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Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development.

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Inada and Ido identified Leptospira sp. as the pathogen responsible for Weil's Disease in 1915. Later, it was confirmed that Leptospira causes leptospirosis. The host microorganism's interaction at the cellular level remained misunderstood for many years. Although different bacterial components have been isolated and purified, the complexity of the molecular interactions between these components and the host and the molecular mechanisms responsible for the systemic dysfunctions still needs to be fully unveiled. Leptospirosis affects virtually all animal species. Its cellular pathophysiology must involve a ubiquitous cellular mechanism in all eukaryotes. Na/K-ATPase is the molecular target of the leptospiral endotoxin (glycolipoprotein-GLP). Na/K-ATPase dysfunctions on different types of cells give rise to the organ disorders manifested in leptospirosis. Concomitantly, the development of a peculiar metabolic disorder characterized by dyslipidemia, with increased levels of circulating free fatty acids and an imbalance in the fatty acid/albumin molar ratio, triggers events of cellular lipotoxicity. Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis. Leptospirosis involves diverse molecular mechanisms and alteration in patient inflammatory and metabolic status. Nonetheless, Na/K-ATPase is critical in the disease, and it is targeted by GLP, its components, and other molecules, such as fatty acids, that inhibit or trigger intracellular signaling through this enzyme. Herein, we overview the role of Na/K-ATPase during leptospirosis infection as a potential therapeutic target or an indicator of disease severity.

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The present study investigated the effects of murici and tapereba on improving hepatic and inflammatory biomarkers in high-fat-diet rats. Female Wistar rats were divided into five groups (n = 10/group): control (CON), high-fat diet (HF), murici drink + high-fat diet (Mu-HF), tapereba drink + high-fat diet (Tap-HF), and murici and tapereba blend drink + high-fat diet (MT-HF). Drinks were offered daily for 60 days, following which body and liver weights, hepatosomatic indexes, serum parameters, inflammatory profile, and antioxidant activity (DPPH and ORAC) were analyzed. The cell death of hepatic cells was evaluated using flow cytometry. It was observed that weight gain was similar among the groups, while glycemia was lower in the MT-HF group. A high-fat diet increased the concentration of cholesterol total, ALT, IL-1ß (in plasma and liver), and TNF-α (in the liver), and this was reduced by treatment with the fruit-based beverages. The other evaluated parameters showed no statistically significant difference. Compared to the CON and HF groups, the groups that received the drinks had higher cellular antioxidant activity and reduced oxidative stress, lipid oxidation, and development of pro-inflammatory cytokines, such as IL-1ß. A high-fat diet induced higher cell death in hepatic tissue, which was prevented by the murici, tapereba, and the fruit-blend drinks. The consumption of murici, tapereba, and fruit-blend-based beverages showed beneficial effects on liver metabolism; therefore, they may serve as a nutritional approach for preventing and treating non-alcoholic liver disease.

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Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.

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Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells' Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology.

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Fungal diseases are a significant cause of morbidity and mortality worldwide, primarily affecting immunocompromised patients. Aspergillus, Pneumocystis, and Cryptococcus are opportunistic fungi and may cause severe lung disease. They can develop mechanisms to evade the host immune system and colonize or cause lung disease. Current fungal infection treatments constitute a few classes of antifungal drugs with significant fungi resistance development. Amphotericin B (AmB) has a broad-spectrum antifungal effect with a low incidence of resistance. However, AmB is a highly lipophilic antifungal with low solubility and permeability and is unstable in light, heat, and oxygen. Due to the difficulty of achieving adequate concentrations of AmB in the lung by intravenous administration and seeking to minimize adverse effects, nebulized AmB has been used. The pulmonary pathway has advantages such as its rapid onset of action, low metabolic activity at the site of action, ability to avoid first-pass hepatic metabolism, lower risk of adverse effects, and thin thickness of the alveolar epithelium. This paper presented different strategies for pulmonary AmB delivery, detailing the potential of nanoformulation and hoping to foster research in the field. Our finds indicate that despite an optimistic scenario for the pulmonary formulation of AmB based on the encouraging results discussed here, there is still no product registration on the FDA nor any clinical trial undergoing ClinicalTrial.gov.

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Malaria is caused by the protozoan Plasmodium sp and affects millions of people worldwide. Its clinical form ranges from asymptomatic to potentially fatal and severe. Current treatments include single drugs such as chloroquine, lumefantrine, primaquine, or in combination with artemisinin or its derivatives. Resistance to antimalarial drugs has increased; therefore, there is an urgent need to diversify therapeutic approaches. The disease cycle is influenced by biological, social, and anthropological factors. This longevity and complexity contributes to the records of drug resistance, where further studies and proposals for new therapeutic formulations are needed for successful treatment of malaria. Nanotechnology is promising for drug development. Preclinical formulations with antimalarial agents have shown positive results, but only a few have progressed to clinical phase. Therefore, studies focusing on the development and evaluation of antimalarial formulations should be encouraged because of their enormous therapeutic potential.

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Muscle and adipose tissue produce irisin during exercise. Irisin is thermogenic adipomyokine, improves glucose and lipid metabolism, and ameliorates the effects of obesity-driven inflammation, metabolic syndrome, and diabetes. In addition, exercise-induced irisin activates anti-inflammatory pathways and may play an essential role in improving the outcomes of inflammatory conditions, such as coronavirus disease (COVID-19). COVID-19 infection can activate different intracellular receptors and modulate various pathways during the course of the disease. The cytokine release storm (CRS) produced is significant because it promotes the context for systemic inflammation, which increases the risk of mortality in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). In addition, viral infection and the resulting organ damage may stimulate the mitogen-activated protein kinase(MAPK) and toll-like receptor 4 (TLR4)/toll interleukin receptor (TIR)-domain-containing adaptor (MyD88) pathways while negatively modulating the AMP-activated protein kinase (AMPK) pathway, leading to increased inflammatory cytokine production. Exercise-induced irisin may counteract this inflammatory modulation by decreasing cytokine production. Consequently, increased irisin levels, as found in healthy patients, may favor a better prognosis in patients with SARS-CoV2. This review aims to explore the molecular mechanisms underlying the anti-inflammatory properties of irisin in mitigating CRS and preventing severe outcomes due to infection with SARS-CoV2.

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Chronic obstructive pulmonary disease (COPD) is one of the leading global causes of morbidity and mortality. A hallmark of COPD is progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. Different cell types, including macrophages, epithelial cells, neutrophils, and T lymphocytes, contribute to COPD pathophysiology. Alteration in cell functions results in the generation of an oxidative and inflammatory microenvironment, which contributes to disease progression. Current treatments include inhaled corticosteroids and bronchodilator therapy. However, these therapies do not effectively halt disease progression. Due to the complexity of its pathophysiology, and the risk of exacerbating symptoms with existing therapies, other specific and effective treatment options are required. Therapies directly or indirectly targeting the oxidative imbalance may be promising alternatives. This review briefly discusses COPD pathophysiology, and provides an update on the development and clinical testing of novel COPD treatments.

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An insult can trigger a protective response or even cell death depending on different factors that include the duration and magnitude of the event and the ability of the cell to activate protective intracellular signals, including inflammatory cytokines. Our previous work showed that the treatment of Lister Hooded rat retinal cell cultures with 50 ng/mL phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, increases the survival of retinal ganglion cells (RGCs) kept in culture for 48 h after axotomy. Here we aim to analyze how PMA modulates the levels of TNF-α and IL-1ß (both key inflammatory mediators) and the impact of this modulation on RGCs survival. We hypothesize that the increase in RGCs survival mediated by PMA treatment depends upon modulation of the levels of IL-1ß and TNF-α. The effect of PMA treatment was assayed on cell viability, caspase 3 activation, TNF-α and IL-1ß release and TNF receptor type I (TNFRI) and TNF receptor type II (TNFRII) levels. PMA treatment increases IL-1ß and TNF-α levels in 15 min in culture and increases the release of both cytokines after 30 min and 24 h, respectively. Both IL-1ß and TNF-α levels decrease after 48 h of PMA treatment. PMA treatment also induces an increase in TNFRII levels while decreasing TNFRI after 24 h. PMA also inhibited caspase-3 activation, and decreased ROS production and EthD-1/calcein ratio in retinal cell cultures leading to an increase in cell viability. The neutralization of IL-1ß (anti-IL1ß 0,1ng/mL), the neutralization of TNF-α (anti-TNF-α 0,1ng/mL) and the TNF-α inhibition using a recombinant soluble TNFRII abolished PMA effect on RGCs survival. These data suggest that PMA treatment induces IL1ß and TNF-α release and modulation of TNFRI/TNFRII expression promoting RGCs survival after axotomy.

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