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Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2ß did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.

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Cardiac remodeling is defined as molecular, cellular, and interstitial changes that manifest clinically as alterations in the size, shape, and function of the heart. Despite the pharmacological approaches, cardiac remodeling-related mortality rates remain high. Therefore, other therapeutic options are being increasingly studied. This review highlights the role of omega-3 as an adjunctive therapy to attenuate cardiac remodeling, with an emphasis on its antioxidant and anti-inflammatory actions.

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Cardiovascular disease is a leading cause of death worldwide. Heart failure is a cardiovascular disease with high prevalence, morbidity, and mortality. Several natural compounds have been studied for attenuating pathological cardiac remodeling. Orange juice has been associated with cardiovascular disease prevention by attenuating oxidative stress. However, most studies have evaluated isolated phytochemicals rather than whole orange juice and usually under pathological conditions. In this study, we evaluated plasma metabolomics in healthy rats receiving Pera or Moro orange juice to identify possible metabolic pathways and their effects on the heart. METHODS: Sixty male Wistar rats were allocated into 3 groups: control (C), Pera orange juice (PO), and Moro orange juice (MO). PO and MO groups received Pera orange juice or Moro orange juice, respectively, and C received water with maltodextrin (100 g/L). Echocardiogram and euthanasia were performed after 4 weeks. Plasma metabolomic analysis was performed by high-resolution mass spectrometry. Type I collagen was evaluated in picrosirius red-stained slides and matrix metalloproteinase (MMP)-2 activity by zymography. MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-4, type I collagen, and TNF-α protein expression were evaluated by Western blotting. RESULTS: We differentially identified three metabolites in PO (N-docosahexaenoyl-phenylalanine, diglyceride, and phosphatidylethanolamine) and six in MO (N-formylmaleamic acid, N2-acetyl-L-ornithine, casegravol isovalerate, abscisic alcohol 11-glucoside, cyclic phosphatidic acid, and torvoside C), compared to controls, which are recognized for their possible roles in cardiac remodeling, such as extracellular matrix regulation, inflammation, oxidative stress, and membrane integrity. Cardiac function, collagen level, MMP-2 activity, and MMP-9, TIMP-2, TIMP-4, type I collagen, and TNF-α protein expression did not differ between groups. CONCLUSION: Ingestion of Pera and Moro orange juice induces changes in plasma metabolites related to the regulation of extracellular matrix, inflammation, oxidative stress, and membrane integrity in healthy rats. Moro orange juice induces a larger number of differentially expressed metabolites than Pera orange juice. Alterations in plasma metabolomics induced by both orange juice are not associated with modifications in cardiac extracellular matrix components. Our results allow us to postulate that orange juice may have beneficial effects on pathological cardiac remodeling.

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BACKGROUND: Stroke is a leading cause of mortality and disability, and its sequelae are associated with inadequate food intake which can lead to sarcopenia. The aim of this study is to verify the effectiveness of creatine supplementation on functional capacity, strength, and changes in muscle mass during hospitalization for stroke compared to usual care. An exploratory subanalysis will be performed to assess the inflammatory profiles of all participants, in addition to a follow-up 90 days after stroke, to verify functional capacity, muscle strength, mortality, and quality of life. METHODS: Randomized, double-blind, unicenter, parallel-group trial including individuals with ischemic stroke in the acute phase. The duration of the trial for the individual subject will be approximately 90 days, and each subject will attend a maximum of three visits. Clinical, biochemical, anthropometric, body composition, muscle strength, functional capacity, degree of dependence, and quality of life assessments will be performed. Thirty participants will be divided into two groups: intervention (patients will intake one sachet containing 10g of creatine twice a day) and control (patients will intake one sachet containing 10g of placebo [maltodextrin] twice a day). Both groups will receive supplementation with powdered milk protein serum isolate to achieve the goal of 1.5g of protein/kg of body weight/day and daily physiotherapy according to the current rehabilitation guidelines for patients with stroke. Supplementation will be offered during the 7-day hospitalization. The primary outcomes will be functional capacity, strength, and changes in muscle mass after the intervention as assessed by the Modified Rankin Scale, Timed Up and Go test, handgrip strength, 30-s chair stand test, muscle ultrasonography, electrical bioimpedance, and identification of muscle degradation markers by D3-methylhistidine. Follow-up will be performed 90 days after stroke to verify functional capacity, muscle strength, mortality, and quality of life. DISCUSSION: The older population has specific nutrient needs, especially for muscle mass and function maintenance. Considering that stroke is a potentially disabling event that can lead the affected individual to present with numerous sequelae, it is crucial to study the mechanisms of muscle mass loss and understand how adequate supplementation can help these patients to better recover. TRIAL REGISTRATION: The Brazilian Clinical Trials Registry (ReBEC) RBR-9q7gg4 . Registered on 21 January 2019.

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BACKGROUND Rheumatoid arthritis (RA) can cause extra-articular manifestations, and the myocardium can be a target. This study aimed to describe structural and functional cardiac echocardiographic variables in RA patients and to evaluate whether vitamin D (VD) levels and inflammation markers, evaluated by Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP), are associated with cardiac remodeling (CR) in this population. MATERIAL AND METHODS This prospective observational study evaluated 90 patients with RA in Botucatu University Hospital wards from 2014 to 2017. Clinical data were recorded, including demographic information, comorbidities, length of disease, and treatment type. Serum VD and C-reactive protein levels were measured, and the DAS28-CRP was calculated. A transthoracic echocardiography study was performed. The outcome evaluated was CR. This parameter was assessed by left ventricular geometric patterns and left atrium diameter. RESULTS We evaluated 90 RA patients. The mean age was 52.9±10.8 years, and 17.8% were male. The length of the disease was 96 (60-180) months. Serum VD levels were 30.7±10.4 ng/mL and the DAS28 was 2.7±0.9. Regarding the CR parameters, 56.7% had altered left ventricular geometric patterns and 25.8% had enlargement of left atrium diameter. Even in multivariate analysis, the left ventricular geometric patterns were not associated with the VD levels and the inflammation marker used. However, sufficient VD levels protect from left atrium enlargement (OR: 0.905; IC 95%: 0.843-0.973; P=0.007). CONCLUSIONS Low serum vitamin D values, but not inflammation, are associated with CR in patients with RA.

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The objective of this study was to assess whether acute green tea (GT) supplementation attenuates inflammatory and oxidative stress biomarkers induced by high-fat, high-saturated (HFHS) meals in obese women, and to assess its ability to modulate circulating microRNA (miRNA) expression. This was a randomized, double-blind, crossover study. The study included obese women over 18 years old who had no comorbidities. In the first moment, patients were instructed to take 2 capsules of placebo or GT (738 mg) at 10:00 p.m. and to fast overnight. The next morning, a blood sample was collected, and an HFHS meal was offered to the patients. Another blood sample was collected 5 hours after the meal. In the second moment, patients who received placebo in the first moment now received the GT and vice-versa. Serum inflammatory and oxidative stress biomarkers were measured, and circulating levels of miRNA were evaluated. Fifteen women with mean age of 35.5±9.9 years were included in the final analysis. There was no difference regarding inflammatory and oxidative stress biomarkers. However, patients who consumed GT had lower circulating expression of 62 miRNAs compared with patients who did not consume GT. Predictive analysis of target genes showed 1,757 targets regulated by the 62 miRNAs. Notably, 5 miRNAs (miR-1297, miR-192-5p, miR-373-3p, miR-595 and miR-1266-5p) regulate genes associated with TGF-beta, CARM1, RSK, and BMP pathways. Our study showed that GT inhibited the expression of miRNAs induced by HFHS meal intake. These results shed light on the mechanisms involved in the beneficial effects of GT ingestion.

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BACKGROUND: Mechanisms involved in cardiac remodelling by aortic regurgitation (AR) and the moment when cardiac dysfunction begins are largely unknown. This study aimed to investigate cardiac morphology and function after 1, 4, 8, and 12 weeks of experimental AR in Wistar rats. Extracellular matrix was also investigated as the potential mechanism that underlies the AR remodelling process. METHODS: Male Wistar rats underwent surgical acute AR (AR group, n=51) or a sham surgery (sham group, n=32). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 12 weeks. Morphometry of cardiac tissue and the activities of metalloproteinase 2 (MMP-2) and tissue metalloproteinase inhibitor-1 (TIMP-1) were analysed. Statistical analysis was performed by two-way ANOVA. Significance level was 5%. RESULTS: The AR group presented an increase in the sphericity index (week 1); an increase in the left atrium, left ventricular mass index, TIMP-1 and MMP-2 activities, and collagen fraction (week 4); an increase in myocyte area (week 8); and a reduction in fraction shortening (week 12). First, the chamber became more spherical; second, MMP-2 and TIMP-1 were activated and this may have contributed to hypertrophy and atrial enlargement, until systolic dysfunction occurred. CONCLUSIONS: This study showed a sequence of abnormalities that preceded myocardial dysfunction in an experimental model of AR. First, haemodynamic volume overload led to a more spherical left ventricle chamber. Second, MMP-2 and TIMP-1 transitorily increased and may have contributed to atrial enlargement, eccentric hypertrophy, and systolic dysfunction.

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AIM: This study aimed to evaluate the association between serum myostatin levels, hospital mortality, and muscle mass and strength following ST-segment elevation myocardial infarction (STEMI). METHODS: This was a prospective observational study. Within 48 hours of admission, bioelectrical impedance and handgrip strength were assessed and blood samples collected for myostatin evaluation. Hospital mortality was recorded. A multiple logistic regression model was also constructed, adjusted by parameters that exhibited significant differences in the univariate analysis, to evaluate the association between myostatin levels and hospital mortality. RESULTS: One hundred and two (102) patients were included: mean age was 60.5±10.6 years, 67.6% were male, and 6.9% died during hospital stay. Univariate analysis showed that patients with lower myostatin levels had higher mortality rates. Serum myostatin levels positively correlated with handgrip strength (r=0.355; p<0.001) and appendicular skeletal muscle mass index (r=0.268; p=0.007). Receiver operating characteristic (ROC) curve analysis revealed that lower myostatin levels were associated with hospital mortality at the <2.20 ng/mL cut-off. Multiple logistic regression showed that higher serum myostatin levels were associated with reduced hospital mortality when adjusted by ß blocker use (OR, 0.228; 95% CI, 0.054-0.974; p=0.046). CONCLUSIONS: Serum myostatin concentrations positively correlated with muscle mass and strength in STEMI patients. Further assessment of serum myostatin association with mortality should be conducted using a larger sample and assessing the additive value to the Global Registry of Acute Coronary Events (GRACE) or thrombolysis in myocardial infarction (TIMI) risk scores.

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