Bothrops lanceolatus snake venom impairs mitochondrial respiration and induces DNA release in human heart preparation.

INTRODUCTION: Envenomations by Bothrops snakebites can induce overwhelming systemic inflammation ultimately leading to multiple organ system failure and death. Release of damage-associated molecular pattern molecules (DAMPs), in particular of mitochondrial origin, has been implicated in the pathophysiology of the deregulated innate immune response. OBJECTIVE: To test whether whole Bothrops lanceolatus venom would induce mitochondrial dysfunction and DAMPs release in human heart preparations. METHODS: Human atrial trabeculae were obtained during cannulation for cardiopulmonary bypass from patients who were undergoing routine coronary artery bypass surgery. Cardiac fibers were incubated with vehicle and whole Bothrops lanceolatus venom for 24hr before high-resolution respirometry, mitochondrial membrane permeability evaluation and quantification of mitochondrial DNA. RESULTS: Compared with vehicle, incubation of human cardiac muscle with whole Bothrops lanceolatus venom for 24hr impaired respiratory control ratio and mitochondrial membrane permeability. Levels of mitochondrial DNA increased in the medium of cardiac cell preparation incubated with venom of Bothrops lanceolatus. CONCLUSION: Our study suggests that whole venom of Bothrops lanceolatus impairs mitochondrial oxidative phosphorylation capacity and increases mitochondrial membrane permeability. Cardiac mitochondrial dysfunction associated with mitochondrial DAMPs release may alter myocardium function and engage the innate immune response, which may both participate to the cardiotoxicity occurring in patients with severe envenomation.

Demographic variables associated with Covid-19 mortality.

Objectives: Covid-19 is a betacoronavirus that was initially transmitted to humans from an animal host. It enters the cell by binding its protein S with angiotensin-converted enzyme receptors. It is transmitted through direct contact and respiratory drops. The most affected population so far are older adults and people with chronic conditions. The objective of this research is to analyze the possible association between the structure of the population pyramid, the Gross Domestic Product, the type of isolation and screening used to detect Covid-19 in the countries with the highest and lowest mortality from this disease. Design and Methods: Some variables take part in the Covid- 19 mortality worldwide, such as the population structure, expressed in the population pyramid by country, the type of isolation adopted in each nation, the Gross Domestic Product (GDP) as well as the type of screening that is implemented in the different countries analyzed. Results: After analyzing the mean difference in the countries with a regressive and progressive population pyramid, an association was identified between the regressive population pyramid structure and the higher mortality rate (p<0.001). Conclusions: The countries with a progressive population pyramid are the most benefited by making their population more screened since the mortality rate decreases significantly compared to the countries with less attribution (p<0.036).

Receptor for advanced glycation end products modulates oxidative stress and mitochondrial function in the soleus muscle of mice fed a high-fat diet.

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE-/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.

Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review.

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

[New therapeutic targets in psoriatic arthritis]. / Nuevas dianas terapéuticas en artritis psoriásica.

Registries estimate that one third of patients with psoriatic arthritis (PsA) are "resistant" to of TNF-alpha blockers. Therefore, the search for new approaches to treatment of this disease may be justified. Currently the treatment options that have proven effective are associated with inhibition of the T cell costimulatory pathway (abatacept and alefacept) and blocking the P40 fraction of IL-12 and IL-23 (ustekinumab). A novel pathway inhibition, which deserves special attention is offered by apremilast. This molecule inhibits phosphodiesterase IV, responsible for hydrolyzing cyclic adenosine monophosphate to adenosine monophosphate, which causes an increase in cAMP. This metabolite is associated with decreased TNF-alpha. It has a modest efficacy (ACR 20 response of 43%), and subsequent studies have shown an improvement in visual analog scale and the SF36 compared to placebo. Currently there are five clinical trials in phase III to assess its effectiveness in parameters of inflammation and radiographic progression. The spectrum of possibilities before treatment failure with anti-TNF alpha, is augmented by the appearance of several reports that show efficacy with the individual use of CD20 inhibitors and IL-1. In patients with rheumatoid arthritis (RA) the effectiveness of molecules that inhibit signal transduction of cytokines (Anti-JAK) has been proven, so it is possible that in the future they may be used in patients with PsA.

Nuevas dianas terapéuticas en artritis psoriásica / New therapeutic targets in psoriatic arthritis

Los registros estiman que un tercio de los pacientes con artritis psoriásica (Aps) son «resistentes» a los bloqueantes del TNF-alfa. Por ello, la búsqueda de nuevos abordajes terapéuticos de la enfermedad es un objetivo que se puede considerar justificado. Actualmente las opciones terapéuticas que han probado su eficacia, son las vinculadas a la inhibición de la vía coestimuladora del linfocito T (abatacept y alefacept) y el bloqueo de la fracción P40 de la IL-12 e IL-23 (ustekinumab). Una novedosa vía de inhibición, que merece especial atención, es la que ofrece Apremilast. Esta molécula inhibe la fosfodiesterasa IV encargada de hidrolizar la adenosina monofosfato cíclica a adenosina monofosfato, lo que provoca un aumento de la cAMP. Este metabolito se relaciona con una disminución del TNF alfa. Capaz de provocar una modesta eficacia (respuesta ACR 20 del 43%), estudios posteriores han demostrado una mejoría en la escala visual analógica y en el SF36 respecto al grupo placebo. Actualmente hay en marcha 5 ensayos clínicos en fase III que evaluarán su eficacia en parámetros de inflamación y de progresión radiográfica. El espectro de posibilidades, ante el fracaso terapéutico con anti-TNF alfa, se amplía con la aparición de diversos reportes donde se ha mostrado eficacia en la utilización individual con agentes inhibidores del CD20 y de la IL-1. Se está demostrando en pacientes con artritis reumatoide (AR) la eficacia de las moléculas que inhiben la transducción de las señales de las citocinas (Anti-JAK), por lo que es posible que en un futuro sean utilizadas en pacientes con Aps (AU)

Registries estimate that one third of patients with psoriatic arthritis (PsA) are "resistant" to of TNF-alpha blockers. Therefore, the search for new approaches to treatment of this disease may be justified. Currently the treatment options that have proven effective are associated with inhibition of the T cell costimulatory pathway (abatacept and alefacept) and blocking the P40 fraction of IL-12 and IL-23 (ustekinumab). A novel pathway inhibition, which deserves special attention is offered by apremilast. This molecule inhibits phosphodiesterase IV, responsible for hydrolyzing cyclic adenosine monophosphate to adenosine monophosphate, which causes an increase in cAMP. This metabolite is associated with decreased TNF-alpha. It has a modest efficacy (ACR 20 response of 43%), and subsequent studies have shown an improvement in visual analog scale and the SF36 compared to placebo. Currently there are five clinical trials in phase III to assess its effectiveness in parameters of inflammation and radiographic progression. The spectrum of possibilities before treatment failure with anti-TNF alpha, is augmented by the appearance of several reports that show efficacy with the individual use of CD20 inhibitors and IL-1. In patients with rheumatoid arthritis (RA) the effectiveness of molecules that inhibit signal transduction of cytokines (Anti-JAK) has been proven, so it is possible that in the future they may be used in patients with PsA (AU)