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Cardiotoxicity is the serious side effect of doxorubicin treatment. Ceramides are formed from the degradation of sphingolipids in cell membranes and play an important role in signaling and modulating biological processes. There is evidence that omega-3 fatty acid administration can act on this pathway. To evaluate the role of the ceramide pathway in the pathophysiology of doxorubicin-induced cardiotoxicity and the effect of omega-3 fatty acid supplementation in the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Sixty male Wistar rats were divided into four groups: Control (C), Doxorubicin (D), Omega-3 fatty acids (W), and Doxorubicin + Omega-3 fatty acids (DW). The groups received omega-3 fatty acids (400 mg/kg/day, via gavage) or water for 6 weeks and doxorubicin (3.5 mg/kg, intraperitoneal) or saline once a week for 4 weeks. Doxorubicin-treated animals showed increases in left atrium and left ventricle diameters, serum triglycerides and cholesterol, malondialdehyde, and protein carbonylation. We also observed a decrease in left ventricular shortening fraction and nSMase1 expression in the heart. Omega-3 fatty acid supplementation attenuated the structural and functional alterations caused by doxorubicin and decreased protein carbonylation. In contrast to doxorubicin, omega-3 fatty acids increased neutral nSMase activity in animals that both received and did not receive doxorubicin but with no effect on nSMase1 protein expression. Omega-3 fatty acid supplementation attenuated the cardiotoxicity caused by doxorubicin. The ceramide pathway may be involved in the pathophysiology of cardiotoxicity, but it is not the mechanism by which omega-3 fatty acids attenuated cardiac dysfunction., Competing Interests: The authors declare that they do not have any conflict of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug widely used to treat cancer, but its use is limited due to multisystemic toxicity. Lipid metabolism is also affected by doxorubicin. Orange juice can reduce dyslipidemia in other clinical situations and has already been shown to attenuate cardiotoxicity. Our aim is to evaluate the effects of Pera orange juice ( Citrus sinensis L. Osbeck ) on mitigating lipid metabolism imbalance, metabolic pathways, and DOX induced cytotoxic effects in the heart and liver., Methods: Twenty-four male Wistar rats were allocated into 3 groups: Control (C); DOX (D); and DOX plus Pera orange juice (DOJ). DOJ received orange juice for 4 weeks, while C and D received water. At the end of each week, D and DOJ groups received 4 mg/kg/week DOX, intraperitoneal. At the end of 4 weeks animals were submitted to echocardiography and euthanasia., Results: Animals treated with DOX decreased water intake and lost weight over time. At echocardiography, DOX treated rats presented morphologic alterations in the heart. DOX increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. It also reduced superoxide dismutase (SOD) activity, increased protein carbonylation in the heart and dihydroethidium (DHE) expression in the liver, decreased glucose transporter type 4 (GLUT4) and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ 1 ) in the heart, and reduced carnitine palmitoyltransferase I (CPT1) in the liver., Conclusion: DOX caused dyslipidemia, liver and cardiac toxicity by increasing oxidative stress, and altered energy metabolic parameters in both organs. Despite not improving changes in left ventricular morphology, orange juice did attenuate oxidative stress and mitigate the metabolic effects of DOX., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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 2β 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.

Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis., Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths., Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Organizing pneumonia (OP) is an interstitial lung disease, and can be cryptogenic, if no cause is identified, or secondary to several conditions. COVID-19-induced persistent inflammation can be associated with interstitial lung disease. We present a review of literature of OP and COVID-19-induced OP with an illustrative case. A 38-year-old man was admitted with COVID-19 that required mechanical ventilation for 56 days. Initial chest computed tomography (CT) revealed diffuse bilateral ground-glass opacities in the lungs with consolidation areas involving 75 % of the parenchyma. After weaning from MV, the patient still required oxygen supplementation. A new chest CT scan also showed extensive diffuse areas of consolidation and ground-glass opacity. OP was hypothesized and 40 mg/day prednisone initiated and continued for six months with resolution of lung functional and image abnormalities. Organizing pneumonia should be included in the differential diagnosis of COVID-19 patients with respiratory symptoms after partial pulmonary recovery., Competing Interests: Declaration of Competing Interest The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Cardiac arrest is an important public health issue, with a survival rate of approximately 15 to 22%. A great proportion of these deaths occur after resuscitation due to post-cardiac arrest syndrome, which is characterized by the ischemia-reperfusion injury that affects the role body. Understanding physiopathology is mandatory to discover new treatment strategies and obtain better results. Besides improvements in cardiopulmonary resuscitation maneuvers, the great increase in survival rates observed in recent decades is due to new approaches to post-cardiac arrest care. In this review, we will discuss physiopathology, etiologies, and post-resuscitation care, emphasizing targeted temperature management, early coronary angiography, and rehabilitation.

Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that clinically manifest as changes in the heart's size, mass, geometry, and function after different stimuli. It is important to emphasize that remodeling plays a pathophysiological role in the onset and progression of ventricular dysfunction and subsequent heart failure. Therefore, strategies to mitigate this process are critical. Different factors, including neurohormonal activation, can regulate the remodeling process and increase cell death, alterations in contractile and regulatory proteins, alterations in energy metabolism, changes in genomics, inflammation, changes in calcium transit, metalloproteases activation, fibrosis, alterations in matricellular proteins, and changes in left ventricular geometry, among other mechanisms. More recently, the role of reactive oxygen species and oxidative stress as modulators of remodeling has been gaining attention. Therefore, this review assesses the role of oxidative stress as a therapeutic target of cardiac remodeling.

Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that manifest clinically as changes in the heart's size, mass, geometry, and function after different injuries. Importantly, remodeling is associated with increased risk of ventricular dysfunction and heart failure. Therefore, strategies to attenuate this process are critical. Reactive oxygen species and oxidative stress play critical roles in remodeling. Importantly, antioxidative dietary compounds potentially have protective properties against remodeling. Therefore, this review evaluates the role of nutrients and food as modulators of cardiac remodeling.

Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.

BACKGROUND Gout is a chronic disease characterized by deposition of monosodium urate crystals, typically manifesting as arthritis. Clinical presentation of gout usually results from activation of local inflammatory response. Despite being one of the oldest diseases in the world, gout pathophysiology is incompletely understood and clinical features are still surprising. Recent reports describe unusual manifestations including atypical joints involvement, tenosynovitis, panniculitis, and multinodular inguinal swelling. Another atypical feature is the acute polyarticular gout with severe systemic inflammatory response. CASE REPORT We report the case of a 55-year-old man presenting with fever, tachycardia, cauda equina syndrome, left-knee arthritis, and systemic inflammatory manifestations. Lumbar spine magnetic resonance imaging showed a 4.0×1.3×2.2 cm calcified mass inside the vertebral canal at the L4-L5 level, causing stenosis of the dural space and intervertebral foramen. Clinical diagnoses were septic knee arthritis and lumbar spine meningioma. Despite antibiotic therapy and left-knee surgical drainage, fever and increased C-reactive protein persisted, and arthritis developed in the elbows and right knee. As cultures were negatives, we then diagnosed gout flare in the affected joints accompanied by a severe systemic inflammatory reaction. A few days after starting colchicine and anti-inflammatory drugs, symptoms and inflammatory markers subsided. It was such a severe attack that we called it a "gout storm". CONCLUSIONS The report highlights the difficulty in diagnosing acute polyarticular gout affecting atypical joints, particularly when faced with a severe systemic inflammatory reaction.