck and waist circumferences) of the participants were recorded. Total mercury and methylmercury (MeHg) content were quantified in hair by ICP-MS and GC-pyro-AFS system. Polymorphisms rs662799, rs693, rs429358 and rs7412 (of genes of apolipoproteins A-V, B, and E at positions 112 and 158, respectively) were genotyped by real-time PCR. The population presented a dyslipidemia profile significantly correlated with high mercury levels. The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) index was also positively correlated with mercury, supporting a possible causal relationship. Allelic distributions were similar to those described in other populations, suggesting that genetic susceptibility may not have a significant role in the lipid alterations found in this work. This study demonstrated for the first time: i) the relationship between mercury exposure and cardiovascular risk-related apolipoproteins in humans, ii) the ApoB levels and the ApoB/ApoA-I index as the risk factors more strongly associated to the mercury-related dyslipidemia in humans, and iii) the prevalence of high/moderate risk of acute myocardial infarction in the vulnerable and chronically exposed-populations of the Amazon, in addition to the genotypic profile of the three most frequent polymorphisms in apolipoproteins of relevance for cardiovascular risk. This early detection of lipid alterations is essential to prevent the development of cardiovascular diseases (CVD), especially in chronically exposed populations such as those found in the Amazon. Therefore, in addition to provide data for the Minamata Convention implementation, our work is in line with the efforts joined by all members of the World Health Organization committed to reducing premature deaths originating from non-communicable diseases by 25% in 2025, including CVD.

Chronic Methylmercury Intoxication Induces Systemic Inflammation, Behavioral, and Hippocampal Amino Acid Changes in C57BL6J Adult Mice.

Methylmercury (MeHg) is highly toxic to the human brain. Although much is known about MeHg neurotoxic effects, less is known about how chronic MeHg affects hippocampal amino acids and other neurochemical markers in adult mice. In this study, we evaluated the MeHg effects on systemic lipids and inflammation, hippocampal oxidative stress, amino acid levels, neuroinflammation, and behavior in adult male mice. Challenged mice received MeHg in drinking water (2 mg/L) for 30 days. We assessed weight gain, total plasma cholesterol (TC), triglycerides (TG), endotoxin, and TNF levels. Hippocampal myeloperoxidase (MPO), malondialdehyde (MDA), acetylcholinesterase (AChE), amino acid levels, and cytokine transcripts were evaluated. Mice underwent open field, object recognition, Y, and Barnes maze tests. MeHg-intoxicated mice had higher weight gain and increased the TG and TC plasma levels. Elevated circulating TNF and LPS confirmed systemic inflammation. Higher levels of MPO and MDA and a reduction in IL-4 transcripts were found in the hippocampus. MeHg-intoxication led to increased GABA and glycine, reduced hippocampal taurine levels, delayed acquisition in the Barnes maze, and poor locomotor activity. No significant changes were found in AChE activity and object recognition. Altogether, our findings highlight chronic MeHg-induced effects that may have long-term mental health consequences in prolonged exposed human populations.

Appetite control: hormones or diet strategies?

PURPOSE OF REVIEW: Appetite control results from metabolic, behavioral, and environmental factors that influence hunger and the desire to eat. We summarize the latest advances in the hormonal and nutritional strategies to control appetite and reduce hunger. RECENT FINDINGS: The fed-hunger-state is regulated by central and peripheric hormones, which modulate energy balance. Leptin, insulin, ghrelin, peptide YY (PYY), and other gut-derived peptides represent the main appetite controllers. The role of orexins, obestatin, and liver-expressed antimicrobial peptide 2 has been uncovered recently. New insights have demonstrated the role of hippocampal activity as a possible mechanism of action. Glucagon-like peptide 1 (GLP1) receptor agonists are well known agents controlling appetite. Association of GLP1 receptor agonist, PYY, or glucose-dependent insulinotropic polypeptide agonists have been tested as new approaches. Appetite-control hormones have also risen as factors involved in the efficacy of bariatric procedures. High-protein, ketogenic diet, and intermittent fasting have been described as nutritional strategies to reduce appetite, although the physiological mechanism and long-term safety remains unclear. SUMMARY: Appetite control has been an important target for the treatment of obesity and associated disorders. New studies have demonstrated promising adoption of dietary approaches, hormone-based drugs, and bariatric surgery to control energy intake. Further research will establish a significant association, benefits, and safety of these new therapies.

Pollutants and nutrition: Are methylmercury effects on blood pressure and lipoprotein profile comparable to high-fat diet in mice?

Human exposure to methylmercury (MeHg) due to contaminated fish intake as part of a high-fat (HFD), high-carbohydrate diets is a reality today for many populations. HFD is associated with hypertension and hyperlipidemia, primary cardiovascular disease (CVD) risk factors. Some studies suggest that MeHg induces those risk factors. We evaluated the effect of MeHg exposure in mice fed with HFD or control diet for eight weeks. In the last experimental 15 days, the half group received a MeHg solution (20 mg/L) replacing water. Blood pressure (BP), heart rate, lipoprotein concentrations, and paraoxonase activity were evaluated. Liver cholesterol, triacylglycerol, and IBA-1+ cells, as well as transcriptional levels of genes related to lipid metabolism and inflammatory response, were also assessed. HFD and both MeHg groups presented increased BP and total cholesterol (TC). In the liver, HFD but not MeHg was related to an increase in TC. Also, MeHg intoxication reduced paraoxonase activity regardless of diet. MeHg intoxication and HFD increased steatosis and the number of IBA-1+ cells and modified some gene transcripts associated with lipid metabolism. In conclusion, we demonstrated that MeHg effects on CVD risk factors resemble those caused by HFD.

Wheat gluten intake increases the severity of experimental colitis and bacterial translocation by weakening of the proteins of the junctional complex.

Gluten is only partially digested by intestinal enzymes and can generate peptides that can alter intestinal permeability, facilitating bacterial translocation, thus affecting the immune system. Few studies addressed the role of diet with gluten in the development of colitis. Therefore, we investigate the effects of wheat gluten-containing diet on the evolution of sodium dextran sulphate (DSS)-induced colitis. Mice were fed a standard diet without (colitis group) or with 4·5 % wheat gluten (colitis + gluten) for 15 d and received DSS solution (1·5 %, w/v) instead of water during the last 7 d. Compared with the colitis group, colitis + gluten mice presented a worse clinical score, a larger extension of colonic injury area, and increased mucosal inflammation. Both intestinal permeability and bacterial translocation were increased, propitiating bacteria migration for peripheral organs. The mechanism by which diet with gluten exacerbates colitis appears to be related to changes in protein production and organisation in adhesion junctions and desmosomes. The protein α-E-catenin was especially reduced in mice fed gluten, which compromised the localisation of E-cadherin and ß-catenin proteins, weakening the structure of desmosomes. The epithelial damage caused by gluten included shortening of microvilli, a high number of digestive vacuoles, and changes in the endosome/lysosome system. In conclusion, our results show that wheat gluten-containing diet exacerbates the mucosal damage caused by colitis, reducing intestinal barrier function and increasing bacterial translocation. These effects are related to the induction of weakness and disorganisation of adhesion junctions and desmosomes as well as shortening of microvilli and modification of the endocytic vesicle route.

L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice.

Beneficial effects of L-arginine on immune responses and bowel function have been reported. Mucositis is a side effect of chemotherapy treatment that affects approximately 40% of patients. This complication is characterized by inflammation that affects the gastrointestinal tract, increasing permeability and causing abdominal pain, nausea, vomiting, and diarrhea, which worsen the patient's nutritional status and increases morbimortality. The aim of this study was to evaluate the effect of pretreating with 2% L-arginine supplementation in water on mucositis as induced by 5-fluorouracil (5-FU; a single dose of 200 mg/kg body weight) in Swiss male mice. The effect of L-arginine on weight, intestinal permeability, morphology, and the histopathological score of the small intestine (from 0 to 12), oxidative stress, myeloperoxidase (MPO), and N-acetylglucosaminidase (NAG) activities were evaluated. Intestinal length improvement was observed, in addition to the partial recovery of the mucosal architecture. L-arginine attenuated the histopathological score and MPO activity. There was also an improvement in intestinal permeability, despite weight loss after 5-FU administration. In conclusion, L-arginine can positively impact intestinal mucositis by promoting partial mucosal recovery, reducing inflammation and improving intestinal permeability.

Combination of Azathioprine and Aminosalicylate Treatment Prevent Risk of Cardiovascular Disease in Women with Ulcerative Colitis by Reducing Inflammation.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with involvement of the immune system. Chronic inflammatory diseases have been associated with increased risk of cardiovascular disease (CVD) but few studies have assessed this risk in patients with UC and the influence of drug treatment. Thus, we evaluated the risk of development of CVD in women with UC in clinical remission, considering the drug treatment. MATERIAL AND METHODS: Twenty-one women with UC participated in this study: 12 used aminosalicylates (ASA group) and 9 used azathioprine added to aminosalicylates (AZA+ASA group). The healthy control group was matched for age. We evaluated blood pressure, body composition, and biochemical and immunological parameters. RESULTS: Compared to the respective control group, the UC groups showed expansion of body fat and less lean body mass. Blood pressure, pro-inflammatory cytokines, nitric oxide, C reactive protein, erythrocyte sedimentation rate (ESR), and anti-oxidized LDL antibodies were higher in UC groups. Only AZA+ASA group showed increased anti-inflammatory cytokines (IL-10 and TGF-ß). Framingham scores showed higher risk of CVD in UC groups. UC groups were compared and women treated with azathioprine showed reduction of total protein, globulin, ESR, and lymphocytes, with increased IL-6, TNF, IL-10, and TGF-ß. CONCLUSIONS: Our data suggest that women with UC in clinical remission have a higher risk for development of atherosclerosis and CVD when compared to the control group, while women treated with azathioprine seem more protected than those treated only with aminosalicylates, due to better regulation of the inflammatory process.

Evaluation of the Treatment with Akkermansia muciniphila BAA-835 of Chemotherapy-induced Mucositis in Mice.

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, IL1ß, 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.

Mas receptor deficiency is associated with worsening of lipid profile and severe hepatic steatosis in ApoE-knockout mice.

The classical renin-angiotensin system pathway has been recently updated with the identification of additional molecules [such as angiotensin converting enzyme 2, ANG-(1-7), and Mas receptor] that might improve some pathophysiological processes in chronic inflammatory diseases. In the present study, we focused on the potential protective role of Mas receptor activation on mouse lipid profile, liver steatosis, and atherogenesis. Mas/apolipoprotein E (ApoE)-double-knockout (DKO) mice (based on C57BL/6 strain of 20 wk of age) were fed under normal diet and compared with aged-matched Mas and ApoE-single-knockout (KO), as well as wild-type mice. Mas/ApoE double deficiency was associated with increased serum levels of atherogenic fractions of cholesterol, triglycerides, and fasting glucose compared with wild-type or single KO. Serum levels of HDL or leptin in DKO were lower than in other groups. Hepatic lipid content as well as alanine aminotransferase serum levels were increased in DKO compared with wild-type or single-KO animals. Accordingly, the hepatic protein content of mediators related to atherosclerotic inflammation, such as peroxisome proliferator-activated receptor-α and liver X receptor, was altered in an adverse way in DKO compared with ApoE-KO. On the other hand, DKO mice did not display increased atherogenesis and intraplaque inflammation compared with ApoE-KO group. In conclusion, Mas deletion in ApoE-KO mice was associated with development of severe liver steatosis and dyslipidemia without affecting concomitant atherosclerosis. Mas receptor activation might represent promising strategies for future treatments targeting both hepatic and metabolic alterations in chronic conditions clustering these disorders.

Are We Ready to Recommend Capsaicin for Disorders Other Than Neuropathic Pain?

Capsaicin, a lipophilic, volatile compound, is responsible for the pungent properties of chili peppers. In recent years, a significant increase in investigations into its properties has allowed the production of new formulations and the development of tools with biotechnological, diagnostic, and potential therapeutic applications. Most of these studies show beneficial effects, improving antioxidant and anti-inflammatory status, inducing thermogenesis, and reducing white adipose tissue. Other mechanisms, including reducing food intake and improving intestinal dysbiosis, are also described. In this way, the possible clinical application of such compound is expanding every year. This opinion article aims to provide a synthesis of recent findings regarding the mechanisms by which capsaicin participates in the control of non-communicable diseases such as obesity, diabetes, and dyslipidemia.

Dietary gluten worsens hepatic steatosis by increasing inflammation and oxidative stress in ApoE-/- mice fed a high-fat diet.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder in the world. We have seen that gluten intake exacerbated obesity and atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice. In this study, we investigated the effect of gluten consumption on inflammation and oxidative stress in the liver of mice with NAFLD. Male ApoE-/- mice were fed a gluten-free (GF-HFD) or gluten-containing (G-HFD) high-fat diet for 10 weeks. Blood, liver, and spleen were collected to perform the analyses. The animals of the gluten group had increased hepatic steatosis, followed by increased serum AST and ALT. Gluten intake increased hepatic infiltration of neutrophils, macrophages, and eosinophils, as well as the levels of chemotaxis-related factors CCL2, Cxcl2, and Cxcr3. The production of the TNF, IL-1ß, IFNγ, and IL-4 cytokines in the liver was also increased by gluten intake. Furthermore, gluten exacerbated the hepatic lipid peroxidation and nitrotyrosine deposition, which were associated with increased production of ROS and nitric oxide. These effects were related to increased expression of NADPH oxidase and iNOS, as well as decreased activity of superoxide dismutase and catalase enzymes. There was an increased hepatic expression of the NF-κB and AP1 transcription factors, corroborating the worsening effect of gluten on inflammation and oxidative stress. Finally, we found an increased frequency of CD4+FOXP3+ lymphocytes in the spleen and increased gene expression of Foxp3 in the livers of the G-HFD group. In conclusion, dietary gluten aggravates NAFLD, exacerbating hepatic inflammation and oxidative stress in obese ApoE-deficient mice.

Platelet-activating factor and protease-activated receptor 2 cooperate to promote neutrophil recruitment and lung inflammation through nuclear factor-kappa B transactivation.

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.

Butyrate: implications for intestinal function.

PURPOSE OF REVIEW: Butyrate is physiologically produced by the microbial fermentation of dietary fibers and plays a plurifunctional role in intestinal cells. This review examines the recent findings regarding the role and mechanisms by which butyrate regulates intestinal metabolism and discusses how these findings could improve the treatment of several gastrointestinal disorders. RECENT FINDINGS: Butyrate is more than a primary nutrient that provides energy to colonocytes and acts as a cellular mediator in those cells through several mechanisms. One remarkable property of butyrate is its ability to inhibit histone deacetylases, which is associated with the direct effects of butyrate and results in gene regulation, immune modulation, cancer suppression, cell differentiation, intestinal barrier regulation, oxidative stress reduction, diarrhea control, visceral sensitivity and intestinal motility modulation. All of these actions make butyrate an important factor for the maintenance of gut health. SUMMARY: From studies published over 30 years, there is no doubt of the important role that butyrate plays in maintaining intestinal homeostasis. However, despite these effects, clinical studies are still required to validate the routine use of butyrate in clinical practice and, specifically, in the treatment of intestinal diseases.

Pro-inflammatory effects of the mushroom Agaricus blazei and its consequences on atherosclerosis development.

PURPOSE: Extracts of the mushroom Agaricus blazei (A. blazei) have been described as possessing immunomodulatory and potentially cancer-protective activities. However, these effects of A. blazei as a functional food have not been fully investigated in vivo. METHODS: Using apolipoprotein E-deficient (ApoE(-/-)) mice, an experimental model of atherosclerosis, we evaluated the effects of 6 or 12 weeks of A. blazei supplementation on the activation of immune cells in the spleen and blood and on the development of atherosclerosis. RESULTS: Food intake, weight gain, blood lipid profile, and glycemia were similar between the groups. To evaluate leukocyte homing and activation, mice were injected with (99m)Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of A. blazei-supplemented animals. Analysis of the spleen showed higher levels of activation of neutrophils, NKT cells, and monocytes as well as increased production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more activated in the supplemented group. Atherosclerotic lesion areas were larger in the aorta of supplemented mice and exhibited increased numbers of macrophages and neutrophils and a thinner fibrous cap. A. blazei-induced transcriptional upregulation of molecules linked to macrophage activation (CD36, TLR4), neutrophil chemotaxy (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) were seen after 12 weeks of supplementation. CONCLUSIONS: This is the first in vivo study showing that the immunostimulatory effect of A. blazei has proatherogenic repercussions. A. blazei enhances local and systemic inflammation, upregulating pro-inflammatory molecules, and enhancing leukocyte homing to atherosclerosis sites without affecting the lipoprotein profile.

Helminth infection modulates number and function of adipose tissue Tregs in high fat diet-induced obesity.

BACKGROUND: Epidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms Treg cells exert in the helminth-obesity interface has been poorly investigated. The present study aimed to verify the influence of Heligmosomoides polygyrus infection in early stages of high fat diet-induced obesity. PRINCIPAL FINDINGS: The presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by lower levels of leptin and resistin, lower infiltration of Th1 and Th17 cells in adipose tissue, higher expression of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased Treg frequency in adipose tissue which showed higher expression of cell surface markers of function and activation, like LAP and CD134. The infection could also increase adipose Treg suppressor function in animals on high fat diet. CONCLUSION: These data suggest that H. polygyrus modulates adipose tissue Treg cells with implication for weight gain and metabolic syndrome.

Immunoinflammatory role of apolipoprotein E4 in malnutrition and enteric infections and the increased risk for chronic diseases under adverse environments.

Apolipoprotein E plays a crucial role in cholesterol metabolism. The immunomodulatory functions of the human polymorphic APOE gene have gained particular interest because APOE4, a well-recognized risk factor for late-onset Alzheimer's disease, has also been recently linked to increased risk of COVID-19 infection severity in a large UK biobank study. Although much is known about apoE functions in the nervous system, much less is known about APOE polymorphism effects on malnutrition and enteric infections and the consequences for later development in underprivileged environments. In this review, recent findings are summarized of apoE's effects on intestinal function in health and disease and the role of APOE4 in protecting against infection and malnutrition in children living in unfavorable settings, where poor sanitation and hygiene prevail, is highlighted. The potential impact of APOE4 on later development also is discussed and gaps in knowledge are identified that need to be addressed to protect children's development under adverse environments.

Bifidobacterium longum subsp. longum 51A attenuates intestinal injury against irinotecan-induced mucositis in mice.

Intestinal mucositis (IM) is a critical side-effect associated with antineoplastic therapy. Treatment available is only palliative and often not effective. However, alternative therapeutic strategies, such as probiotics, have attracted significant attention due to their immune-modulatory action in several diseases. Thus, the present study aims to elucidate the therapeutic potential of the probiotic strain Bifidobacterium longum 51A in a murine model of mucositis induced by irinotecan. Due to the scarcity of studies on dose-response and viability (probiotic vs paraprobiotic), we first evaluated which dose and cell viability would be most effective in treating mucositis. In this study, the oral pretreatment with viable B. longum 51A at a concentration of 1 × 109 CFU/mL reduced the daily disease activity index (p < 0.01), protected the intestinal architecture, preserved the length of the intestine (p < 0.05), and reduced intestinal permeability (p < 0.01), inflammation, and oxidative damage (p < 0.01) induced by irinotecan. Also, treatment with B. longum 51A increased the production of secretory immunoglobulin A (p < 0.05) in the intestinal fluid of mice with mucositis. Furthermore, B. longum 51A reversed the mucositis-induced increase in Enterobacteriaceae bacterial group in the gut (p < 0.01). In conclusion, these results showed that oral administration of B. longum 51A protects mice against intestinal damage caused by irinotecan, suggesting its use as a potential probiotic in therapy during mucositis.