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VGF mRNA is widely expressed in areas of the nervous system known to degenerate in Amyotrophic Lateral Sclerosis (ALS), including cerebral cortex, brainstem and spinal cord. Despite certain VGF alterations are reported in animal models, little information is available with respect to the ALS patients. We addressed VGF peptide changes in fibroblast cell cultures and in plasma obtained from ALS patients, in parallel with spinal cord and plasma samples from the G93A-SOD1 mouse model. Antisera specific for the C-terminal end of the human and mouse VGF proteins, respectively, were used in immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), while gel chromatography and HPLC/ESI-MS/MS were used to identify the VGF peptides present. Immunoreactive VGF C-terminus peptides were reduced in both fibroblast and plasma samples from ALS patients in an advanced stage of the disease. In the G93A-SOD1 mice, the same VGF peptides were also decreased in plasma in the late-symptomatic stage, while showing an earlier down-regulation in the spinal cord. In immunohistochemistry, a large number of gray matter structures were VGF C-terminus immunoreactive in control mice (including nerve terminals, axons and a few perikarya identified as motoneurons), with a striking reduction already in the pre-symptomatic stage. Through gel chromatography and spectrometry analysis, we identified one form likely to be the VGF precursor as well as peptides containing the NAPP- sequence in all tissues studied, while in the mice and fibroblasts, we revealed also AQEE- and TLQP- peptides. Taken together, selective VGF fragment depletion may participate in disease onset and/or progression of ALS.

The hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene larger than 30 repeats has been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent papers investigated the possible pathogenic role and associated clinical phenotypes of intermediate C9ORF72 repeat expansion ranging between 20 and 30 repeats. Some studies suggested its pathogenicity for typical Parkinson’s disease (PD), atypical parkinsonian syndromes, FTD with/without parkinsonism, and ALS with/without parkinsonism or with/without dementia. In our study, we aimed to screen patients affected by atypical parkinsonian syndromes or PD complicated by psychosis or dementia for the presence of C9ORF72 repeat expansions, and in unrelated age- and sex-matched healthy controls. Consecutive unrelated patients with atypical parkinsonian syndromes and patients with PD complicated by psychosis or dementia were included in this study. Atypical parkinsonian syndromes were further divided into two groups: one with patients who met the criteria for the classic forms of atypical parkinsonism [multiple system atrophy (MSA), Lewy body disease (LBD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] ;and patients who did not meet the above criteria, named non-classical atypical parkinsonism with or without dementia. Ninety-two unrelated patients (48 men, 44 women) were enrolled. None of the patients was found to be carriers of C9ORF72 repeat expansions with more than 30 repeats. Intermediate 20–30 repeat expansions were detected in four female patients (4.3 %). Three of them presented clinical features of atypical parkinsonian syndromes, two with non-classical atypical parkinsonism and dementia FTD-like, and one with non-classical atypical parkinsonism without dementia. The other patient presented clinical features of typical PD complicated by psychosis. Among 121 control subjects, none presented long or short expansion for the C9ORF72 gene. Our findings seem to support the hypothesis that the hexanucleotide expansions of C9ORF72 gene with intermediate repetitions between 20 and 29 repetitions could be associated with typical PD with psychosis or dementia and atypical parkinsonisms with dementia (non-classical atypical parkinsonism with dementia FTD-like) or without dementia (non-classical atypical parkinsonism upper MND-like), although the causal relationship is still unclear. In these latter patients, parkinsonism, more or less levodopa responsive, constituted the symptomatological central core at onset.

Recent genetic studies suggest a Sardinian type of amyotrophic lateral sclerosis (ALS). Thus, ALS incidence, prevalence and survival were investigated in a large population of Sardinians aimed to disclose population-specific patterns and their temporal changes. This is a population-based incidence and prevalence study in northern and central Sardinia, insular Italy (over 700,000 population). Incidence rates were computed for the time interval 1995–2009 and by quinquennia. Prevalence was computed for prevalence days 31 December 2004 and 2009. Onset-based survival for 1995–2009 is also reported. All ALS patients (El Escorial Criteria) in the study area were retrospectively included. The ALS crude incidence from 2005–2009 was 2.5 (95 % CIs: 0.1, 4.9), 3.4 in men and 1.6 in women. Onset occurred most often between the age of 65–74 years in men and 55–64 years in women. The ALS incidence tended to increase over the period 1995–2009. The mean age at onset was 61.7 years with no difference based on gender, varying significantly from 59.9 years in 1995–1999 to 63.9 years in 2005–2009. On December 31, 2009, the ALS crude prevalence was 10.8 per 100,000 (95 % CIs: 8.6, 13.1), 13.8 in men and 8.0 in women, whereas it was 6.3 per 100,000 (95 % CIs: 4.1, 8.6) on December 31, 2004 (M:F ratio of 0.95). Mean survival from onset was 37.0 months, with no difference based on gender, and a tendency to decrease during the period 1995–2009, in relation to type and age of onset. The population-based incidence and prevalence data of ALS in Sardinians indicate an increase of the disease occurrence over the past 40 years, providing support for a population-specific variant of ALS in Sardinia.

In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion. In this review, we updated evidence on the effects of SCFAs potentially improving metabolic control in type 2 diabetes.

Background Hyperglycemic non-diabetic stroke patients have a worse prognosis than both normoglycemic and diabetic patients. Aim of this study was to assess whether hyperglycemia is an aggravating factor or just an epiphenomenon of most severe strokes. Methods In this retrospective study, 1219 ischemic or hemorrhagic stroke patients (73.7 ± 13.1 years) were divided into 4 groups: 0 = non-hyperglycemic non-diabetic, 1 = hyperglycemic non-diabetic, 2 = non-hyperglycemic diabetic and 3 = hyperglycemic diabetic. Hyperglycemia was defined as fasting blood glucose ≥ 126 mg/dl (≥ 7 mmol/l) measured the morning after admission, while the diagnosis of diabetes was based on a history of diabetes mellitus or on a glycated hemoglobin ≥ 6.5% (≥ 48 mmol/mol), independently of blood glucose levels. All diabetic patients, except 3, had Type 2 diabetes. The 4 groups were compared according to clinical history, stroke severity indicators, acute phase markers and main short term stroke outcomes (modified Rankin scale ≥ 3, death, cerebral edema, hemorrhagic transformation of ischemic lesions, fever, oxygen administration, pneumonia, sepsis, urinary infection and heart failure). Results Group 1 patients had more severe strokes, with larger cerebral lesions and higher inflammatory markers, compared to the other groups. They also had a high prevalence of atrial fibrillation, prediabetes, previous stroke and previous arterial revascularizations. In this group, the highest frequencies of cerebral edema, hemorrhagic transformation, pneumonia and oxygen administration were obtained. The prevalence of dependency at discharge and in-hospital mortality were equally high in Group 1 and Group 3. However, in multivariate analyses including stroke severity, cerebral lesion diameter, leukocytes and C-reactive protein, Group 1 was only independently associated with hemorrhagic transformation (OR 2.01, 95% CI 0.99–4.07), while Group 3 was independently associated with mortality (OR 2.19, 95% CI 1.32–3.64) and disability (OR 1.70, 95% CI 1.01–2.88). Conclusions Hyperglycemic non-diabetic stroke patients had a worse prognosis than non-hyperglycemic or diabetic patients, but this group was not independently associated with mortality or disability when size, severity and inflammatory component of the stroke were accounted for.

Osteoporosis is a major public health burden that is expected to further increase as the global population ages. In the last twenty years, advanced glycation end products (AGEs) have been shown to be critical mediators both in the pathogenesis and development of osteoporosis and other chronic degenerative diseases related to aging. The accumulation of AGEs within the bone induces the formation of covalent cross-links with collagen and other bone proteins which affects the mechanical properties of tissue and disturbs bone remodelling and deterioration, underlying osteoporosis. On the other hand, the gradual deterioration of the immune system during aging (defined as immunosenescence) is also characterized by the generation of a high level of oxidants and AGEs. The synthesis and accumulation of AGEs (both localized within the bone or in the systemic circulation) might trigger a vicious circle (in which inflammation and aging merged in the word “Inflammaging”) which can establish and sustain the development of osteoporosis. This narrative review will update the molecular mechanisms/pathways by which AGEs induce the functional and structural bone impairment typical of osteoporosis.

The insulin-like growth factor 1 (IGF-1) stimulates expression and secretion of vascular endothelial growth factor-A (VEGF-A), the main actor in ocular neovascularization, by RPE cells. Activity of IGF-1 is regulated by interaction between its receptor and Caveolin-1 (Cav-1), the main component of caveolae. The aim of this study was to investigate whether modulation of Cav-1 expression affects synthesis and secretion of VEGF-A. ARPE-19 cells were transfected with small interfering RNA for Cav-1 (si-Cav-1) and with control siRNA (si-CTR) and stimulated with IGF-1. We found that down-regulation of Cav-1 did not affect activation of IGF-1R but regulated in an opposite manner the phosphorylation of Akt and Erk1/2. Moreover, we found that IGF-1 increased mRNA levels of VEGF-A in both si-CTR and in si-Cav-1 ARPE-19 cells and that Cav-1 silencing significantly reduced basal and IGF-1-stimulated VEGF-A release. Then we investigated the response of the microvascular endothelial cell line HMEC-1 to secretory products of ARPE-19 cells by evaluating wound healing closure, finding that conditioned media from si-Cav-1-ARPE-19 cells reduced endothelial cell migration rate. These data demonstrate that Cav-1 regulates secretion of VEGF-A, and that the depletion of Cav-1 reduces IGF-1 induced VEGF-A secretion in ARPE-19 cells and the migratory potential of their secretory products.

In post-stroke dysphagia, early identification of patients at highest risk of failing swallowing recovery (SR) would be useful to decide which of them should undergo percutaneous endoscopic gastrostomy. The studies on this subject were numerous but generally based on small statistical samples. In this retrospective study, 1232 patients with ischemic or hemorrhagic stroke (73.7 ± 13.0 years, 51% men) were assessed: 593 non-dysphagic, 351 partially dysphagic and 288 totally dysphagic. Among the latter, 45.1% could not recover oral intake. A score to assess the risk of failing SR was obtained from the group with total dysphagia, and further 210 patients with total post-stroke dysphagia were utilized for validation. A regular progression of stroke severity markers, complications and mortality was observed from non-dysphagic, to partially dysphagic, up to totally dysphagic patients. Among the latter, seven variables were independently associated with failure of SR, and formed the “DIsPHAGIc score”: cerebral lesion Diameter ≥ 6 cm (+ 1), left frontal Ischemia (− 1), Partial anterior circulation syndrome (− 1), Hypoxia (+ 1), Antiplatelet drug (+ 1), GCS verbal reaction < 4 (+ 1), Internal capsule ischemia (− 1). The area under the ROC curve was 0.79 (95% CI 0.74–0.85). For total scores ≥ 2 there was a high risk of failing SR, with specificity 76.9%, sensitivity 72.1% and accuracy 74.7%. The application of the DIsPHAGIc score to the validation sample provided almost identical results. The evolution of post-stroke dysphagia towards irreversibility can be predicted by a simple, reproducible and robust scoring system based on 7 variables commonly available during hospitalization.

Vascular endothelial growth factor-A (VEGF-A) has a pathologic role in microvascular diabetic complication, such as diabetic retinopathy (DR). miR-126 plays an important role in vascular development and angiogenesis by regulating the expression of VEGF-A. Since levels of miR-126 have been found downregulated in diabetes, this study is aimed at investigating whether hyperglycemia affects expression of miR-126 in a retinal pigment epithelium cell line. ARPE-19 cells were transfected with miR-126 inhibitor or with miR-126 mimic and the respective scramble negative control. After 24 hours, medium was replaced and cells were cultured for 24 hours in normal (CTR) or diabetic condition (HG). Then, we analyzed mRNA levels of miR-126, VEGF-A, PI3KR2, and SPRED1. We also evaluated protein amount of HIF-1α, PI3KR2, and SPRED1 and VEGF-A secretion. The results showed that exposure of ARPE-19 cells to HG significantly decreased miR-126 levels; mRNA levels of VEGF-A and PI3KR2 were inversely correlated with those of miR-126. Overexpression of miR-126 under HG restored HIF-1α expression and VEGF-A secretion to the level of CTR cells. These results indicate that reduced levels of miR-126 may contribute to DR progression by increasing expression of VEGF-A in RPE cells. In addition, we provide evidence that upregulation of miR-126 in RPE cells counteracts the rise of VEGF-A secretion induced by hyperglycemia. In conclusion, our data support a role of miR-126 mimic-approach in counteracting proangiogenic effects of hyperglycemia.

The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.