RUOLO DELLA MITOCONDRIOGENESI NELLA NEUROPROTEZIONE:NUOVI APPROCCI ALLA TERAPIA SPERIMENTALE DELL'ISCHEMIA CEREBRALE

Mitochondrial bioenergetic failure, with severe ATP depletion and reactive oxygen species (ROS) overgeneration occurs during cerebral ischemia. We hypothesized that stimulation of mitochondrial biogenesis could help reduce cerebral ischemic damage. We observed that levels of proliferator-activated receptor \u3b3 coactivator 1\u3b1 and nuclear respiratory factor-1 were reduced in primary mouse cortical neurons under oxygen-glucose deprivation (OGD). OGD also reduced neuronal mitochondrial mass and function, as assessed by mtDNA measurement and citrate synthase activity. The glycogen synthase kinase-3 (GSK-3) inhibitor SB216763 activated an efficient mitochondrial biogenesis program in control cortical neurons and counteracted the OGD-mediated mitochondrial biogenesis impairment. Further, SB induced an antioxidant response that reduced mitochondrial reactive oxygen species generation and ischemic neuronal damage. Two other structurally unrelated GSK-3 inhibitors mimicked SB216763 effects. In presence of diverse mitochondrial inhibitors the protective effects of SB216763 were abolished. When systemically administered in vivo, SB216763 reduced the infarct size and recovered the loss of mitochondrial DNA in mice subjected to permanent middle cerebral artery occlusion. Finally, we observed that levels of mitochondrial biogenesis markers were induced by metformin or SRT2183 (a Sirtris molecule that activates SIRT1) treatments. Moreover, metformin and SRT2183 reduced OGD-mediated ischemic neuronal damage. We conclude that strategies to restore mitochondrial biogenesis impairment during cerebral ischemia and to reduce reactive oxygen species might pave the way of novel promising therapies for future treatment of cerebral ischemia

Partial-Body Cryotherapy Acutely Augments Resting Metabolism in Obese Women

Cryotherapy has been shown to reduce pro-inflammatory response, relieve pain and enhance muscles\u2019 post-exercise recovery. Cryostimulation could be also proposed as an alternative strategy to trigger cold-induced thermogenesis in overweight/obese subjects. In this study, 16 obese (BMI: 32\ub14 kg/m2) women (43.4\ub14.8 years) underwent Partial-Body Cryotherapy (PBC) (-130\ub0C x 150sec) for 5 days (1/day, h 07:00 AM). Resting energy metabolism (REE) was assessed by indirect calorimetry pre- and post-PBC on day 1 and day 5. Subjects were energy-controlled (physical activity and dietary intake). Before 5th-day PBC, REE was increased by 5.5% versus pre-1st-day PBC values (1755\ub1265 vs. 1664\ub1241 kcal/day; p=0.0005). With a similar design, in a larger sample of 80 subjects (F=61; M=19; 34.4\ub111.1 years; BMI: 24.4\ub14.8 kg/m2), REE augmented by 1.89% (p=0.02) after PBC of day 1. In a multivariate analysis, multiple regression output a positive relationship between cryostimulated REE and body weight (Spearman r=0.68; p<0.0001, Figure). Altogether, these preliminary data suggest that cold-induced thermogenesis could be explored as an alternative therapy to combat weight gain and obesity. Longitudinal studies could test chronic effects of cryotherapy, estimating the extent of the metabolic adaptations that could be favorably preserved

Advanced Glycation end products (AGEs) in food: focusing on Mediterranean pasta

5Advanced glycation end products, also known as glycotoxins, are a diverse group of highly oxidant compounds with pathogenic significance in aged-chronic disease, including diabetes, cardiovascular disease and neurodegenerative disease. They are produced physiologically in the body when reducing sugar binds to a free amino acid group of macromolecules. Thus conditions such as hyperglycemia and/or oxidative stress can favor AGE product formation, contributing to ageing processes and the exacerbation of pathological states. Beside endogenous AGEs, dietary AGE intake contributes significantly to the body AGE pool. It assumes that if dietary AGE intake gets lower, any chronic disease, such as diabetes and cardiovascular disease can be ameliorated, and even cured. For this reason, recently great attention has been made on the identification and quantification of AGE products in the consumed foods. Here we reviewed some knowledge, found in literature, concerning the formation of AGEs in food, their gastrointestinal absorption, and their toxic effects. In addition original data on AGE content in the Mediterranean pasta was discussed in relation to their production processes and cooking time.openopenAbate, G.; Delbarba, A.; Marziano, M.; Memo, M.; Uberti, D.Abate, Giulia; Delbarba, Andrea; Marziano, Mariagrazia; Memo, Maurizio; Uberti, Daniela Letizi

Anabolic steroids purchased on the Internet as a cause of prolonged hypogonadotropic hypogonadism

OBJECTIVE: To report a case of hypogonadotropic hypogonadism due to the chronic abuse of anabolic steroids purchased over the Internet. DESIGN: Case report. SETTING: Endocrinology unit of the University of Brescia. PATIENT(S): A 34-year-old man. INTERVENTION(S): A single dose (100 μg) of triptorelin (triptorelin test). MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen normalization, levels of serum testosterone, follicle-stimulating hormone, and luteinizing hormone. RESULT(S): Within 1 month, the patient's serum testosterone was in the normal range, and he reported a return to normal energy and libido. CONCLUSION(S): The World Anti-Doping Code has proved to be a very powerful and effective tool in the harmonization of antidoping efforts worldwide, but it is insufficient to combat this illegal phenomenon. To tackle the serious side effects caused by doping we believe that it is necessary to increase monitoring and adopt severe sanctions, particularly with regard to Internet sites

Gonadal Function in Male Patients With Metastatic Renal Cell Cancer Treated With Sunitinib

Background/aim: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. Patients and methods: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. Results: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. Conclusion: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib

Liquid levothyroxine formulations in patients taking drugs interfering with L-T4 absorption

PurposeTo describe the current knowledge on thyroid hormonal profile in patients on liquid L-T4 therapy and drugs known to interfere with L-T4 absorption. MethodsA PubMed/MEDLINE, Web of Science, and Scopus research was performed. Case reports, case series, original studies and reviews written in English and published online up to 31 August 2022 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review. ResultsThe available data showed that novel levothyroxine formulations circumvent gastric pH impairment due to multiple interfering drugs such as proton pump inhibitors, calcium or iron supplements, sevelamer, aluminum/magnesium hydroxide and sodium alginate. ConclusionNew formulations can be taken simultaneously with drugs interfering with L-T4 absorption, in particular liquid formulations. Softgel capsules need more studies to support these data

Modified percutaneous ethanol injection of parathyroid adenoma in primary hyperparathyroidism.

Surgery is the treatment of choice for symptomatic primary hyperparathyroidism; unlikely few patients do not meet established surgical criteria or have comorbid conditions that prohibit surgery. In these subjects, medical therapy alone offers little hope for a sustained long normocalcemic period. However percutaneous ethanol injection (PEI) may represent an alternative therapeutic procedure. It is currently in use for the treatment of secondary or tertiary hyperparathyroidism, however, few studies or case reports suggest it for the treatment of primary hyperparathyroidism. Moreover, little information is available about the long-term follow-up, where incomplete necrosis or the spreading of ethanol in the surrounding tissues is often reported. We believe that many of the side effects could be correlated to procedure itself. Taking these experiences into account, we have reasoned that in order to limit these side effects, we had to modify the standard PEI procedure. We reported this preliminary experience describing our modified PEI procedure

Prognostic value of thyrotropin receptor antibodies (TRAb) in Graves' disease: a 120 months prospective study

In most trials, at least 30-60% of patients with Graves' disease treated with antithyroid drugs relapse within 2 years after therapy withdrawal. At present, there are no prognostic parameters available early in treatment to indicate patients likely to achieve long-term remission. Because thyrotropin receptor autoantibodies (TRAb) are specific for Graves' disease, we evaluated the ability of their levels and of their rate of change to predict long-term prognosis. In our study 216 consecutive patients with newly diagnosed Graves' disease started a therapy with methimazole. Patients were treated until they achieved euthyroidism and TRAb were measured at 6-month intervals throughout a follow up of 120 months. Our study demonstrated that at the onset of hyperthyroidism patients' age, sex, fT4 levels and goiter size had no prognostic value in predicting long-term prognosis (respectively p = 0.79; p = 0.98; p = 0.83; p = 0.89). On the contrary, at the time of diagnosis TRAb titer was a good predictor of the final outcome (p<0.001); a titer equal to (or) more than 46.5 UI/L could identify patients who had never achieved long-term remission with a sensitivity of 52% and a specificity of 78%. Also fall rate of TRAb at 6 months of follow up and after therapy withdrawal were useful to predict the final outcome (p<0.001). At 6 months of follow up the time of therapy withdrawal, a decrease of TRAb lower than 52.3% or even its increase could identify patients who had never achieved permanent remission with a sensitivity of 55% and a specificity of 79.1%. No single parameter among TRAb, satisfactory identified a sub-set of patients who achieved long remission. Accordingly to our data, the best result in predicting long term remission is probably given by the presence of at least one of the two features evaluated at 6 months (TRAb titer and/or percentage of TRAb fall rate), with a sensitivity of 63% and specificity of 88%. TRAb titers evaluated both at the onset of hyperthyroidism that at 6 months of therapy or their rate of fall at 6 months and at ATD withdrawal are predictors of outcome. However, the presence of at least one, between titers of TRAb or their rate of fall at six months, resulted to be the best predictor of remission with the higher sensitivity and specificity

Fine needle cytology of complex thyroid nodules.

OBJECTIVE: To evaluate whether a preliminary aspiration (ASP) of the cystic component and/or using spinal needles in complex thyroid nodules (CTN) could improve the adequacy of cytological sampling. METHODS: Between January 2004 and December 2006, 386 consecutive patients with CTN were enrolled in this prospective investigation. Ultrasound (US) fine needle aspiration cytology (FNAC) of the solid component of the nodule (one nodule per patient) was performed using two different 25 gauge needles, with (Yale Spinal, YS) or without (Neolus, NS) a stylet, in alternate sequence on consecutive patients. In addition, a subgroup of patients presenting larger cystic component (approximately 50%) was submitted to total aspiration of the cystic component (ASP+) or not submitted (ASP-) before US-FNAC, in alternate sequence within each needle type group. All the samplings were performed by a single endocrinologist. RESULTS: Adequate specimens were observed in 163 (84.5%) and 183 (94.8%) nodules investigated by NS and YS respectively. Sampling with the stylet needle was associated with an overall significant reduction of non-diagnostic specimens (15.5% vs 5.2% by NS and YS respectively, P < 0.001). The favourable result obtained with YS was independent from preliminary aspiration of the cystic component (ASP+: 14.8% vs 5.7% by NS and YS; ASP-: 16.2% vs 4.8%, not significant). A logistic regression analysis, taking into account nodule size and presence of intranodal vascularity at eco-colour evaluation of the solid component, confirmed that needle type was the only significant predictor of successful sampling (odds ratio 3.6 (95% confidence interval 1.7-7.6), P < 0.001). CONCLUSIONS: Our data show that adopting stylet needles to perform FNAC in CTN may significantly improve the percentage of adequate sampling. On the other hand, preliminary aspiration of CTN with large cystic component does not add any advantage

Conformational altered p53 affects neuronal function: relevance for the response to toxic insult and growth-associated protein 43 expression

The role of p53 in neurodegenerative diseases is essentially associated with neuronal death. Recently an alternative point of view is emerging, as altered p53 conformation and impaired protein function have been found in fibroblasts and blood cells derived from Alzheimer's disease patients. Here, using stable transfected SH-SY5Y cells overexpressing APP751wt (SY5Y-APP) we demonstrated that the expression of an unfolded p53 conformation compromised neuronal functionality. In particular, these cells showed (i) augmented expression of amyloid precursor protein (APP) and its metabolites, including the C-terminal fragments C99 and C83 and β-amyloid peptide (ii) high levels of oxidative markers, such as 4-hydroxy-2-nonenal Michael-adducts and 3-nitro-tyrosine and (iii) altered p53 conformation, mainly due to nitration of its tyrosine residues. The consequences of high-unfolded p53 expression resulted in loss of p53 pro-apoptotic activity, and reduction of growth-associated protein 43 (GAP-43) mRNA and protein levels. The role of unfolded p53 in cell death resistance and lack of GAP-43 transcription was demonstrated by ZnCl(2) treatment. Zinc supplementation reverted p53 wild-type tertiary structure, increased cells sensitivity to acute cytotoxic injury and GAP-43 levels in SY5Y-APP clone