mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.

The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages.

The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.

The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24 mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans.

NLRP1 inflammasome promotes senescence and senescence-associated secretory phenotype.

Background: Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as senescence-associated secretory phenotype (SASP), some of which are produced by the NLRP3 inflammasome. Here, we present evidence that the NLRP1 inflammasome is a DNA damage sensor and a key mediator of senescence.

Methods: Senescence was induced in fibroblasts in vitro and in mice.

Does Donor Age Have Effects on Senescence Biomarkers in Kidney-Transplanted Patients?

Renal transplantation is an effective treatment for severe chronic kidney diseases. However, young patients often face a scarcity of kidneys from donors of similar age, resulting in the transplantation of older organs, which increase the risk of graft rejection and several complications compared with older individuals who receive kidneys from donors of similar age or younger. This article focuses on studying different senescence biomarkers in donors and patients who received kidneys from various age ranges complying with the STROBE requirements.

How the Disruption of Mitochondrial Redox Signalling Contributes to Ageing.

In the past, mitochondrial reactive oxygen species (mtROS) were considered a byproduct of cellular metabolism. Due to the capacity of mtROS to cause oxidative damage, they were proposed as the main drivers of ageing and age-related diseases. Today, we know that mtROS are cellular messengers instrumental in maintaining cellular homeostasis.

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype.

Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition.

L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation.

Aims: Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis.

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria.

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1.

Inhibition of the NLRP3 inflammasome prevents ovarian aging.

Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging.

Potential Role of the Mitochondria for the Dermatological Treatment of Papillon-Lefèvre.

The Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder caused by mutations in the Cathepsin C (CTSC) gene, characterized by periodontitis and palmoplantar hyperkeratosis. The main inflammatory deficiencies include oxidative stress and autophagic dysfunction. Mitochondria are the main source of reactive oxygen species; their impaired function is related to skin diseases and periodontitis.

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging.

Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice.

A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes.

Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer.

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages.

Is AMP-Activated Protein Kinase Associated to the Metabolic Changes in Primary Ovarian Insufficiency?

Primary ovarian insufficiency (POI) is a critical fertility defect characterized by anticipated impairment of the follicular reserve, which pathophysiological mechanisms have not yet been identified. We have investigated the possible relationship between AMP-activated protein kinase (AMPK) and the pathophysiology of POI. We studied 35 POI patients with altered levels of follicle-stimulating hormone (FSH) and estradiol and increased percentage of overweight compared with 20 healthy women.

A Diet Rich in Saturated Fat and Cholesterol Aggravates the Effect of Bacterial Lipopolysaccharide on Alveolar Bone Loss in a Rabbit Model of Periodontal Disease.

Increasing evidence connects periodontitis with a variety of systemic diseases, including metabolic syndrome, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). The proposal of this study was to evaluate the role of diets rich in saturated fat and cholesterol in some aspects of periodontal diseases in a lipopolysaccharide (LPS)-induced model of periodontal disease in rabbits and to assess the influence of a periodontal intervention on hyperlipidemia, atherosclerosis, and NAFLD progression to non-alcoholic steatohepatitis. Male rabbits were maintained on a commercial standard diet or a diet rich in saturated fat (3% lard /) and cholesterol (1.

Molecular inflammation and oxidative stress are shared mechanisms involved in both myocardial infarction and periodontitis.

Background And Objective: Our aims were to improve the understanding of the pathogenic relationship between cardiovascular diseases and periodontitis and to generate new perspectives in the prevention and treatment of acute myocardial infarction (AMI) and periodontitis. The present study evaluates possible differences in inflammation, oxidative stress, and autophagy markers among subject suffering AMI, periodontitis, or both, to explore possible common pathogenic mechanisms.

Material And Methods: A total of 260 subjects were enrolled in the study: 106 subjects that survived to a first AMI (AMI group) and 154 subjects had no cardiac events in their clinical record (control group).

Sequential Changes of NLRP3 Inflammasome Activation in Sepsis and its Relationship With Death.

Introduction: Inflammasomes are recognized as key components of the innate immune response in sepsis. We aimed to describe the transcriptional expression of nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3), and serum interleukin-1β (IL-1 β) in critically ill patients, their changes over the first week and their prognostic value in septic patients.

Methods: Prospective study including patients with sepsis based on Sepsis-3 definitions and a control group of critically ill patients without sepsis.

Mitochondrial Adaptations in the Growing Heart.

The heart pumps blood throughout the whole life of an organism, without rest periods during which to replenish energy or detoxify. Hence, cardiomyocytes, the working units of the heart, have mechanisms to ensure constitutive production of energy and detoxification to preserve fitness and function for decades. Even more challenging, the heart must adapt to the varying conditions of the organism from fetal life to adulthood, old age, and pathological stress.

Blockade of the NLRP3 inflammasome improves metabolic health and lifespan in obese mice.

Aging is the major risk factor for many metabolic chronic diseases. Several metabolic pathways suffer a progressive impairment during aging including body composition and insulin resistance which are associated to autophagy dysfunction and increased inflammation. Many of these alterations are aggravated by non-healthy lifestyle such as obesity and hypercaloric diet which have been shown to accelerate aging.

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.

NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity.

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice.

Aging and the Inflammasomes.

The inflammasomes are innate immune system sensors that control the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules originating from host proteins, leading to the release of pro-inflammatory cytokines, Il1b and IL18, and a particular inflammatory type of cell death termed pyroptosis. It is broadly considered that chronic inflammation may be a common link in age-related diseases, aging being the greatest risk factor for the development of chronic diseases. In this sense, we discuss the role of inflammasomes in non-infectious inflammation and their interest in aging and age-related diseases.

Inflammasomes in Clinical Practice: A Brief Introduction.

Inflammasomes are multiprotein complexes formed and activated after exposure to pathogenic microbes and host danger signals that control the maturation and production of IL-1β and IL-18. Their implication in different diseases such as cardiovascular, neurodegenerative, psychiatric, and metabolic diseases opens a door to developing new therapeutic perspectives. However, the rapid increase in the knowledge about inflammasomes is associated with their involvement in clinical practice.