Adipose tissue plasticity mediated by the counterregulatory axis of the renin-angiotensin system: Role of Mas and MrgD receptors.

The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.

ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.

Periodontal pathogen Aggregatibacter actinomycetemcomitans JP2 correlates with colonic leukocytes decrease and gut microbiome imbalance in mice.

AIM: Evidence suggests that translocation of oral pathogens through the oral-gut axis may induce intestinal dysbiosis. This study aimed to evaluate the impact of a highly leukotoxic Aggregatibacter actinomycetemcomitans (Aa) strain on the gut microbiota, intestinal mucosal integrity and immune system in healthy mice. METHODS: Eight-week-old male C57BL6 mice were divided into control (n = 16) and JP2 groups (n = 19), which received intragastric gavage with PBS and with a suspension of Aa JP2 (HK921), respectively, twice a week for 4 weeks. Colonic lamina propria, fecal material, serum, gingival tissues, and mandibles were obtained for analyses of leukocyte populations, inflammatory mediators, mucosal integrity, alveolar bone loss, and gut microbiota. Differences between groups for these parameters were examined by non-parametric tests. RESULTS: The gut microbial richness and the number of colonic macrophages, neutrophils, and monocytes were significantly lower in Aa JP2-infected mice than in controls (p < .05). In contrast, infected animals showed higher abundance of Clostridiaceae, Lactobacillus taiwanensis, Helicobacter rodentium, higher levels of IL-6 expression in colonic tissues, and higher splenic MPO activity than controls (p < .05). No differences in tight junction expression, serum endotoxin levels, and colonic inflammatory cytokines were observed between groups. Infected animals presented also slightly more alveolar bone loss and gingival IL-6 levels than controls (p < .05). CONCLUSION: Based on this model, intragastric administration of Aa JP2 is associated with changes in the gut ecosystem of healthy hosts, characterized by less live/recruited myeloid cells, enrichment of the gut microbiota with pathobionts and decrease in commensals. Negligible levels of colonic pro-inflammatory cytokines, and no signs of mucosal barrier disruption were related to these changes.

Bisphenol S exposure induces cardiac remodeling and aggravates high-fat diet-induced cardiac hypertrophy in mice.

Bisphenol S (BPS) is widely used in the manufacture products and increase the risk of cardiovascular diseases. The effect of the association between obesity and BPS on cardiac outcomes is still unknown. Male C57BL/6 mice were divided into standard chow diet (SC; 15 kJ/g), standard chow diet + BPS (SCB), high-fat diet (HF; 21 kJ/g), and high-fat diet + BPS (HFB). Over 12 weeks, the groups were exposed to BPS through drinking water (dose: 25 µg/Kg/day) and/or a HF diet. We evaluated: body mass (BM), total cholesterol, systolic blood pressure (SBP), left ventricle (LV) mass, and cardiac remodeling. In the SCB group, BM, total cholesterol, and SBP increase were augmented in relation to the SC group. In the HF and HFB groups, these parameters were higher than in the SC and SCB groups. Cardiac hypertrophy was evidenced by augmented LV mass and wall thickness, and ANP protein expression in all groups in comparison to the SC group. Only the HFB group had a thicker LV wall than SCB and HF groups, and increased cardiomyocyte area when compared with SC and SCB groups. Concerning cardiac fibrosis, SCB, HF, and HFB groups presented higher interstitial collagen area, TGFß, and α-SMA protein expression than the SC group. Perivascular collagen area was increased only in the HF and HFB groups than SC group. Higher IL-6, TNFα, and CD11c protein expression in all groups than the SC group evidenced inflammation. All groups had elevated CD36 and PPARα protein expression in relation to the SC group, but only HF and HFB groups promoted cardiac steatosis with increased perilipin 5 protein expression than the SC group. BPS exposure alone promoted cardiac remodeling with pathological concentric hypertrophy, fibrosis, and inflammation. Diet-induced remodeling is aggravated when associated with BPS, with marked hypertrophy, alongside fibrosis, inflammation, and lipid accumulation.

Environmental Endocrinology: Parabens Hazardous Effects on Hypothalamic-Pituitary-Thyroid Axis.

Parabens are classified as endocrine-disrupting chemicals (EDCs) capable of interfering with the normal functioning of the thyroid, affecting the proper regulation of the biosynthesis of thyroid hormones (THs), which is controlled by the hypothalamic-pituitary-thyroid axis (HPT). Given the crucial role of these hormones in health and the growing evidence of diseases related to thyroid dysfunction, this review looks at the effects of paraben exposure on the thyroid. In this study, we considered research carried out in vitro and in vivo and epidemiological studies published between 1951 and 2023, which demonstrated an association between exposure to parabens and dysfunctions of the HPT axis. In humans, exposure to parabens increases thyroid-stimulating hormone (TSH) levels, while exposure decreases TSH levels in rodents. The effects on THs levels are also poorly described, as well as peripheral metabolism. Regardless, recent studies have shown different actions between different subtypes of parabens on the HPT axis, which allows us to speculate that the mechanism of action of these parabens is different. Furthermore, studies of exposure to parabens are more evident in women than in men. Therefore, future studies are needed to clarify the effects of exposure to parabens and their mechanisms of action on this axis.

Bioactive food and exercise in chronic kidney disease: Targeting the mitochondria.

Chronic kidney disease (CKD), which affects 10%-15% of the population, associates with a range of complications-such as cardiovascular disease, frailty, infections, muscle and bone disorders and premature ageing-that could be related to alterations of mitochondrial number, distribution, structure and function. As mitochondrial biogenesis, bioenergetics and the dynamic mitochondrial networks directly or indirectly regulate numerous intra- and extracellular functions, the mitochondria have emerged as an important target for interventions aiming at preventing or improving the treatment of complications in CKD. In this review, we discuss the possible role of bioactive food compounds and exercise in the modulation of the disturbed mitochondrial function in a uraemic milieu.

Modulation of the renin-angiotensin system in white adipose tissue and skeletal muscle: focus on exercise training.

Overactivation of the renin-angiotensin (Ang) system (RAS) increases the classical arm (Ang-converting enzyme (ACE)/Ang II/Ang type 1 receptor (AT1R)) to the detriment of the protective arm (ACE2/Ang 1-7/Mas receptor (MasR)). The components of the RAS are present locally in white adipose tissue (WAT) and skeletal muscle, which act co-operatively, through specific mediators, in response to pathophysiological changes. In WAT, up-regulation of the classical arm promotes lipogenesis and reduces lipolysis and adipogenesis, leading to adipocyte hypertrophy and lipid storage, which are related to insulin resistance and increased inflammation. In skeletal muscle, the classical arm promotes protein degradation and increases the inflammatory status and oxidative stress, leading to muscle wasting. Conversely, the protective arm plays a counter-regulatory role by opposing the effect of Ang II. The accumulation of adipose tissue and muscle mass loss is associated with a higher risk of morbidity and mortality, which could be related, in part, to overactivation of the RAS. On the other hand, exercise training (ExT) shifts the balance of the RAS towards the protective arm, promoting the inhibition of the classical arm in parallel with the stimulation of the protective arm. Thus, fat mobilization and maintenance of muscle mass and function are facilitated. However, the mechanisms underlying exercise-induced changes in the RAS remain unclear. In this review, we present the RAS as a key mechanism of WAT and skeletal muscle metabolic dysfunction. Furthermore, we discuss the interaction between the RAS and exercise and the possible underlying mechanisms of the health-related aspects of ExT.

High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats.

Metabolic syndrome is a cluster of metabolic risk factors that is linked to central obesity, elevated blood pressure, insulin resistance (IR), and dyslipidemia, where the renin-angiotensin system (RAS) may provide a link among them. This study aimed to evaluate volume exercise effects comparing low vs. high volume of chronic aerobic exercise on RAS axes in skeletal muscle in a diet-induced obesity (DIO) rat model. For this, male Wistar-Kyoto rats were fed a standard chow (SC) diet or a high-fat (HF) diet for 32 wk. Animals receiving the HF diet were randomly divided into low exercise volume (LEV, 150 min/wk) and high exercise volume (HEV, 300 min/wk) at the 20th week. After 12 wk of aerobic treadmill training, the body mass and composition, blood pressure, glucose and lipid metabolism, RAS axes, insulin signaling, and inflammatory pathway were performed. HEV slowed the body mass gain, reduced intra-abdominal fat pad and leptin levels, improved total and peripheral body composition and inflammatory cytokine, reduced angiotensin II type 1 receptor expression, and increased Mas receptor protein expression compared with the HF animals. Sedentary groups (SC and HF) presented lower time to exhaustion and maximal velocity compared with the LEV and HEV groups. Both exercise training groups showed reduced resting systolic blood pressure and heart rate, improved glucose tolerance, IR, insulin signaling, and lipid profile. We conclude that the HEV, but not LEV, shifted the balance of RAS toward the ACE2/Mas receptor axis in skeletal muscle, presenting protective effects against the DIO model.

Brazil nut-enriched diet modulates bone mineral density and body composition in an experimental model of chronic kidney disease.

OBJECTIVE: This study investigates the effects of a Brazil nut-enriched diet on body composition and bone parameters in CKD animal model. METHODS: Male Wistar rats were assigned to the following groups: Sham (n=8), Nx (n=6), nephrectomized rats, and NxBN (n=6), nephrectomized rats and an enricheddiet with 5% Brazil nut. Body composition parameters were obtained by dual-energy X- ray absorptiometry (DXA). Bioclin kits determined plasmatic calcium. The femurs werecollected to determine absolute mass and length, bone mineral density, and biomechanical tests. RESULTS: The NxBN group exhibited a higher total body bone mineral density (BMD) value than the Nx group (0.177±0.004g/cm2vs 0,169±0.003g/cm2; p=0.0397). No significant differences were observed regarding absolute mass, length, BMD, and biomechanical parameters in the femurs of the groups. Moreover, no significant differences were found in plasmatic calcium levels among the groups. CONCLUSIONS: Brazil-nut enriched diet modulated BMD in CKD experimental model, and further studies are demanded to understand the pathways involved in this finding.

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Brazil Nut-Enriched Diet Modulates Enteric Glial Cells and Gut Microbiota in an Experimental Model of Chronic Kidney Disease.

Introduction: Chronic kidney disease (CKD) promotes gut dysbiosis, and enteric glial reactivity, a feature of intestinal inflammation. Brazil nut modulated enteric glial profile in healthy animals and could modulate these cells in 5/6 nephrectomized rats.Methods: A 5/6 nephrectomy-induced CKD and Sham-operated rats were divided as follows: CKD and Sham received a standard diet and CKD-BN and Sham-BN received a 5% Brazil nut enriched-diet. The protein content of glial fibrillary acid protein (GFAP), enteric glial marker, and GPx protein content and activity were assessed in the colon. The major phyla of gut microbiota were assessed.Results: CKD-BN group presented a decrease in GFAP content (p = 0.0001). The CKD-BN group modulated the abundance of Firmicutes, increasing its proportion compared to the CKD group. The CKD-BN group showed increased GPx activity in the colon (p = 0.0192), despite no significant difference in protein content.Conclusion: Brazil nut-enriched diet consumption decreased enteric glial reactivity and modulated gut microbiota in the CKD experimental model.

Brazil nuts potential: effects on lipid peroxidation and heart health in nephrectomized rats.

OBJECTIVES: To investigate the effects of a Brazil nut-enriched diet on the wall thickness and the left ventricular chamber diameter of the heart, and lipid peroxidation in a CKD-induced model. METHODS: Male Wistar rats at 12 weeks of age were divided into two groups (n=16/group): the Nx group, which underwent 5/6 nephrectomy, and the Sham group, as a control. After 5 weeks, the groups were subdivided according to diet (n=8/group): the Nx and Sham groups received a control diet; the Nx5% and Sham5% groups received a diet enriched with 5 % Brazil nuts for 8 weeks. The left ventricular thickening and chamber diameter were determined. Plasma biochemical parameters were evaluated. Analysis of thiobarbituric acid reactive substances (TBARS) and antioxidant enzyme activity was performed in the plasma and the left ventricle (LV). LV mRNA expression of nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) was evaluated by reverse transcription-polymerase chain reaction. RESULTS: The Nx5% group showed a remodeled LV wall with decreased thickness compared to the Nx group (p=0.016). Furthermore, LV TBARS concentration was reduced in the Nx5% group (p=0.0064). In addition, the Nx5% group showed an increase in plasma GPx activity (p=0.0431). No significant results were found concerning the LV mRNA expression of NF-κB and Nrf2 genes. CONCLUSIONS: A Brazil nut-enriched diet decreased LV thickness and LV TBARS concentration and increased GPx activity in a 5/6 nephrectomy experimental model, making it a promising adjuvant therapy to improve antioxidant status and cardiovascular outcomes in chronic kidney disease.

Tributyltin-induced visceral adiposity is associated with impaired redox balance in white adipose tissue of male rats.

Tributyltin (TBT) is an organotin compound that has several adverse health effects, including the development of obesity. Although obesity is strongly associated with adipose redox imbalance, there is a lack of information on whether TBT promotes a pro-oxidative environment in WAT. Thus, adult male Wistar rats were randomly exposed to either vehicle (ethanol 0.4%) or TBT (1000 ng/kg) for 30 days. Body and fat pad masses, visceral fat morphology, lipid peroxidation, protein carbonylation, redox status markers, and catalase activity were evaluated. TBT promoted increased adiposity and visceral fat, with hypertrophic adipocytes, but did not alter body mass and subcutaneous fat. ROS production and lipid peroxidation were elevated in TBT group, as well as catalase protein expression and activity, although protein oxidation and glutathione peroxidase protein expression remained unchanged. In conclusion, this is the first study to demonstrate that subacute TBT administration leads to visceral adipose redox imbalance, with increased oxidative stress. This enlights the understanding of the metabolic toxic outcomes of continuous exposure to TBT in mammals.

Potential role of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects million women worldwide, presenting a complex pathophysiology that has not been fully elucidated yet. Recently, it has been suggested that PCOS triggers the endoplasmic reticulum (ER) stress, thus being associated with unfolded protein response (UPR) activation. Indeed, the UPR response has been associated with several pathological conditions, including in the reproductive system. Several studies demonstrated that ovarian UPR markers are upregulated in PCOS, being associated with worst ovarian outcomes, and this was ameliorated by ER stress inhibition. In this review, we aim to summarize the main findings from previous studies covering this topic, in an attempt to clarify the potential role of ER stress and the UPR response in the pathophysiology of PCOS.

Effects of Probiotic-Enriched Minas Cheese (Lactobacillus acidophilus La-05) on Cardiovascular Parameters in 5/6 Nephrectomized Rats.

Dairy foods have become an interest in chronic kidney disease (CKD) due to their nutritional profile, which makes them a good substrate for probiotics incorporation. This study evaluated the effect of probiotic-enriched Minas cheese with Lactobacillus acidophilus La-05 in an experimental rat model for CKD on cardiac, inflammatory, and oxidative stress parameters. Male Wistar rats were divided into 4 groups (n = 7/group): 5/6 nephrectomy + conventional Minas cheese (NxC); 5/6 nephrectomy + probiotic Minas cheese (NxPC); Sham + conventional Minas cheese (ShamC); Sham + probiotic Minas cheese (ShamPC). Offering 20 g/day of Minas cheese with Lact. acidophilus La-05 (108-109 log CFU/g) for 6 weeks. The cardiomyocyte diameter was determined. Superoxide dismutase (SOD) activity in plasma, heart, kidney, and colon tissue was performed. At the end of supplementation, no significant changes in lipid profile and renal parameters were found. The NxPC group showed a decrease in cardiomyocyte diameter compared to the NxC group (16.99 ± 0.85 vs. 19.05 ± 0.56 µm, p = 0.0162); also they showed reduced plasmatic SOD activity (502.8 ± 49.12 vs. 599.4 ± 94.69 U/mL, p < 0.0001). In summary, probiotic-enriched Minas cheese (Lact. acidophilus La-05) consumption suggests a promisor cardioprotective effect and was able to downregulate SOD activity in a rat model of CKD.

Renin-angiotensin system modulation through enalapril and/or exercise training improves visceral adiposity in obese mice.

INTRODUCTION: Obesity-related metabolic diseases occur as a result of disruptions in white adipose tissue (WAT) plasticity, especially through visceral fat accumulation and adipocyte hypertrophy. This study aimed to evaluate the impact of renin-angiotensin system (RAS) and bradykinin receptors modulation by enalapril treatment and/or exercise training on WAT morphology and related deleterious outcomes. METHODS: Male C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At the 8th week, HF-fed animals were divided into sedentary (HF), enalapril treatment (HF-E), exercise training (HF-T), and enalapril treatment plus exercise training (HF-ET) groups. Following the experimental protocol, body mass gain, adiposity index, insulin resistance, visceral WAT morphometry, renin-angiotensin system, and bradykinin receptors were evaluated. RESULTS: The HF group displayed increased adiposity, larger visceral fat mass, and adipocyte hypertrophy, which was accompanied by insulin resistance, overactivation of Ang II/AT1R arm, and favoring of B1R in bradykinin receptors profile. All interventions ameliorated visceral adiposity and related outcomes by favoring the Ang 1-7/MasR arm and the B2R expression in B1R/B2R ratio. However, combined therapy additively reduced Ang II/Ang 1-7 ratio. CONCLUSION: Our results suggest that Ang 1-7/MasR arm and B2R activation might be relevant targets in the treatment of visceral obesity.

Supplementation of diet with Brazil nut modulates body composition, bone parameters, and lipid peroxidation in Wistar rats.

Oxidative stress, adipose tissue, and bone compartments can be disturbed in chronic diseases. Non-pharmacological strategies, such as Brazil nuts (BNs), can improve these parameters. This study evaluated the effects of BN supplementation at different concentrations on body composition, lipid profile, and peroxidation in healthy rats. Male Wistar rats were divided into three groups: control (CT), Brazil nut 5% (BN5), and Brazil nut 10% (BN10) groups. Body composition, brown adipose tissue (BAT), plasma lipid peroxidation, and lipid profile were evaluated in the three groups. The BN5 group showed an improvement in all bone parameters compared with that of the CT group (p  < .0001). The BN5 and BN10 groups showed reduced plasma lipid peroxidation compared with that of the CT group (p = .0009), whereas the BN10 group presented lower BAT lipid peroxidation than that of the other groups (p = .01). High-density lipoprotein-cholesterol (HDL-c) levels were higher in the BN5 group than in the CT group (p = .01). Conclusively, the use of BNs in a controlled manner promoted improvement in bone parameters, HDL-c levels, and lipid peroxidation in healthy rats. PRACTICAL APPLICATIONS: Nuts has been included in the diet because of their versatility, acceptance, and easy access. Among them, Brazil nut (BN) is considered one of the major known food sources of selenium as well as a source of fibers, unsaturated fatty acids, and phenolic compounds. Studies have shown that BN supplementation is effective in reducing oxidative stress, inflammation, lipid peroxidation, and selenium deficiency when used as a non-pharmacological strategy in experimental models of chronic diseases and in clinical trials. The present study showed that controlled administration of BN improved bone parameters, high-density lipoprotein-cholesterol levels, and lipid peroxidation in healthy rats. Therefore, BN is a promising non-pharmacological agent for the prevention of the onset of chronic non-communicable diseases.

Evaluation of the effects produced by subacute tributyltin administration on vascular reactivity of male wistar rats.

Tributyltin chloride (TBT) is an organotin compound widely used in several high biocides for agroindustrial applications, such as fungicides, and marine antifouling paints leading to endocrine disrupting actions, such as imposex development in mollusks. In female rats, TBT has been shown to promote ovarian dysfunction, reduction of estrogen protective effect in the vascular morphophysiology, at least in part by oxidative stress consequences. Estrogen causes coronary endothelium-dependent and independent vasodilation. However, the TBT effects on cardiovascular system of male rats are not fully understood. The aim of this study was to evaluate the effects of subacute TBT exposure in aorta vascular reactivity from male wistar rats. Rats were randomly divided into three groups: control (C), TBT 500 ng/kg/day and TBT 1000 ng/kg/day. TBT was administered daily for 30 days by oral gavage. We found that TBT exposure enhanced testosterone serum levels and it was also observed obesogenic properties. TBT exposure evoked an increase in endothelium-dependent and independent phenylephrine-induced contraction, associated to an inhibition in eNOS activity. On the other hand, it was observed an enhancement of iNOS and NF-kB protein expression. We also observed an increase in oxidative stress parameters, such as superoxide dismutase (SOD) and catalase expression, and also an increase in malondialdehyde production. Finally, TBT exposure produced aortic intima-media thickness. Taken together, these data suggest a potential cardiovascular toxicological effect after subacute TBT exposure in male rats.

5/6 nephrectomy affects enteric glial cells and promotes impaired antioxidant defense in the colonic neuromuscular layer.

AIMS: Chronic kidney disease (CKD) produces multiple repercussions in the gastrointestinal tract (GIT), such as alterations in motility, gut microbiota, intestinal permeability, and increased oxidative stress. However, despite enteric glial cells (EGC) having important neural and immune features in GIT physiology, their function in CKD remains unknown. The present study investigates colonic glial markers, inflammation, and antioxidant parameters in a CKD model. MAIN METHODS: A 5/6 nephrectomized rat model was used to induce CKD in rats and Sham-operated animals as a control to suppress. Biochemical measures in plasma and neuromuscular layer such as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity were carried out. Kidney histopathology was evaluated. Colon morphology analysis and glial fibrillary acid protein (GFAP), connexin-43 (Cx43), nuclear factor-kappa B (NF-κB) p65, and GPx protein expression were performed. KEY FINDINGS: The CKD group exhibited dilated tubules and tubulointerstitial fibrosis in the reminiscent kidney (p = 0.0002). CKD rats showed higher SOD activity (p = 0.004) in plasma, with no differences in neuromuscular layer (p = 0.9833). However, GPx activity was decreased in the CKD group in plasma (p = 0.013) and neuromuscular layer (p = 0.0338). Morphological analysis revealed alterations in colonic morphometry with inflammatory foci in the submucosal layer and neuromuscular layer straightness in CKD rats (p = 0.0291). In addition, GFAP, Cx43, NF-κBp65 protein expression were increased, and GPx decreased in the neuromuscular layer of the CKD group (p < 0.05). SIGNIFICANCE: CKD animals present alterations in colonic cytoarchitecture and decreased layer thickness. Moreover, CKD affects the enteric glial network of the neuromuscular layer, associated with decreased antioxidant activity and inflammation.

Comparison between aerobic exercise training and enalapril treatment as tools to improve diet-induced metabolic-associated fatty liver disease: Effects on endoplasmic reticulum stress markers.

AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.