Role of NLRP3-inflammasone in functional decline in physiological aging. Implications for cardio-metabolic events.

Aging constitutes the major risk factor for metabolic disabilities onset and cardiovascular disease. Clinically, is associated with an increase in IL1β and IL18, which are cytokines released after inflammasome-dependent caspase-1 activation. This suggests that prevalence and severity of age-related diseases is partly due to chronic inflammasome activation and its contribution to increased inflammatory state. Age-related systemic inflammation is overall produced in numerous organs, including the heart and metabolic tissues such as liver. It is widely believed that a common mechanism drives to several declining disorders triggering adverse impact on healthy aging and affecting therefore, the quality of life and healthspan. This common nexus is termed inflamm-aging. The idea of inflammaging refers to a progressive increase of a proinflammatory state, a systemic low-grade inflammatory process that contributes to the onset and development of chronic diseases and degenerative changes as we age. Interestingly, age-related chronic low-grade inflammation leads to functional decline in many organs even in the absence of a particular disease. Inflammation could be defined as an acute reaction in response to infection or tissue damage to point out a particular injury. Nonetheless, when inflammation becomes chronic, it may trigger collateral damage and in some cases, autoimmune pathologies. Sometimes, inflammatory responses are stress-associated or host-derived signals that are known as damage-associated molecular patterns (DAMPs), which are released as a result of tissue homeostasis imbalance, such as self-derived ATP, cholesterol crystals, uric acid, glucose or environment-derived silica, among others. The inflammasome is a complex of multimeric proteins that consist of an intracellular sensor protein, the Nod-like receptor (NLR); the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and, the proinflammatory caspase-1 precursor. The most in depth studied inflammasome is NLRP3, which is activated by a wide spectrum of stress and danger signals. Additionally, NLRP3 is special among innate immunity sensors, since is the only inflammasome that can be activated in response to a diverse gamut of host-derived metabolic “danger signals” to trigger “sterile inflammation”, which means an inflammatory response not caused by microbes. NLRP3- inflammasome mediated processes are therefore, crucial for both immunological and metabolic regulation. Importantly, it has been demonstrated that a large number of host-derived NLRP3-inflammasome activators tend to accumulate during the aging process, such as cholesterol crystals, resulting from acquired dietary patterns that maintain the chronic inflammatory state over time, together with the chronic lowgrade inflammation that aging itself involves, highly contribute to cardiometabolic diseases prevalence and severity. Autophagy is the main mechanism in charge of damaged organelles accumulation clearance, and its regulation depends on both intracellular and extracellular signals. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are genes involved in longevity and central regulators of autophagic machinery. Under nutrient limiting conditions autophagy becomes active by AMPK, via various mechanisms. However, when mTOR is activated autophagy gets inhibited. Both longevity genes are masters’ regulators of metabolism and there is existing evidence reporting that rather the activation of AMPK or mTOR attenuation enhance cardiac function. AMPK is essential to maintain cardio-metabolic homeostasis. This kinase has shown to be cardioprotective during ischemia. According to some research, mouse models lacking AMPK functionality, had exarcebated myocardial infarction. Activation of AMPK by metformin reduced overload- induced cardiac hypertrophy. Interestingly, it has been recently reported that nutraceutical compounds, including resveratrol, hydroxytyrosol or some flavonols among others, have AMPK-mediated therapeutic effects on diabetes mellitus and CVD, which gives a natural approach to AMPK pathway activation and cardio-metabolic events control. Cardio-metabolic events, such as type 2 diabetes mellitus, insulin resistance, metabolic syndrome, or cardiovascular disease, are determined by an individual’s age. Age-associated chronic inflammatory responses together with western-type lifestyle and certain acquired behavioral habits may induce autophagy impairment, shortened healthspan and a bad quality of life during aging. Data from the World Health Organization (WHO), estimate that by 2050 the proportion of the world’s population over 60 years old, will nearly double, which will represent an increase of 10%. Getting older is the major risk factor for the development of chronic diseases and represents an extraordinary financial burden on the health care systems, constituting a sanitary and a socioeconomic matter. Developing new strategies to attenuate chronic inflammatory state during aging might be a potential target to avoid many age-related cardiometabolic diseases. Here, we demonstrate that either the ablation of NLRP3-inflammasome or its specific pharmacological inhibition with the molecule MCC950, not only might contribute to lifespan, but also to extend healthspan, which is ultimately, the most appealing interest of becoming older.Premio Extraordinario de Doctorado U

AMPK Phosphorylation Modulates Pain by Activation of NLRP3 Inflammasome

Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation are associated with several metabolic and inflammatory diseases. In this study, we investigated the role of AMPK/NLRP3 inflammasome axis in the molecular mechanism underlying pain perception. Results: Impairment in AMPK activation induced by compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice ( p < 0.001) associated with marked NLRP3 inflammasome protein activation and increased serum levels of interleukin-1b (IL-1b) (24.56 – 0.82 pg/ml) and IL-18 (23.83 – 1.882 pg/ml) compared with vehicle groups (IL-1b: 8.15 – 0.44; IL-18:4.92 – 0.4). This effect was rescued by increasing AMPK phosphorylation via metformin treatment ( p < 0.001), caloric restriction diet ( p < 0.001), or NLRP3 inflammasome genetic inactivation using NLRP3 knockout (nlrp3-/ - ) mice ( p < 0.001). Deficient AMPK activation and overactivation of NLRP3 inflammasome axis were also observed in blood cells from patients with fibromyalgia (FM), a prevalent human chronic pain disease. In addition, metformin treatment (200 mg/daily), which increased AMPK activation, restored all biochemical alterations examined by us in blood cells and significantly improved clinical symptoms, such as, pain, fatigue, depression, disturbed sleep, and tender points, in patients with FM. Innovation and Conclusions: These data suggest that AMPK/NLRP3 inflammasome axis participates in chronic pain and that NLRP3 inflammasome inhibition by AMPK modulation may be a novel therapeutic target to fight against chronic pain and inflammatory diseases as FM. Antioxid. Redox Signal. 24, 157–170.Junta de Andalucía CTS11

Cardiovascular diseases, NLRP3 inflammasome, and western dietary patterns

Cardiovascular diseases (CVD) are the leading cause of death worldwide, with high prevalence in industrialized countries. Cardiovascular risk factors are mainly influenced by diet, which like other lifestyle factors can be modified to either reduce or increase cardiovascular risk. Other metabolic diseases such as metabolic syndrome, type II diabetes mellitus, and obesity are associated to CVD and highly influenced by the diet. Inflammation has demonstrated to be a key factor in the biological progress of these diseases. Interestingly, IL-1β which is associated to several steps in the development of atherosclerosis, heart disease, and the association of obesity and type II diabetes with CVD, is activated by the inflammasome complex, a multiprotein complex composed of an intracellular sensor, typically a Nod-like receptor (NLR), the precursor procaspase-1, and the adaptor ASC (apoptosis-associated speck-like protein containing a CARD. In the last years, inflammasome complex has been studied in depth and has been associated with the effect of unhealthy diets both from a clinical and experimental view point. We have reviewed the evidences supporting the role of the inflammasome complex in the development of cardiovascular pathology by unhealthy diets and the therapeutic perspectives

Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds

Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor which is activated by increases in adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and/or adenosine diphosphate (ADP)/ATP ratio, and increases different metabolic pathways such as fatty acid oxidation, glucose transport and mitochondrial biogenesis. In this sense, AMPK maintains cellular energy homeostasis by induction of catabolism and inhibition of ATP-consuming biosynthetic pathways to preserve ATP levels. Several studies indicate a reduction of AMPK sensitivity to cellular stress during aging and this could impair the downstream signaling and the maintenance of the cellular energy balance and the stress resistance. However, several diseases have been related with an AMPK dysfunction. Alterations in AMPK signaling decrease mitochondrial biogenesis, increase cellular stress and induce inflammation, which are typical events of the aging process and have been associated to several pathological processes. In this sense, in the last few years AMPK has been identified as a very interesting target and different nutraceutical compounds are being studied for an interesting potential effect on AMPK induction. In this review, we will evaluate the interaction of the different nutraceutical compounds to induce the AMPK phosphorylation and the applications in diseases such as cancer, type II diabetes, neurodegenerative diseases or cardiovascular diseases

NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice

While NLRP3‐inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3‐inflammasome protected mice from age‐related increased insulin sensitivity, reduced IGF‐1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the agedependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt‐mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age‐associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.Andalusian regional government; Consejería de Salud de la Junta de Andalucia, Grant/ Award Number: PI‐0036‐2014; Ministerio de economía y competitividad, Grant/Award Number: SAF2017‐84494‐C2‐1‐

Uso del aceite del cáñamo para la prevención y/o el tratamiento de la fibromialgia

Uso del aceite de cáñamo para la prevención y/o el tratamiento de la fibromialgia. La presente invención se relaciona con el uso del aceite de cáñamo en la elaboración de una composición para la prevención y/o el tratamiento de la fibromialgia, que pueda tener interés tanto en la industria farmacéutica como alimentaria.Españ

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement

Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications

Stress-induced depressive behaviors require a functional NLRP3 inflammasome

et al.Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study shows the implication of NLRP3 inflammasome in animal model of stress-induced depression. Accordingly, we show here that in the absence of a NLRP3 inflammasome, prolonged stress does not provoke depressive behaviors or microglial activation in mice or dampen hippocampal neurogenesis. Indeed, NLRP3 deletion or inhibition of microglial activation impairs the stress-induced alterations associated with depression. According to these findings in animal model, the inflammasome could be a target for new therapeutic interventions to prevent depression in patients.This work has been supported by Grupo de Investigacion Junta de Andalucia CTS113, Consejería de Salud of the Junta de Andalucia (PI0036-2014), Fundación Ramón Areces, and the Departamento Gobernamental de Investigaciones Científicas y Tecnológicas (DGICYT: BFU2008-01,552 and BFU2011-27,207).Peer Reviewe