Unacylated ghrelin reduces skeletal muscle reactive oxygen species generation and inflammation and prevents high-fat diet-induced hyperglycemia and whole-body insulin resistance in rodents

Excess reactive oxygen species (ROS) generation and inflammation may contribute to obesity-associated skeletal muscle insulin resistance. Ghrelin is a gastric hormone whose unacylated form (UnAG) is associated with whole-body insulin sensitivity in humans and may reduce oxidative stress in nonmuscle cells in vitro. We hypothesized that UnAG 1) lowers muscle ROS production and inflammation and enhances tissue insulin action in lean rats and 2) prevents muscle metabolic alterations and normalizes insulin resistance and hyper-glycemia in high-fat diet (HFD)-induced obesity. In 12-week-old lean rats, UnAG (4-day, twice-daily subcutaneous 200-mg injections) reduced gastrocnemius mitochondrial ROS generation and inflammatory cytokines while enhancing AKT-dependent signaling and insulinstimulated glucose uptake. In HFD-treated mice, chronic UnAG overexpression prevented obesity-associated hyperglycemia and whole-body insulin resistance (insulin tolerance test) as well as muscle oxidative stress, inflammation, and altered insulin signaling. In myotubes, UnAG consistently lowered mitochondrial ROS production and enhanced insulin signaling, whereas UnAG effects were prevented by small interfering RNA-mediated silencing of the autophagy mediator ATG5. Thus, UnAG lowers mitochondrial ROS production and inflammation while enhancing insulin action in rodent skeletal muscle. In HFD-induced obesity, these effects prevent hyperglycemia and insulin resistance. Stimulated muscle autophagy could contribute to UnAG activities. These findings support UnAG as a therapeutic strategy for obesity-associated metabolic alterations

Niobium and Zirconium Phosphates as Green and Water-Tolerant Catalysts for the Acid-Catalyzed Valorization of Bio-Based Chemicals and Real Lignocellulosic Biomasses

Commercial niobium and synthesized zirconium phosphates were tested as water-tolerant heterogeneous acid catalysts in the hydrothermal conversion of different bio-based substrates. Different acid-catalyzed reactions were performed using biomass-derived model compounds and more complex real lignocellulosic biomasses as the substrate. The conversion of glucose and cellulose was preliminarily investigated. Then, a wide plethora of raw lignocellulosic biomasses, such as conifer wood sawdust, Jerusalem artichoke, sorghum, miscanthus, foxtail millet, hemp and Arundo donax, were valorized towards the production of water-soluble saccharides, 5-hydroxymethylfurfural (HMF), levulinic acid (LA) and furfural. The different catalytic performances of the two phosphates were explained on the basis of their acid features, total acidity, Brønsted/Lewis acid sites ratio and strength. Moreover, a better insight into their structure–acidity relationship was proposed. The different acid properties of niobium and zirconium phosphates enabled us to tune the reaction towards target products, achieving from glucose maximum HMF and LA yields of 24.4 and 24.0 mol%, respectively. Remarkably, when real Jerusalem artichoke biomass was adopted in the presence of niobium and zirconium phosphate, maximum yields of furanic compounds and cellulose-derived sugars of 12.7 and 50.0 mol%, respectively, were obtained, after only 1 h of reaction. The synthesized hydrolysates, which were found to be rich in C5 and C6 carbohydrates, can be better exploited for the cascade production of more added-value bio-products

Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease

Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 \ub5g twice a day) normalizes CKD-induced loss of gastrocnemius muscle mass and a cluster of high tissue mitochondrial reactive oxygen species generation, high proinflammatory cytokines, and low insulin signaling activation. Consistent with these results, human uremic serum enhanced mitochondrial reactive oxygen species generation and lowered insulin signaling activation in C2C12 myotubes while concomitant UnAG incubation completely prevented these effects. Importantly, UnAG enhanced muscle mitophagy in vivo and silencing RNA-mediated autophagy protein 5 silencing blocked UnAG activities in myotubes. UnAG therefore normalizes CKD-induced skeletal muscle oxidative stress, inflammation, and low insulin signaling as well as muscle loss. UnAG effects are mediated by autophagy activation at the mitochondrial level. UnAG administration and mitophagy activation are novel potential therapeutic strategies for skeletal muscle metabolic abnormalities and their negative clinical impact in CKD.-Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease

n-3 PUFA-Enriched Diet Preserves Skeletal Muscle Mitochondrial Function and Redox State and Prevents Muscle Mass Loss in Mice with Chronic Heart Failure

Rationale and Methods: Skeletal muscle derangements, potentially including mitochondrial dysfunction with altered mitochondrial dynamics and high reactive oxygen species (ROS) generation, may lead to protein catabolism and muscle wasting, resulting in low exercise capacity and reduced survival in chronic heart failure (CHF). We hypothesized that 8-week n-3-PUFA isocaloric partial dietary replacement (Fat = 5.5% total cal; EPA + DHA = 27% total fat) normalizes gastrocnemius muscle (GM) mitochondrial dynamics regulators, mitochondrial and tissue pro-oxidative changes, and catabolic derangements, resulting in preserved GM mass in rodent CHF [Myocardial infarction (MI)-induced CHF by coronary artery ligation, left-ventricular ejection fraction <50%]. Results: Compared to control animals (Sham), CHF had a higher GM mitochondrial fission-fusion protein ratio, with low ATP and high ROS production, pro-inflammatory changes, and low insulin signalling. n-3-PUFA normalized all mitochondrial derangements and the pro-oxidative state (oxidized to total glutathione ratio), associated with normalized GM cytokine profile, and enhanced muscle-anabolic insulin signalling and prevention of CHF-induced GM weight loss (all p < 0.05 vs. CHF and p = NS vs. S). Conclusions:n-3-PUFA isocaloric partial dietary replacement for 8 weeks normalizes CHF-induced derangements of muscle mitochondrial dynamics regulators, ROS production and function. n-3-PUFA mitochondrial effects result in preserved skeletal muscle mass, with potential to improve major patient outcomes in clinical settings

Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148

Confluent endothelial cells respond poorly to the proliferative signals of VEGF. Comparing isogenic endothelial cells differing for vascular endothelial cadherin (VE-cadherin) expression only, we found that the presence of this protein attenuates VEGF-induced VEGF receptor (VEGFR) 2 phosphorylation in tyrosine, p44/p42 MAP kinase phosphorylation, and cell proliferation. VE-cadherin truncated in β-catenin but not p120 binding domain is unable to associate with VEGFR-2 and to induce its inactivation. β-Catenin–null endothelial cells are not contact inhibited by VE-cadherin and are still responsive to VEGF, indicating that this protein is required to restrain growth factor signaling. A dominant-negative mutant of high cell density–enhanced PTP 1 (DEP-1)//CD148 as well as reduction of its expression by RNA interference partially restore VEGFR-2 phosphorylation and MAP kinase activation. Overall the data indicate that VE-cadherin–β-catenin complex participates in contact inhibition of VEGF signaling. Upon stimulation with VEGF, VEGFR-2 associates with the complex and concentrates at cell–cell contacts, where it may be inactivated by junctional phosphatases such as DEP-1. In sparse cells or in VE-cadherin–null cells, this phenomenon cannot occur and the receptor is fully activated by the growth factor

A Comparison of Divergent Thinking Abilities Between Healthy Elderly Subjects and MCI Patients: Preliminary Findings and Implications

Objective: Divergent thinking (DT) has attracted research interest because of its potential role in early diagnosis and rehabilitation programs for patients affected by neurodegenerative diseases. Recently, DT has received even more attention because of its proven relationship with cognitive reserve (CR) and the possibility of a standardized assessment. However, few studies have investigated this ability in dementia patients, and even less is known about patients affected by Mild Cognitive Impairment (MCI). Thus, this study aims to investigate DT abilities in MCI patients. Methods: A total of 25 MCI patients and 25 healthy controls subjects (HC; from a random selection of 50) matched for age, gender, and educational level were enrolled. General cognitive functioning was measured by the Montreal Cognitive Assessment (MoCA), while the Abbreviated Torrance Test for Adults (ATTA) was selected to measure DT. Results: MANOVA analysis did not reveal any significant differences in DT abilities between MCI patients and HC except for the figural indicator score. A logistic hierarchical regression analysis revealed that the figural indicator score added an 8% of accuracy in the prediction of the group variable over the general cognition measure (MoCA). Conclusion: MCI patients seem to perform significantly worse than HC only in the figural DT score and this evidence has significant practical implications. First, that figural DT seemed to decrease even earlier than verbal DT and could therefore be taken into account for early diagnosis of MCI patients. On the contrary, the sparing of all the other DT skills (such as verbal DT skills, fluency, flexibility, originality, and elaboration) may suggest that, given its relationship with CR, verbal DT could instead be considered a possible target for prevention or early cognitive stimulation interventions

Intestinal microbiota changes induced by TNF-inhibitors in IBD-related spondyloarthritis

BACKGROUND: The close relationship between joints and gut inflammation has long been known and several data suggest that dysbiosis could link spondyloarthritis (SpA) to inflammatory bowel diseases (IBD). The introduction of biological drugs, in particular tumour necrosis factor inhibitors (TNFi), revolutionised the management of both these diseases. While the impact of conventional drugs on gut microbiota is well known, poor data are available about TNFi. AIM: To investigate the impact of TNFi on gut microbiota. METHODS: We evaluated 20 patients affected by enteropathic arthritis, naïve for biological drugs, treated with TNFi at baseline and after 6 months of therapy. All patients followed a Mediterranean diet. Patients performed self-sampling of a faecal sample at baseline and after 6 months of therapy. NGS-based ITS and 16S rRNA gene sequencing was performed, followed by the taxonomic bioinformatics analysis. RESULTS: After 6 months of therapy, we detected a remarkable increase in Lachnospiraceae family (Δ +10.3, p=0.04) and Coprococcus genus (Δ +2.8, p=0.003). We also noted a decreasing trend in Proteobacteria (Δ −8.0, p=0.095) and Gammaproteobacteria (Δ −9, p=0.093) and an increasing trend in Clostridia (Δ +8.2, p=0.083). We did not find differences between TNFi responders (SpA improvement or IBD remission achieved) and non-responders in terms of alpha and beta diversity. CONCLUSIONS: Our findings are consistent with the hypothesis that TNFi therapy tends to restore the intestinal eubiosis

Molecular identification of <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> in oral biopsies of Crohn’s disease patients

Oral lesions may be found in patients with Crohn’s disease (CD), in a percentage up to 20%. The aim of this study was to investigate a possible relationship between Mycobacterium avium subsp. paratuberculosis (MAP) and oral lesions in CD patients. 23 oral biopsies were examined performing IS900 Nested PCR; 9 of them were positive: 8 from CD patients and 1 from a control. Our purpose is to go on with this study, amplifying the number of subjects examined and testing subjects with oral lesions related to diseases other than CD to verify the specific association between MAP and oral lesions in CD patients

Clinical practice guidelines in Brazil : developing a national programme

In Brazil, governmental and non-governmental organisations develop practice guidelines (PGs) in order to optimise patient care. Although important improvements have been made over the past years, many of these documents still lack transparency and methodological rigour. In order to conduct a critical analysis and define future steps in PG development in Brazil, we carried out a structured assessment of strengths, weaknesses, opportunities and threats (SWOT analysis) for the development of a national guideline programme. Participants consisted of academia, methodologists, medical societies and healthcare system representatives. In summary, the PG development process has improved in Brazil and current investments in methodological research and capacity-building are ongoing. Despite the centralised processes for public PGs, standardised procedures for their development are not well established and human resources are insufficient in number and capacity to develop the amount of trustworthy documents needed. Brazil’s capacity could be strengthened and initial efforts have been made such as the adoption of standards proposed by world-renowned institutions in PG development and enhancement of the involvement of key stakeholders. Further steps involve the alignment between health technology assessment and PG processes for synergy and the development of a national network to promote the interaction between groups involved in the development of PGs. The lessons learned from this paper could be used to foster debate on guideline development, especially for countries facing similar threats on this topic

Gastric bypass-induced weight loss alters obesity-associated patterns of plasma pentraxin-3 and systemic inflammatory markers

Systemic inflammation contributes to obesity-associated complications. The short pentraxin C-reactive protein (CRP) is a validated inflammatory marker, whereas long pentraxin-3 (PTX3) limits inflammation and is adaptively stimulated by proinflammatory cytokines in vitro. Severely obese (SO) patients (body mass index [BMI]>40] have the highest obesity-associated complications and increasingly undergo surgical treatment. SO-associated changes in plasma PTX3 and their interactions with systemic inflammation are, however, unknown