Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3. Methods: Four‐week‐old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx‐T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes. Results: After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx‐T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes. Conclusion: Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.Fund for Scientific Research de Bélgica (FNRS)-PDR/T.0026.2

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Tissu adipeux: Organe endocrinien?

Le tissu adipeux sécrète divers peptides dotés de propriétés régulatrices et globalement appelés adipocytokines, suite à leur ressemblance structurelle avec les cytokines « classiques ». Certaines adipocytokines agissent à distance, par voie endocrine, sur leurs tissus-cibles (leptines, adiponectine …), d’autres agissent localement par voie autocrine ou paracrine (TNFα, facteurs angiogéniques et motigéniques …). Toute modification à la hausse ou à la baisse, de la masse grasse s’accompagnera inévitablement d’une modification de production de ces peptides. Ces modifications vont jouer un rôle dans l’étiopathogénie et les complications associées à l’obésité, la cachexie ou la lipoatrophie

Effects of vanadate on the expression of genes involved in fuel homeostasis in animal models of Type I and Type II diabetes.

Vanadium is a trace element that has raised increasing interest in diabetology since the discovery of its insulin-like properties in vitro and in vivo. This brief article reviews the most recent data concerning the beneficial effects of vanadium compounds on fuel homeostasis in animal models of insulinopenic (Type I) or insulin-resistant (Type II) diabetes. These studies open obvious therapeutic possibilities in diabetes, and more particularly, in states of insulin resistance

Tissu adipeux: Une glande endocrine?

Le tissu adipeux sécrète divers peptides dotés de propriétés régulatrices et globalement appelés adipocytokines, suite à leur ressemblance structurelle avec les cytokines « classiques ». Certaines adipocytokines agissent à distance, par voie endocrine, sur leurs tissus-cibles (leptines, adiponectine …), d’autres agissent localement par voie autocrine ou paracrine (TNFα, facteurs angiogéniques et motigéniques …). Toute modification à la hausse ou à la baisse, de la masse grasse s’accompagnera inévitablement d’une modification de production de ces peptides. Ces modifications vont jouer un rôle dans l’étiopathogénie et les complications associées à l’obésité, la cachexie ou la lipoatrophie

Obésité humaine d'origine monogénique

Le système « leptine-mélanocortines » contrôle le poids corporel de l’individu. Ce système induit la satiété, augmente les dépenses énergétiques et entraîne une série d’adaptations hormonales permettant la survie de l’individu à un environnement où l’apport énergétique est limité. Des mutations de gènes émaillant ce système sont responsables des premiers cas d’obésité monogénique décrits chez l’homme. Leur étude a permis de mieux comprendre l’importance physiopathologique de ce système, ce qui pourrait peut-être in fine déboucher sur de nouvelles stratégies thérapeutiques

The insulin-like properties of vanadium : new perspectives for the treatment of insulin resistance and diabetes ?

Vanadium is an ubiquitous trace element in nature. It is found at very low concentrations in most living organisms, but conclusive demonstration of its essentiality for mammals is still lacking. In vitro, vanadium salts mimic most, thought not all, effects of insulin on various cell types. One hypothesis ascribes these effects to enhanced phosphorylation of the insulin receptor, but it is still unresolved whether this results from a stimulation of the tyrosine kinase present in the receptor itself, from a direct esterification (vanadylation) of tyrosine residues or from a inhibition of a tyrosine phosphatase. The alternative hypothesis suggests that vanadium salts act at steps distal to the insulin receptor. In vivo, pharmacological doses of oral vanadate are practically without effect on glucose homeostasis in normal rats, but cause a spectacular fall of blood glucose levels in animals made insulin-deficient and diabetic by streptozotocin injection (model of Type I diabetes). We first confirmed this glucose-lowering effect of vanadate. Next, we demonstrated that this beneficial action could be maintained for more than two months, was observed during glucose tolerance tests as well as under basal conditions, and did not result from a rise in circulating insulin levels. Euglycemic-hyperinsulinemic clamp studies further showed that chronic treatment with vanadium salts restored the ability of insulin to stimulate peripheral glucose disposal and to inhibit hepatic glucose production in diabetic rats. These results are in agreement with those of in vitro studies performed on tissues obtained from similar animals. A shift of the predominating gluconeogenic flux into a glycolytic flux was particularly striking in liver of treated-diabetic rats. We demonstrated that this effect of vanadate was due to correction of altered expression of genes involved in hepatic glucose metabolism. In vivo studies have, however, not solved the controversy about the cellular mechanisms implicated in the glucose-lowering action of vanadium compounds. The tyrosine kinase activity of insulin receptors from tissues of treated-diabetic rats has been found to be enhanced or unchanged. If the latter finding is correct, this suggests that vanadate acts at a postreceptor level. Beside insulin deficiency, resistance of target tissues to the action of insulin is the other major cause of glucose intolerance. All means susceptible to increase the sensitivity to the hormone or to bypass its action may thus prove extremely useful for controlling perturbations of glucose metabolism. We therefore investigated whether oral vanadate can improve glucose homeostasis in hyperinsulinemic, insulin-resistant rats and mice (models of Type II diabetes). In genetically obese and mildly glucose-intolerant fa/fa rats, 3 months of vanadate treatment markedly decreased plasma insulin levels and improved the tolerance to glucose loads. This improvement could not simply be explained by the lower body weight gain resulting from the anoresigenic action of the element, not by a decrease in insulin counter-regulatory hormones. Changes in FFA levels with subsequent attenuation of the “glucose-fatty acid” cycle were also excluded. The beneficial effects of vanadate can rather be ascribed to a direct correction of impaired tissue sensitive to insulin. Englycemic-hyperinsulinemic clamps have shown that the increment of whole-body glucose disposal brought about by insulin is larger in fa/fa rats treated with vanadate, and that the increase in glucose uptake occurs essentially in muscles. This is particular interest because muscle is the major site of insulin-mediated glucose disposal. Since we found no change in insulin receptor number or affinity, and others did not observe any alteration of receptor tyrosine kinase activity, vanadate action is likely to involve step(s) distal to the receptor. As glucose transport is the rate-limiting step for glucose metabolism, we investigated whether vanadate treatment affects the expression of the insulin-responsive glucose transporter, GLUT4. Both GLUT4 mRNA and protein were unmodified in muscle of treated fa/fa rats. This suggests that a functional improvement of glucose transporters, due to more efficient translocation to plasma membrane and/or increased intrinsic activity, probably plays a major role in the beneficial effect of vanadate. Vanadate was also effective in ob/ob mice, in which insulin resistance leads to overt diabetes. Marked and sustained decreases in plasma glucose and insulin concentrations were observed. The cellular mechanisms involved are likely to be similar to those in fa/fa rats. In addition, the glucose-lowering effect of vanadate indirectly prevents the exhaustion of pancreatic insulin stores. In conclusion, the insulin-like properties of vanadium salts are not a mere curiosity. They will certainly help elucidating the cellular and molecular mechanisms of insulin action and the causes of its perturbations. In particular, vanadium salts may be instrumental in finding a solution to the difficult problem of insulin resistance. It is significant that the NIH has just launched a clinical research programme “Vanadium salts in the clinical treatment of Diabetes Mellitus”. We believe that our studies in insulin-resistant animals have paved the way of such clinical studiesThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199

Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome.

Obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines may link obesity to its co-morbidities. Most adipokines with pro-inflammatory properties are overproduced with increasing adiposity, while some adipokines with anti-inflammatory or insulin-sensitizing properties, like adiponectin are decreased. This dysregulation of adipokine production may promote obesity-linked metabolic disorders and cardiovascular disease. Besides considering adipokines, this review will also highlight the cellular key players and molecular mechanisms involved in adipose inflammation. Targeting the changes in the cellular composition of adipose tissue, the underlying molecular mechanisms, and the altered production of adipokines may have therapeutic potential in the management of the metabolic syndrome