Explore the vast range of titles available.

Respiratory syncytial virus (RSV) can cause severe respiratory illness in infants, immunocompromised, and older adults. Despite its burden, no vaccine or specific treatment is available. RSV infection is associated with increased reactive oxygen species (ROS) production, degradation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), and decreased antioxidant enzymes (AOEs), leading to oxidative damage and lung injury. Hydrogen sulfide (H2S) is an endogenous gaseous molecule that plays a physiological role in numerous cellular processes and a protective role in multiple pathological conditions, displaying vasoactive, cytoprotective, anti-inflammatory, and antioxidant activities. H2S can promote NRF2 activation through the sulfhydration of Kelch-like ECH-associated protein 1, the cytoplasmic repressor of NRF2. Here we investigated whether increasing cellular H2S levels could rescue NRF2 and NRF2-dependent gene expression in RSV-infected primary airway epithelial cells. We found that treatment with the H2S donor GYY4137 significantly increased NRF2 levels and AOEs gene expression by decreasing KEAP1 levels, and by modulating pathways involved in RSV-induced NRF2 degradation, such as NRF2 ubiquitination, and promyelocytic leukemia (PML) protein levels. These results suggest that the administration of exogenous H2S can positively impact the altered redox balance associated with RSV infection, which represents an important determinant of RSV-induced lung disease.

Hypoxia-inducible factors (HIFs) are transcription factors that enable cells to adapt to low-oxygen environments. Viruses can exploit this pathway to enhance infection, making HIF modulation a potential antiviral strategy. In previous in vitro studies, we found that respiratory syncytial virus (RSV) stabilizes HIFs under normoxic conditions with inhibition of HIF-1α reducing replication. Despite several HIF-modulating compounds being tested or approved in other non-infectious models, little is known about their efficacy against respiratory viruses in relevant animal models. This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. We found that the inhibition of HIF-1α worsened clinical disease parameters while simultaneously improving airway function. Blocking HIF-1α also significantly reduced peak RSV replication in the lung. In contrast, the inhibition of HIF-2α was associated with improved clinical parameters, no changes in airway function, and reduced viral replication following RSV infection. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration.

This study evaluated the effects of omega-3 on inflammation, oxidative stress, and energy metabolism parameters in the brain of mice subjected to high-fat diet-induced obesity model. Body weight and visceral fat weight were evaluated as well. Male Swiss mice were divided into control (purified low-fat diet) and obese (purified high-fat diet). After 6 weeks, the groups were divided into control + saline, control + omega-3, obese + saline, and obese + OMEGA-3. Fish oil (400 mg/kg/day) or saline solution was administrated orally, during 4 weeks. When the experiment completed 10 weeks, the animals were euthanized and the brain and visceral fat were removed. The brain structures (hypothalamus, hippocampus, prefrontal cortex, and striatum) were isolated. Treatment with omega-3 had no effect on body weight, but reduced the visceral fat. Obese animals showed increased inflammation, increased oxidative damage, decreased antioxidant enzymes activity and levels, changes in the Krebs cycle enzyme activities, and inhibition of mitochondrial respiratory chain complexes in the brain structures. Omega-3 treatment partially reversed the changes in the inflammatory and in the oxidative damage parameters and attenuated the alterations in the antioxidant defense and in the energy metabolism (Krebs cycle and mitochondrial respiratory chain). Omega-3 had a beneficial effect on the brain of obese animals, as it partially reversed the changes caused by the consumption of a high-fat diet and consequent obesity. Our results support studies that indicate omega-3 may contribute to obesity treatment.

Cystathionine-y-lyase (CSE) is a critical enzyme for hydrogen sulfide (H2S) biosynthesis and plays a key role in respiratory syncytial virus (RSV) pathogenesis. The transcription factor NRF2 is the master regulator of cytoprotective and antioxidant gene expression, and is degraded during RSV infection. While some evidence supports the role of NRF2 in CSE gene transcription, its role in CSE expression in airway epithelial cells is not known. Here, we show that RSV infection decreased CSE expression and activity in primary small airway epithelial (SAE) cells, while treatment with tert-butylhydroquinone (tBHQ), an NRF2 inducer, led to an increase of both. Using reporter gene assays, we identified an NRF2 response element required for the NRF2 inducible expression of the CSE promoter. Electrophoretic mobility shift assays demonstrated inducible specific NRF2 binding to the DNA probe corresponding to the putative CSE promoter NRF2 binding sequence. Using chromatin immunoprecipitation assays, we found a 50% reduction in NRF2 binding to the endogenous CSE proximal promoter in SAE cells infected with RSV, and increased binding in cells stimulated with tBHQ. Our results support the hypothesis that NRF2 regulates CSE gene transcription in airway epithelial cells, and that RSV-induced NRF2 degradation likely accounts for the observed reduced CSE expression and activity.

The aim of this study was to assess inflammatory parameters, oxidative stress and energy metabolism in the hypothalamus of diet-induced obese mice. Male Swiss mice were divided into two study groups: control group and obese group. The animals in the control group were fed a diet with adequate amounts of macronutrients (normal-lipid diet), whereas the animals in the obese group were fed a high-fat diet to induce obesity. Obesity induction lasted 10 weeks, at the end of this period the disease model was validated in animals. The animals in the obese group had higher calorie consumption, higher body weight and higher weight of mesenteric fat compared to control group. Obesity showed an increase in levels of interleukin 1β and decreased levels of interleukin 10 in the hypothalamus. Furthermore, increased lipid peroxidation and protein carbonylation, and decreased level of glutathione in the hypothalamus of obese animals. However, there was no statistically significant difference in the activity of antioxidant enzymes, superoxide dismutase and catalase. The obese group had lower activity of complex I, II and IV of the mitochondrial respiratory chain, as well as lower activity of creatine kinase in the hypothalamus as compared to the control group. Thus, the results from this study showed changes in inflammatory markers, and dysregulation of metabolic enzymes in the pathophysiology of obesity.

The current paradigms of prevention and treatment are unable to curb obesity rates, which indicates the need to explore alternative therapeutic approaches. Obesity leads to several damages to the body and is an important risk factor for a number of other chronic diseases. Furthermore, despite the first alterations in obesity being observed and reported in peripheral tissues, studies indicate that obesity can also cause brain damage. Obesity leads to a chronic low-grade inflammatory state, and the therapeutic manipulation of inflammation can be explored. In this context, the use of n-3 PUFA (especially in the form of fish oil, rich in EPA and DHA) may be an interesting strategy, as this substance is known by its anti-inflammatory effect and numerous benefits to the body, such as reduction of TAG, cardiac arrhythmias, blood pressure and platelet aggregation, and has shown potential to help treat obesity. Thereby, the aim of this narrative review was to summarise the literature related to n-3 PUFA use in obesity treatment. First, the review provides a brief description of the obesity pathophysiology, including alterations that occur in peripheral tissues and at the central nervous system. In the sequence, we describe what are n-3 PUFA, their sources and their general effects. Finally, we explore the main topic linking obesity and n-3 PUFA. Animal and human studies were included and alterations on the whole organism were described (peripheral tissues and brain).

Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to activate this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previous studies, we found that respiratory syncytial virus (RSV), a leading cause of respiratory illness, stabilizes HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α (PT2385) inhibitors in RSV-infected BALB/c mice. We found that inhibition of HIF-1α worsen clinical disease parameters, while simultaneously improving lung inflammation and airway function. Additionally, blocking HIF-1α resulted in significantly reduced viral titer at early and peak time points of RSV replication. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, enhanced immune responses and reduced early and peak lung viral replication. Analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of the compounds that are currently in use or under therapeutic consideration.

Obesity causes inflammation in the adipose tissue and can affect the central nervous system, leading to oxidative stress and mitochondrial dysfunction. Therefore, it becomes necessary to seek new therapeutic alternatives. Gold nanoparticles (GNPs) could take carnitine to the adipose tissue, thus increasing fatty acid oxidation, reducing inflammation, and, consequently, restoring brain homeostasis. The objective of this study was to investigate the effects of GNPs associated with carnitine on the neurochemical parameters of obesity-induced mice. Eighty male Swiss mice that received a normal lipid diet (control group) or a high-fat diet (obese group) for 10 weeks were used. At the end of the sixth week, the groups were divided for daily treatment with saline, GNPs (70 µg/kg), carnitine (500 mg/kg), or GNPs associated with carnitine, respectively. Body weight was monitored weekly. At the end of the tenth week, the animals were euthanized and the mesenteric fat removed and weighed; the brain structures were separated for biochemical analysis. It was found that obesity caused oxidative damage and mitochondrial dysfunction in brain structures. Treatment with GNPs isolated reduced oxidative stress in the hippocampus. Carnitine isolated decreased the accumulation of mesenteric fat and oxidative stress in the hippocampus. The combination of treatments reduced the accumulation of mesenteric fat and mitochondrial dysfunction in the striatum. Therefore, these treatments in isolation, become a promising option for the treatment of obesity.

RSV and SARS-CoV-2 are prone to co-infection with other respiratory viruses. In this study, we use RSV/SARS-CoV-2 co-infection to evaluate changes to clinical disease and viral replication in vivo. To consider the severity of RSV infection, effect of sequential infection, and the impact of infection timing, mice were co-infected with varying doses and timing. Compared with a single infection of RSV or SARS-CoV-2, the co-infection of RSV/SARS-CoV-2 and the primary infection of RSV followed by SARS-CoV-2 results in protection from SARS-CoV-2-induced clinical disease and reduces SARS-CoV-2 replication. Co-infection also augmented RSV replication at early timepoints with only the low dose. Additionally, the sequential infection of RSV followed by SARS-CoV-2 led to improved RSV clearance regardless of viral load. However, SARS-CoV-2 infection followed by RSV results in enhanced SARS-CoV-2-induced disease while protecting from RSV-induced disease. SARS-CoV-2/RSV sequential infection also reduced RSV replication in the lung tissue, regardless of viral load. Collectively, these data suggest that RSV and SARS-CoV-2 co-infection may afford protection from or enhancement of disease based on variation in infection timing, viral infection order, and/or viral dose. In the pediatric population, understanding these infection dynamics will be critical to treat patients and mitigate disease outcomes.

Major depression is a heterogeneous psychiatric disorder whose pathophysiology is not clearly established yet. Some studies have shown that oxidative stress and mitochondrial dysfunction are involved in the development of major depression. Since most depressed patients do not achieve complete remission of symptoms, new therapeutic alternatives are needed and omega-3 has been highlighted in this scenario. Therefore, we have investigated the effects of omega-3 on behavioral and biochemical parameters in rats submitted to chronic mild stress (CMS). Male Wistar rats were submitted to CMS for 40 days. After the CMS period, we administered a 500 mg/kg dose of omega-3 orally, once a day, for 7 days. The animals submitted to CMS presented anhedonia, had no significant weight gain, presented increased levels of lipid peroxidation and protein carbonylation, and inhibition of complex I and IV activities of the mitochondrial respiratory chain. The treatment with omega-3 did not reverse anhedonia; however, it reversed weight change, increased lipid peroxidation and protein carbonylation levels, and partially reversed the inhibition of mitochondrial respiratory chain complexes. The findings support studies that state that major depression is associated with mitochondrial dysfunction and oxidative stress, and that omega-3 supplementation could reverse some of these changes, probably due to its antioxidant properties.