Role of adjuvant Crohn's disease exclusion diet plus enteral nutrition in asymptomatic pediatric Crohn's disease having biochemical activity: A randomized, pilot study.

BACKGROUND: Conventional therapy can result in remission in mild-moderate pediatric Crohn's disease (CD). However, some patients experience loss of response to biological drugs despite increased dosage. METHODS: We planned to determine that CD exclusion diet plus partial enteral nutrition offers additional benefits in asymptomatic children with CD having elevated fecal calprotectin. A randomized, open-label, pilot, controlled interventional study was conducted in children with CD while on medical treatment and elevated fecal calprotectin on routine testing. Patients continued their medications and were randomized into a group that received CD exclusion diet plus partial enteral nutrition for 12 weeks and one that continued a regular diet. RESULTS: Twenty-one patients participated: 11 received CD exclusion diet plus partial enteral nutrition and 10, regular diet. Median fecal calprotectin in the CD exclusion diet plus partial enteral nutrition decreased in 9/11 to 50% of baseline, remaining practically unchanged in the regular diet, except for two patients (p = 0.005). Body mass index z-score increased in the CD exclusion diet plus partial enteral nutrition. Only 1/11 patients in the CD exclusion diet plus partial enteral nutrition group, while 4/10 in the regular diet, experienced clinical relapse (p = 0.149). Only one patient in the CD exclusion diet plus partial enteral nutrition, while eight in the regular diet, were considered to need their biologic treatment intensified (p = 0.005); 2/11 in the CD exclusion diet plus partial enteral nutrition had the dose or frequency of the biologic reduced vs. none (0/10) in the regular diet group. The short Pediatric Crohn's Disease Activity Index and anthropometry showed no significant changes in either group. CONCLUSIONS: Diet therapy could be a useful addition to medications in children with CD in apparent remission, but elevated fecal calprotectin. TRIAL REGISTRATION: Clinical trial number: NCT05034458.

Enfermedad celíaca y otras patologías relacionadas con el gluten / Celiac disease and other pathologies related to gluten

Se intentan aclarar los conceptos diferenciales de enfermedad celíaca, sensibilidad al gluten no celíaca y alergia al trigo. Se abordan las manifestaciones clínicas junto al Score clínico desarrollado en el Servicio para calcular matemáticamente la presencia de enfermedad celíaca. Finalmente, se aborda el tartamiento, seguimiento, y las nuevas patologías relacionadas a la enfermedad

Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity.

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium postdevelopment. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity.

Normalization of NAD+ Redox Balance as a Therapy for Heart Failure.

BACKGROUND: Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction. METHODS: We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD(+) ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD(+) pool also were tested. RESULTS: Increased NADH/NAD(+) and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD(+) levels by stimulating the NAD(+) salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD(+) ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD(+) redox balance either genetically or pharmacologically. CONCLUSIONS: We show that mitochondrial protein hyperacetylation due to NAD(+) redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD(+) imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD(+) precursors are feasible in humans.

Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced ß cell mass, fewer proliferating ß cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from ß cells in mice.

Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis.

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis.

Sensibilidad al gluten: presentación de tres casos / Gluten sensitivity: presentation of three cases

En los últimos años, ha cobrado mayor interés la existencia de un cuadro clínico muy similar al de la enfermedad celíaca, que no se ajusta a los cánones tradicionales de diagnóstico. Se trata de pacientes con una alta sospecha diagnóstica de enfermedad celíaca, que presentan serología y biopsia de intestino delgado normal. La literatura relata, desde la década del 80, la existencia de un síndrome que relaciona el gluten de la dieta con un efecto tóxico generador de síntomas gastrointestinales en presencia de una mucosa normal. A esta entidad se la denominó síndrome de Cooper-Cook. En los últimos años, ha habido numerosas publicaciones que hacen referencia a esta entidad, pero ahora bajo la denominación de sensibilidad al gluten. En el siguiente artículo, se presentan tres casos clínicos que hacen referencia a esta enfermedad.

In the last few years, the existence of a clinical profile similar to celiac disease has become important; this disease does not adapt to the traditional diagnosis canons. It is related to a number of patients who are diagnosed as having the celiac disease but present normal serology and small bowel's biopsy. Since the 80's, medical literature reports the existence of a syndrome that connects gluten diet with a toxic effect that produces gastrointestinal symptoms even though the mucosa remains normal. This disease is called the Cooper-Cook syndrome. Over the last few years, there have been lots of publications about this disease under the name "gluten sensitivity". In the following article, three clinical cases that refer to this condition are presented.

[Gluten sensitivity: presentation of three cases]. / Sensibilidad al gluten: presentación de tres casos.

In the last few years, the existence of a clinical profile similar to celiac disease has become important; this disease does not adapt to the traditional diagnosis canons. It is related to a number of patients who are diagnosed as having the celiac disease but present normal serology and small bowel's biopsy. Since the 80's, medical literature reports the existence of a syndrome that connects gluten diet with a toxic effect that produces gastrointestinal symptoms even though the mucosa remains normal. This disease is called the Cooper-Cook syndrome. Over the last few years, there have been lots of publications about this disease under the name "gluten sensitivity". In the following article, three clinical cases that refer to this condition are presented.

Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.

Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage.

RATIONALE: AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target. OBJECTIVE: We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. METHODS AND RESULTS: In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth. CONCLUSIONS: Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.