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Background/Objectives: Photobiomodulation (PBM) is a non-invasive, low-level laser treatment shown to improve insulin resistance, glucose metabolism, and obesity-related inflammation. This study examined whether PBM could acutely enhance mitochondrial efficiency and energy metabolism in women with obesity. Methods: In a randomized, crossover within-subject design, 16 women with obesity (43 ± 5 years; BMI: 36 ± 4 kg/m2) and 16 sedentary normal-weight women (43 ± 5 years; BMI: 22.7 ± 2 kg/m2) underwent PBM (front and back exposure; red light, 633–660 nm; NIR, 850–940 nm) and a sham stimulation (SHAM), as a control, for 12 min. Resting energy expenditure (REE) was assessed via indirect calorimetry before and after exposure. Secondary measures included skin autofluorescence, heart rate, blood pressure, profile of mood states, rate of perceived exertion (RPE), and flexibility. Diet and physical activity were controlled. Results: A 2 × 2 × 2 ANOVA revealed a significant group × time interaction (F3,60 = 3.054, p = 0.03) and a main effect of time (F1,60 = 10.88, p = 0.001). Women with obesity showed a significant increase in REE post-PBM compared to pre-PBM (+9.3%, 1624 ± 314 vs. 1486 ± 327 kcal/day; p < 0.001), with no change in the respiratory exchange ratio. Additionally, RPE decreased and flexibility improved in both groups following PBM. Front and back skin temperatures increased significantly post-PBM, with greater changes observed in the back versus the front. Conclusions: These preliminary findings indicate that PBM acutely enhances energy utilization efficiency in women with obesity, increasing resting energy expenditure without modifying substrate oxidation. PBM may represent a promising non-invasive adjunctive strategy for improving the metabolic health of obese individuals.

Background Nutrigenomics elucidate the ability of bioactive food components to influence gene expression, protein synthesis, degradation and post-translational modifications. Resveratrol (RSV), natural polyphenol found in grapes and in other fruits, has a plethora of health benefits in a variety of human diseases: cardio- and neuroprotection, immune regulation, cancer chemoprevention, DNA repair, prevention of mitochondrial disorder, avoidance of obesity-related diseases. In skeletal muscle, RSV acts on protein catabolism and muscle function, conferring resistance against oxidative stress, injury and cell death, but its action mechanisms and protein targets in myogenesis process are not completely known. Myogenesis is a dynamic multistep process regulated by Myogenic Regulator Factors (MRFs), responsible of the commitment of myogenic cell into skeletal muscle: mononucleated undifferentiated myoblasts break free from cell cycle, elongate and fuse to form multinucleated myotubes. Skeletal muscle hypertrophy can be defined as a result of an increase in the size of pre-existing skeletal muscle fibers accompanied by increased protein synthesis, mainly regulated by Insulin Like Growth Factor 1 (IGF-1), PI3-K/AKT signaling pathways. Aim of this work was the study of RSV effects on proliferation, differentiation process and hypertrophy in C2C12 murine cells. Methods To study proliferative phase, cells were incubated in growth medium with/without RSV (0.1 or 25 μM) until reaching sub confluence condition (24, 48, 72 h). To examine differentiation, at 70% confluence, cells were transferred in differentiation medium both with/without RSV (0.1 or 25 μM) for 24, 48, 72, 96 hours. After 72 hours of differentiation, the genesis of hypertrophy in neo-formed myotubes was analyzed. Results Data showed that RSV regulates cell cycle exit and induces C2C12 muscle differentiation. Furthermore, RSV might control MRFs and muscle-specific proteins synthesis. In late differentiation, RSV has positive effects on hypertrophy: RSV stimulates IGF-1 signaling pathway, in particular AKT and ERK 1/2 protein activation, AMPK protein level and induces hypertrophic morphological changes in neo-formed myotubes modulating cytoskeletal proteins expression. Conclusions RSV might control cell cycle promoting myogenesis and hypertrophy in vitro , opening a novel field of application of RSV in clinical conditions characterized by chronic functional and morphological muscle impairment.

This narrative non-systematic review addresses the sex-specific differences observed both in prenatal period and, subsequently, in early childhood. Indeed, gender influences the type of birth and related complications. The risk of preterm birth, perinatal diseases, and differences on efficacy for pharmacological and non-pharmacological therapies, as well as prevention programs, will be evaluated. Although male newborns get more disadvantages, the physiological changes during growth and factors like social, demographic, and behavioural reverse this prevalence for some diseases. Therefore, given the primary role of genetics in gender differences, further studies specifically targeted neonatal sex-differences will be needed to streamline medical care and improve prevention programs.

The possible influence exerted by mechanical factors and/or compressive phenomena on myocardial strain parameters in healthy individuals with opposite obesity phenotypes (android vs gynoid) has never been previously investigated. Accordingly, we aimed at evaluating the relationship between anthropometrics, such as the waist-to-hip ratio (WHR), modified Haller index (MHI, the ratio of chest transverse diameter over the distance between sternum and spine), and epicardial adipose tissue (EAT), and left ventricular (LV)-global longitudinal strain (GLS), in healthy women with opposite obesity phenotypes (android vs gynoid). Forty healthy women with obesity (body mass index (BMI) ≥30 Kg/m  and WHR ≥0.85 (\"android group\") (52.5±13.2 yrs), 40 age- and BMI-matched healthy women with obesityand WHR <0.78 (\"gynoid group\") (49.8±13.4 yrs) and 40 age-matched healthy women without obesity (BMI <30 Kg/m ) (controls) (50.3±12.5 yrs) were retrospectively analyzed. All women underwent transthoracic echocardiography implemented with echocardiographic strain analysis of all cardiac chambers. Correlation between LV-GLS and anthropometrics (WHR, MHI, and EAT) was assessed in both groups of obese women. Age, WHR, homeostasis model assessment for insulin resistance (HOMA-IR), and left ventricular mass index (LVMi) were included in the logistic regression analysis performed for evaluating the independent predictors of reduced LV-GLS magnitude (less negative than -20%) in women with android obesity. Compared to the other groups of women, those with android obesity were found with significantly greater LVMi, higher LV filling pressures, and lower biventricular and biatrial deformation indices. A strong inverse correlation between LV-GLS and all anthropometrics (WHR, MHI, and EAT) was demonstrated in both groups of women with obesity. Univariate logistic regression analysis revealed that WHR (OR 1.58, 95%CI 1.22-2.03, p<0.001) and LVMi (OR 1.09, 95%CI 1.02-1.16, p=0.006) were independently correlated with LV-GLS impairment in women with android obesity. On multivariate logistic regression analysis, the WHR maintained a statistically significant association with the above-mentioned outcome (OR 1.68, 95%CI 1.14-2.48, p=0.009). Receiver operating characteristic (ROC) curve analysis showed that a WHR value ≥1.01 had 93% sensitivity and 100% specificity for detecting LV-GLS impairment in women with android obesity (AUC=0.98; 95%CI 0.96-1.00). Anthropometrics may strongly influence cardiac mechanics in healthy women with obesity. The WHR is associated with reduced LV-GLS magnitude in healthy women with android obesity, independent of age, glycometabolic status, and LV size.

Background and Aims. Hepatocellular carcinoma (HCC) is the common tumor of the liver. Unfortunately, most HCC seem to be resistant to conventional chemotherapy and radiotherapy. The poor efficacy of antitumor agents is also due, at least in part, to the inefficient drug delivery and metabolism exerted by the steatotic/cirrhotic liver that hosts the tumor. Thus, novel approaches in chemotherapy may be needed to improve the survival rate in patients with HCC. Metformin (METF) has been found to lower HCC risk; however, the mechanisms by which METF performs its anticancer activity are not completely elucidated. Previous studies have showed METF action on growth inhibition in the liver in a dose/time-dependent manner and its antitumor role by targeting multiple pathways. We investigated molecular effects of METF in an in vitro human hepatoma model (HepG2), studying cell cycle regulators, tumorigenesis markers, and insulin-like growth factor (IGF) axis regulation. Materials and Methods. HepG2 cells were treated with METF (400 μM) for 24, 48, and 72 hours. METF action on cell cycle progression and cellular pathways involved in metabolism regulation was evaluated by gene expression analysis, immunofluorescence, and Western blot assay. Results. By assessing HepG2 cell viability, METF significantly decreased growth cell capacity raising KLF6/p21 protein content. Moreover, METF ameliorated the cancer microenvironment reducing cellular lipid drop accumulation and promoting AMPK activity. The overexpression of IGF-II molecule and the IGF-I receptor that plays a main role in HCC progression was counteracted by METF. Furthermore, the protein content of HCC principal tumor markers, CK19 and OPN, linked to the metastasis process was significantly reduced by METF stimulus. Conclusion. Our data show that METF could suppress HepG2 proliferation, through induction of cell cycle arrest at the G0/G1 phase. In addition, METF effect on the cancer microenvironment and on the IGF axis leads to the development of new METF therapeutic use in HCC treatment.

IntroductionLong-COVID is a broadly defined condition and there are no effective therapies. Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations. Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of long-COVID, including in the mechanisms of its cardiovascular manifestations. The present study aimed to evaluate the effectiveness of a treatment with blockers of histamine receptors in patients with long-COVID who did not respond to other therapies.MethodsIn all, 14 patients (F/M = 9/5; 49.5 ± 11.5 years) and 13 controls (F/M = 8/5; 47.3 ± 8.0 years) with long-COVID symptoms attributed to MCA were evaluated. Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later.ResultsLong-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients, and the improvement grade was significantly greater in treated patients compared to controls. No significant differences in the outcomes were observed in the controls.ConclusionsOur data confirm that histamine receptors blockade may be an effective target to successfully treat long-COVID. Our finding supports the underlying role of MCA in the pathophysiology of long-COVID.

A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals.

Habitual Physical Activity Is Associated With Intrahepatic Fat Content in Humans Gianluca Perseghin , MD 1 2 3 , Guido Lattuada , PHD 1 , Francesco De Cobelli , MD 2 4 , Francesca Ragogna , PHD 1 , Georgia Ntali , MD 1 , Antonio Esposito , MD 4 , Elena Belloni , MD 4 , Tamara Canu 4 , Ileana Terruzzi , PHD 1 , Paola Scifo , PHD 5 , Alessandro Del Maschio , MD 2 4 6 and Livio Luzi , MD 1 2 3 1 Internal Medicine, Section of Nutrition/Metabolism, San Raffaele Scientific Institute, Milan, Italy 2 Unit of Clinical Spectroscopy, San Raffaele Scientific Institute, Milan, Italy 3 Center “Physical Exercise for Health and Wellness,” Faculty of Exercise Sciences, Università degli Studi di Milano, Milan, Italy 4 Diagnostic Radiology, San Raffaele Scientific Institute, Milan, Italy 5 Nuclear Medicine, San Raffaele Scientific Institute, Milan, Italy 6 Università Vita e Salute San Raffaele, Milan, Italy Address correspondence and reprint requests to Gianluca Perseghin, MD, Faculty of Exercise Sciences, Università degli Studi di Milano and San Raffaele Scientific Institute, Internal Medicine, via Olgettina 60, 20132, Milan, Italy. E-mail: perseghin.gianluca{at}hsr.it Abstract OBJECTIVE —Fatty liver may be involved in the pathogenesis of type 2 diabetes. Physical exercise is a tool to improve insulin sensitivity, but little is known about its effect on intrahepatic fat (IHF) content. The purpose of this study was to examine the association of habitual physical activity, insulin resistance, and adiponectin with IHF content. RESEARCH DESIGN AND METHODS —Participants were 191 (77 female and 114 male) apparently healthy, nonalcoholic individuals (aged 19–62 years; BMI 17.0–35.5 kg/m 2 ). IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1 H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of >5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes. RESULTS —A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25, 11, 25, and 2% in quartile 1, 2, 3, and 4, respectively; χ 2 = 15.63; P = 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson’s r = −0.27; P < 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r = −0.25; P < 0.001). CONCLUSIONS —This study demonstrated that a higher level of habitual physical activity is associated with a lower IHF content and suggested that this relationship may be due to the effect of exercise per se. FFA, free fatty acid HOMA, homeostasis model assessment HOMA2-%B, HOMA2-derived index of β-cell insulin sensitivity HOMA2-%S, HOMA2-derived index of insulin sensitivity IHF, intrahepatic fat MRS, magnetic resonance spectroscopy NAFLD, nonalcoholic fatty liver disease TSH, thyroid-stimulating hormone Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted November 30, 2006. Received October 2, 2006. DIABETES CARE

Background The prevalence of prediabetes is increasing in the global population and its metabolic derangements may expose to a higher risk to develop type 2 diabetes (T2D) and its cardiovascular burden. Lifestyle modifications might have considerable benefits on ameliorating metabolic status. Alternative biomarkers, such as circulating miR-21, has been recently discovered associated with dysglycemia. Here we evaluated, in a longitudinal cohort of dysglycemic population the relation between the circulating miR-21/ROS/HNE levels and the habit-intervention (HI) after 1 year of follow-up. Methods 1506 subjects from DIAPASON study were screened based on the Findrisc score. Of them, 531 subjects with Findrisc ≥ 9 were selected for dysglycemia (ADA criteria) and tested for circulating miR-21, ROS and HNE levels, as damaging-axis. 207 subjects with dysglycemia were re-evaluated after 1-year of habit intervention (HI). Repeated measures tests were used to evaluate changes from baseline to 1-year of follow-up. The associations between glycemic parameters and miR-21/ROS/HNE were implemented by linear regression and logistic regression models. Results After HI, we observed a significant reduction of miR-21/ROS/HNE axis in dysglycemic subjects, concomitantly with ameliorating of metabolic parameters, including insulin resistance, BMI, microalbuminuria, reactive hyperemia index and skin fluorescence. Significant positive interaction was observed between miR-21 axis with glycaemic parameters after HI. Lower miR-21 levels after HI, strongly associated with a reduction of glycemic damaging-axis, in particular, within-subjects with values of 2hPG < 200 mg/dL. Conclusions Our findings demonstrated that HI influenced the epigenetic changes related to miR-21 axis, and sustain the concept of reversibility from dysglycemia. These data support the usefulness of novel biological approaches for monitoring glycemia as well as provide a screening tool for preventive programmes.

The targeting of nutraceutical treatment to skeletal muscle damage is an emerging area of research, driven by the need for new therapies for a range of muscle-associated diseases. L-Carnitine (CARN) is an essential nutrient and plays a key role in mitochondrial β-oxidation and in the ubiquitin-proteasome system regulation. As a dietary supplement to improve athletic performance, CARN has been studied for its potential to enhance β-oxidation. However, CARN effects on myogenesis, mitochondrial activity, and hypertrophy process are not completely elucidated. This in vitro study aims to investigate CARN role on skeletal muscle remodeling, differentiation process, and myotubes formation. We analyzed muscle differentiation and morphological features in C2C12 myoblasts exposed to 5 mM CARN. Our results showed that CARN was able to accelerate C2C12 myotubes formation and induce morphological changes, characterizing the start of hypertrophy process. In addition, CARN improved AKT activation and downstream cellular signaling pathways involved in skeletal muscle atrophy process prevention. Also, CARN positively regulated the pathways involved in oxidative stress defense. In this work, we provide an interesting novel mechanism of the potential therapeutic use of CARN to treat pathological conditions characterized by skeletal muscle morphological and functional impairment, oxidative stress production, and atrophy process in aging.