Effects of an intensive inpatient rehabilitation program in elderly patients with obesity

Objective: The aim of this study was to assess the short-term effectiveness of an intensive inpatient multidimensional rehabilitation program (MRP), including diet, exercise, and behavioral therapy, in elderly patients with severe obesity. Methods: Forty-four elderly patients (old; age 69.3 \ub1 3.5 years, BMI 41.9 \ub1 14.9) were analyzed against 215 younger patients (young; age 48.2 \ub1 18.5 years, BMI 43.9 \ub1 9.4), who were used as controls. All patients underwent MRP, based on group therapy guided by a multidisciplinary team (physicians, dietitians, exercise trainers, psychologists). We evaluated changes in anthropometry, cardiovascular risk factors, physical fitness, quality of life, and eating behavior. Results: After 3 weeks of MRP, we observed a reduction in body weight (old -3.8%, young -4.3%), BMI (old -3.9%, young -4.4%), waist circumference (old -3.4%, young -4.1%), total cholesterol (old -14.0%, young -15.0%), and fasting glucose (old -8.3%, young -8.1%), as well as improved performance in the Six-Minute-Walk Test (old +28.7%, young +15.3%), chair-stand test (old +24.8%, young +26.9%), and arm-curl test (old +15.2%, young +27.3%). Significant improvement was registered in all other analyzed domains. Conclusion: Our 3-week MRP provided significant clinical and functional improvement, which was similar between elderly and younger patients with severe obesity. In the long-term, this may be translated into better quality of life, through better management of obesity-associated morbidities and reduced frailty

Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment

A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment

Effects of an Intensive Inpatient Rehabilitation Program in Elderly Patients with Obesity

Objective: The aim of this study was to assess the short-term effectiveness of an intensive inpatient multidimensional rehabilitation program (MRP), including diet, exercise, and behavioral therapy, in elderly patients with severe obesity. Methods: Forty-four elderly patients (old; age 69.3 ± 3.5 years, BMI 41.9 ± 14.9) were analyzed against 215 younger patients (young; age 48.2 ± 18.5 years, BMI 43.9 ± 9.4), who were used as controls. All patients underwent MRP, based on group therapy guided by a multidisciplinary team (physicians, dietitians, exercise trainers, psychologists). We evaluated changes in anthropometry, cardiovascular risk factors, physical fitness, quality of life, and eating behavior. Results: After 3 weeks of MRP, we observed a reduction in body weight (old –3.8%, young –4.3%), BMI (old –3.9%, young –4.4%), waist circumference (old –3.4%, young –4.1%), total cholesterol (old –14.0%, young –15.0%), and fasting glucose (old –8.3%, young –8.1%), as well as improved performance in the Six-Minute-Walk Test (old +28.7%, young +15.3%), chair-stand test (old +24.8%, young +26.9%), and arm-curl test (old +15.2%, young +27.3%). Significant improvement was registered in all other analyzed domains. Conclusion: Our 3-week MRP provided significant clinical and functional improvement, which was similar between elderly and younger patients with severe obesity. In the long-term, this may be translated into better quality of life, through better management of obesity-associated morbidities and reduced frailty

Therapeutic use of pantethine in experimental autoimmune encephalomyelitis

La pantetina, un tiolo a basso peso molecolare, rappresenta la forma stabile disulfidica della panteteina, il substrato metabolico che costituisce la parte attiva del coenzima A. Grazie alla capacit\ue0 di abbassare l\u2019indice lipidico senza effetti collaterali documentati, per decenni la pantetina \ue8 stata somministrata a pazienti con disfunzioni metaboliche. Studi recenti hanno dimostrato che la somministrazione di pantetina inibisce l\u2019insorgenza della sindrome infiammatoria cerebrale in un modello animale di malaria, determinando la down-regolazione delle principali risposte cellulari pro-infiammatorie. Inoltre, il trattamento con pantetina \ue8 in grado di migliorare il decorso clinico in altri modelli animali di malattie neurologiche, tra le quali la malattia di Parkinson. Considerato che l\u2019immunometabolismo \ue8 una disciplina che rappresenta una nuova frontiera nell\u2019immunologia, lo scopo di questo studio \ue8 quello di studiare l\u2019effetto metabolico associato alla somministrazione di pantetina sulla patogenesi dell\u2019encefalomielite sperimentale autoimmune (EAE), il modello animale della sclerosi multipla (MS) umana. I nostri esperimenti in vivo hanno dimostrato che il trattamento con pantetina \ue8 in grado di interferire con l\u2019evoluzione della forma recidivante - remittente dell\u2019EAE (RR-EAE), ritardando l\u2019esordio della malattia e riducendo la severit\ue0 del quadro clinico. Inoltre, la somministrazione del farmaco a seguito del manifestarsi dei primi sintomi di malattia, ha determinato un indicativo miglioramento del decorso e della severit\ue0 della RR-EAE. Come dimostrato da analisi neuropatologiche, questi rilevanti dati clinici sono associati ad una diminuzione degli infiltrati infiammatori e del grado di demielinizzazione a livello del midollo spinale di topi trattati con pantetina. Utilizzando un nuovo sistema di imaging in vivo (IVIS 200; Caliper Life Science), \ue8 stato inoltre dimostrato che gli animali trattati con pantetina presentano un ridotto leakage della barriera emato-encefalica (BEE) durante la fase pre-clinica della RR-EAE. Un ulteriore dato molto importante \ue8 la significativa riduzione della capacit\ue0 proliferativa antigene-specifica delle cellule T isolate dai linfonodi drenanti di animali trattati con pantetina, se paragonato alle cellule isolate da animali non-trattati. I linfociti ottenuti da topi trattati hanno presentato anche una diminuzione nella produzione di citochine pro-infiammatorie durante il picco iniziale di malattia. Inoltre, i studi condotti in vitro suggeriscono che il pre-trattamento con pantetina ha un effetto bloccante sull\u2019adesione integrino-dependente delle cellule T encefalitogeniche. La pantetina ha inoltre un effetto inibitorio anche sull\u2019adesione in vivo delle cellule T attivate, effetto dimostrato tramite l\u2019utilizzo di microscopia intravitale in un modello di infiammazione dei vasi cerebrali. Analisi eseguite tramite ImageStream System hanno evidenziato come l\u2019inibizione sulla capacit\ue0 adesiva delle cellule T PLP-specifiche non possa essere spiegata tramite cambiamenti di espressione integrinica o della capacit\ue0 delle integrine di formare cluster indotti tramite attivazione chemochinica. Dato che la funzionalit\ue0 delle integrine non dipende solo dalla loro avidit\ue0 per i ligandi, ma anche dalla loro localizzazione all\u2019interno di rafts lipidici ricchi di colesterolo presenti sulla superficie cellulare, si \ue8 analizzata l\u2019influenza del trattamento con pantetina sulla conformazione dei rafts lipidici sulle cellule T attivate. Sorprendentemente, gli esperimenti condotti hanno evidenziato che il pre-trattamento con pantetina \ue8 in grado di ridurre notevolmente la formazione di rafts lipidici e la loro clusterizzazione sulle cellule T, nonostante le integrine fossero ancora organizzate in grandi caps polarizzati come sulle cellule T non trattate. Per analizzare pi\uf9 a fondo l\u2019effetto globale della pantetina sulle cellule T attivate, si sono effettuati studi di metabolomica, i quali hanno evidenziato un effetto metabolico molto significativo della pantetina sulle cellule T trattate. In particolare, il trattamento con pantetina ha un effetto molto marcato su cellule T memory, se paragonate a cellule T na\uefve, modulando almeno 45 diversi pathways metabolici e causando un forte aumento della quantit\ue0 di coenzima A disponibile, il quale va principalmente ad aumentare l\u2019efficienza del ciclo di Krebs. Questi dati sembrerebbero indicare una capacit\ue0 da parte della pantetina di regolare molto finemente il metabolismo delle cellule T patogeniche responsabili del danno al sistema nervoso centrale osservato nella MS. In conclusione i nostri risultati dimostrano che la pantetina ha un effetto immuno-modulatorio sull\u2019EAE attraverso la riduzione dell\u2019attivazione e dell\u2019adesivit\ue0 delle cellule T patogeniche ed il mantenimento dell\u2019integrit\ue0\u2019 della BEE. Considerando il basso costo del farmaco, la sua sicura somministrazione in assenza di effetti collaterali e i nostri nuovi risultati, questo tiol a basso peso molecolare potrebbe rappresentare un approccio terapeutico efficace nel trattamento della MS.Pantethine is a low molecular weight thiol and represents the stable disulfate form of pantetheine, the metabolic substrate constituting the active part of coenzyme A (CoA). For decades, pantethine has been administrated to patients with metabolic disorders for its lipid lowering activity, without any side effect reported. Recent data showed that pantethine prevents the occurrence of cerebral malaria, with the down-regulation of key cellular responses to the inflammatory cerebral syndrome. Immunometabolism represents a new frontier in immunology and the aim of this study was to investigate the effect of metabolic intervention with pantethine on experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis (MS). Our in vivo experiments demonstrated that pantethine treatment prevents the development of chronic and relapsing-remitting EAE by delaying the disease onset and reducing the clinical score. Furthermore, pantethine treatment started after disease onset significantly ameliorated disease course and severity. The surprising clinical results were accompanied by a decrease in inflammatory infiltrates and in demyelination in pantethine treated-mice, proved by our neuropathological studies. Moreover, using IVIS 200 system we found that pantethine treated-mice had a reduced BBB leakage during the pre-clinical phase of relapsing-remitting EAE. Importantly, T-cells isolated from draining lymph nodes of mice treated with pantethine showed a significant reduction in antigen-specific proliferation and pro-inflammatory cytokines production at disease peak when compared with untreated-mice. Furthermore, our data from in vitro experiments demonstrated that pantethine pre-treatment of encephalitogenic T-cells blocked T-cell adhesion on purified integrin ligands. In addition, pantethine inhibited activated T-cell adhesion in vivo using an intravital microscopy model performed in inflamed brain venules. Importantly, pantethine had no effect on chemokine-induced na\uefve T-cell adhesion, proving that pantethine treatment has a selective effect only on activated T-cells. On the other hand, ImageStream analysis show that the important inhibition of proteolipid-specific T-cells adhesion could not be explain by changes on integrin expression or on their ability to form clusters upon chemokine-induce activation. Integrin functionality does not depend only on their avidity for their ligands but also on its localization into cholesterol-rich membrane rafts on cell surface. Thus, we next investigated the role of pantethine treatment on lipid rafts conformation on activated T-cells. Surprisingly, our in vitro experiments demonstrated that pantethine pre-treatment strongly reduced lipid rafts formation and raft clusters on encephalitogenic T-cells, although integrins were still present in big polarized caps. These results suggest that pantethine dissolve lipid rafts on activated T-cell, possibly interfering with the signal transduction necessary to support integrin-dependent firm adhesion. To further understand pantethine effect on in T-cell functions, we performed metabolomics analysis on pantethine-treated activated T-cells. Our data suggested a global metabolic effect of pantethine on T-cells. Overall, pantethine treatment significantly and differently affected the metabolism of memory T lymphocytes with respect to na\uefve T lymphocytes, leading to the modulation of at least 45 metabolic pathways with a huge availability of CoA that greatly enhances the Krebs cycle efficiency. These final consideration made us believe that pantethine could be able to perform a fine metabolic tuning of the pathogenic T-cells involved in demyelinating diseases, as MS. In conclusion, our results demonstrate that pantethine has an immuno-modulatory effect on EAE by reducing T-cell activation and adhesiveness, and maintaining BBB integrity. As pantethine has a low-cost and has successfully administered in different context to man in the absence of side effects, our results suggest that this low molecular weight thiol may represent a valuable new therapeutic approach in MS

Predictors of Ectopic Fat in Humans

In the last decade there has been increasing focus on body fat distribution, rather than on the degree of obesity. More recently, great interest has also been dedicated to ectopic fat deposition in overnourished individuals that reflects a failure of the system of intracellular lipid homeostasis, which, in normal conditions, prevents lipotoxicity in the organs, by confining lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Consequently, excess body weight leads to fat infiltration of multiple organs including liver, pancreas, skeletal muscle, and heart thus forming "ectopic fat". Although overfeeding is considered the main predictor of ectopic fat deposition, other factors may be also involved. The purpose of this review is to evaluate the current available data on the predictors of ectopic fat deposition in humans

Phenotypic Shift of Adipocytes by Cholecalciferol and 1\u3b1,25 Dihydroxycholecalciferol in Relation to Inflammatory Status and Calcium Content

Recent experimental data seem to suggest a relevant role for 1,25[OH]2cholecalciferol (1,25[OH]2D3) in adipocyte physiology and pathophysiology, with some studies showing adipogenic and pro-inflammatory properties, and others lipolytic and anti-inflammatory functions. Moreover, to our knowledge, the role of cholecalciferol (D3) in adipocytes function is still not known. Therefore, the aim of this study was to investigate in vitro the effects of 1,25[OH]2D3, as well as of D3, in 3T3-L1 adipocytes in basal and inflammatory conditions, testing the effects of different calcium concentrations in adipocytes culture medium. In 3T3-L1 adipocytes, CYP27A1 and CYP27B1 mRNA were detected in basal conditions and induced after D3 treatment. Pre-treatment of 3T3-L1 adipocytes not only with 1,25[OH]2D3, but also with D3 before inflammatory stimulation, significantly prevented the increase in gene expression and protein secretion of IL-6 and TNF-\u3b1, and significantly increased IL-10 mRNA and protein production compared with adipocytes treated only with lipopolysaccharide (LPS). Biological effects of D3 were still present after inhibition of P450 activity with ketokonazole. LPS determined a decrease in cell area compared with controls, paralleled by a significant increase in optical density (OD) of lipid droplets, whereas 1,25[OH]2D3 and D3 alone significantly increased adipocytes area and decreased OD. Pretreatment with both forms of vitamin D preserved cells from the reduction in their area observed after LPS treatment. LPS decreased more the area of cells grown in a high calcium medium than of adipocytes grown in a low calcium medium. In the presence of a high calcium medium, 1,25(OH)2D3 treatment preserved cell area, maintaining its anti-inflammatory and adipogenic properties. In conclusion our results show that D3, besides 1,25[OH]2D3, presents anti-inflammatory effects on 3T3-L1, as well as that adipocytes have the enzymatic pathways necessary to locally regulate the production of active forms of vitamin D, capable of influencing adipocyte phenotype and function

Morphological and Functional Changes in the Peritumoral Adipose Tissue of Colorectal Cancer Patients

Objective: The role of peritumoral adipose tissue (AT) has not been extensively studied in colorectal cancer (CRC). Methods: This study was conducted in 20 male subjects undergoing elective surgery for CRC. The differences between the peritumoral visceral adipose tissue (P-VAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) of the patients were described via immunohistochemistry and molecular biology analyses. The interactions between adipocytes and a colon cancer cell line were also investigated by using an in vitro coculture system. Results: The analyses revealed that adipocytes near the tumor were significantly smaller than the adipocytes from other sites. The P-VAT was preferentially infiltrated by a CD68+/CD163+/IDO- macrophage subset with a prevalent reparative inflammatory response, while the macrophages identified in VAT and SAT mainly presented inflammatory features. Furthermore, the P-VAT presented a higher expression of adiponectin compared with other sites. Morphological analysis in vitro showed that after a few days of coculture, 3T3-L1 adipocytes were reduced in number and size with an increase in lipolysis rate and dedifferentiation phenomena. Conclusions: This study reveals important morphological and functional changes in the AT surrounding the tumor as an increase in lipolysis and in adiponectin-producing adipocytes, preferentially infiltrated by a macrophage subset, with prevalent reparative inflammatory response

Morphological and Functional Changes in the Peritumoral Adipose Tissue of Colorectal Cancer Patients

Objective: The role of peritumoral adipose tissue (AT) has not been extensively studied in colorectal cancer (CRC). Methods: This study was conducted in 20 male subjects undergoing elective surgery for CRC. The differences between the peritumoral visceral adipose tissue (P-VAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) of the patients were described via immunohistochemistry and molecular biology analyses. The interactions between adipocytes and a colon cancer cell line were also investigated by using an in vitro coculture system. Results: The analyses revealed that adipocytes near the tumor were significantly smaller than the adipocytes from other sites. The P-VAT was preferentially infiltrated by a CD68+/CD163+/IDO- macrophage subset with a prevalent reparative inflammatory response, while the macrophages identified in VAT and SAT mainly presented inflammatory features. Furthermore, the P-VAT presented a higher expression of adiponectin compared with other sites. Morphological analysis in vitro showed that after a few days of coculture, 3T3-L1 adipocytes were reduced in number and size with an increase in lipolysis rate and dedifferentiation phenomena. Conclusions: This study reveals important morphological and functional changes in the AT surrounding the tumor as an increase in lipolysis and in adiponectin-producing adipocytes, preferentially infiltrated by a macrophage subset, with prevalent reparative inflammatory response

Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease