ANGPTL3 Downregulation Increases Intracellular Lipids by Reducing Energy Utilization.

BACKGROUND: ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an approved and well-tolerated treatment to reduce lipoproteins in familial hypercholesterolemia homozygotes. However, the reduction of hepatic ANGPTL3 synthesis using an antisense oligonucleotide unexpectedly resulted in a dose-dependent increase in liver lipid content and circulating transaminases, resulting in the termination of the clinical trial. Meanwhile, the use of silencing RNAs remains an area of active investigation. Our study sought to investigate whether intracellular downregulation of ANGPTL3 may lead to a primary increase in neutral lipids within the hepatocyte. METHODS: We downregulated ANGPTL3 by silencing RNA in primary human hepatocytes 3-dimensional spheroids, HepG2/LX-2 3-dimensional spheroids, and in HepG2, Hep3B2, and Huh7 cultured in 2 dimensions. RESULTS: ANGPTL3 downregulation increased neutral lipids in all models investigated. Interestingly, ANGPTL3 induced lower intracellular deiodinase type 1 protein levels resulting in a reduction in beta-oxidation and causing an increase in triglycerides stored in lipid droplets. CONCLUSIONS: In conclusion, intracellular ANGPTL3 downregulation by silencing RNA led to an increase in triglycerides content due to a reduction in energy substrate utilization resembling a primary intracellular hepatocyte hypothyroidism.

Association of dietary patterns with sarcopenia in adults aged 50 years and older.

PURPOSE: Although numerous studies have investigated the impact of dietary factors on the prevention of decreased muscle mass and function, limited research has examined the relationship between dietary patterns and sarcopenia. This study aimed to assess the associations between dietary patterns, and sarcopenia, muscle strength, and mass in adults following a Mediterranean diet residing in southern Italian cities. METHODS: This cross-sectional study utilized data from an existing database, comprising 528 individuals aged 50 years or older who underwent health-screening tests at the Clinical Nutrition Unit of the "R.Dulbecco" University Hospital. Strength was assessed through handgrip strength, and appendicular skeletal muscle mass was estimated using bioelectrical impedance analysis. Dietary intake information was collected through a food frequency questionnaire linked to the MetaDieta 3.0.1 nutrient composition database. Principal Component Analysis, a statistical technique identifying underlying relationships among different nutrients, was employed to determine dietary patterns. Multinomial logistic regression analysis was conducted to estimate the odds ratio for sarcopenia or low handgrip strength in relation to the lowest tertile of dietary pattern adherence compared to the highest adherence. RESULTS: The participants had a mean age of 61 ± 8 years. Four dietary patterns were identified, with only the Western and Mediterranean patterns showing correlations with handgrip strength and appendicular skeletal muscle mass. However, only the Mediterranean pattern exhibited a correlation with sarcopenia (r = - 0.17, p = 0.02). The highest tertile of adherence to the Mediterranean dietary pattern demonstrated significantly higher handgrip strength compared to the lowest tertile (III Tertile: 28.3 ± 0.5 kg vs I Tertile: 26.3 ± 0.5 kg; p = 0.01). Furthermore, even after adjustment, the highest tertile of adherence to the Mediterranean pattern showed a significantly lower prevalence of sarcopenia than the lowest adherence tertile (4% vs 16%, p = 0.04). The lowest adherence to the Mediterranean dietary pattern was associated with increased odds of having low muscle strength (OR = 2.38; p = 0.03; 95%CI = 1.05-5.37) and sarcopenia (OR = 9.69; p = 0.0295; %CI = 1.41-66.29). CONCLUSION: A high adherence to the Mediterranean dietary pattern, characterized by increased consumption of legumes, cereals, fruits, vegetables, and limited amounts of meat, fish, and eggs, is positively associated with handgrip strength and appendicular skeletal muscle mass. The highest adherence to this dietary model is associated with the lowest odds of low muscle strength and sarcopenia. Despite the changes brought about by urbanization in southern Italy compared to the past, our findings continue to affirm the superior benefits of the Mediterranean diet in postponing the onset of frailty among older adults when compared to other dietary patterns that are rich in animal foods.

Gut Microbiota Profile Changes in Patients with Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease: A Metagenomic Study.

Gut microbiota imbalances have a significant role in the pathogenesis of Inflammatory Bowel Disease (IBD) and Non-Alcoholic Fatty Liver Disease (NAFLD). Herein, we compared gut microbial composition in patients diagnosed with either IBD or NAFLD or a combination of both. Seventy-four participants were stratified into four groups: IBD-NAFLD, IBD-only, NAFLD-only patients, and healthy controls (CTRLs). The 16S rRNA was sequenced by Next-Generation Sequencing. Bioinformatics and statistical analysis were performed. Bacterial α-diversity showed a significant lower value when the IBD-only group was compared to the other groups and particularly against the IBD-NAFLD group. ß-diversity also showed a significant difference among groups. The higher Bacteroidetes/Firmicutes ratio was found only when comparing IBD groups and CTRLs. Comparing the IBD-only group with the IBD-NAFLD group, a decrease in differential abundance of Subdoligranulum, Parabacteroides, and Fusicatenibacter was found. Comparing the NAFLD-only with the IBD-NAFLD groups, there was a higher abundance of Alistipes, Odoribacter, Sutterella, and Lachnospira. An inverse relationship in the comparison between the IBD-only group and the other groups was shown. For the first time, the singularity of the gut microbial composition in IBD and NAFLD patients has been shown, implying a potential microbial signature mainly influenced by gut inflammation.

MBOAT7 in liver and extrahepatic diseases.

MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.

Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy. METHODS: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. RESULTS: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p < .001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p = .007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. CONCLUSIONS: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.

Pathophysiological Aspects of Muscle Atrophy and Osteopenia Induced by Chronic Constriction Injury (CCI) of the Sciatic Nerve in Rats.

Skeletal muscle atrophy is a condition characterized by a loss of muscle mass and muscle strength caused by an imbalance between protein synthesis and protein degradation. Muscle atrophy is often associated with a loss of bone mass manifesting as osteoporosis. The aim of this study was to evaluate if chronic constriction injury (CCI) of the sciatic nerve in rats can be a valid model to study muscle atrophy and consequent osteoporosis. Body weight and body composition were assessed weekly. Magnetic resonance imaging (MRI) was performed on day zero before ligation and day 28 before sacrifice. Catabolic markers were assessed via Western blot and Quantitative Real-time PCR. After the sacrifice, a morphological analysis of the gastrocnemius muscle and Micro-Computed Tomography (Micro-CT) on the tibia bone were performed. Rats that underwent CCI had a lower body weight increase on day 28 compared to the naive group of rats (p < 0.001). Increases in lean body mass and fat mass were also significantly lower in the CCI group (p < 0.001). The weight of skeletal muscles was found to be significantly lower in the ipsilateral hindlimb compared to that of contralateral muscles; furthermore, the cross-sectional area of muscle fibers decreased significantly in the ipsilateral gastrocnemius. The CCI of the sciatic nerve induced a statistically significant increase in autophagic and UPS (Ubiquitin Proteasome System) markers and a statistically significant increase in Pax-7 (Paired Box-7) expression. Micro-CT showed a statistically significant decrease in the bone parameters of the ipsilateral tibial bone. Chronic nerve constriction appeared to be a valid model for inducing the condition of muscle atrophy, also causing changes in bone microstructure and leading to osteoporosis. Therefore, sciatic nerve constriction could be a valid approach to study muscle-bone crosstalk and to identify new strategies to prevent osteosarcopenia.

A new nutraceutical (Livogen Plus®) improves liver steatosis in adults with non-alcoholic fatty liver disease.

BACKGROUND: Currently, there is no approved medication for non-alcoholic fatty liver disease management. Pre-clinical and clinical studies showed that several bioactive molecules in plants or foods (i.e., curcumin complex, bergamot polyphenol fraction, artichoke leaf extract, black seed oil, concentrate fish oil, picroliv root, glutathione, S-adenosyl-L-methionine and other natural ingredients) have been associated with improved fatty liver disease. Starting from these evidences, our purpose was to evaluate the effects of a novel combination of abovementioned nutraceuticals as a treatment for adults with fatty liver disease. METHODS: A total of 140 participants with liver steatosis were enrolled in a randomized, double-blind, placebo controlled clinical trial. The intervention group received six softgel capsules daily of a nutraceutical (namely Livogen Plus®) containing a combination of natural bioactive components for 12 weeks. The control group received six softgel capsules daily of a placebo containing maltodextrin for 12 weeks. The primary outcome measure was the change in liver fat content (CAP score). CAP score, by transient elastography, serum glucose, lipids, transaminases, and cytokines were measured at baseline and after intervention. RESULTS: After adjustment for confounding variables (i.e., CAP score and triglyceride at baseline, and changes of serum γGT, and vegetable and animal proteins, cholesterol intake at the follow-up), we found a greater CAP score reduction in the nutraceutical group rather than placebo (- 34 ± 5 dB/m vs. - 20 ± 5 dB/m, respectively; p = 0.045). The CAP score reduction (%) was even greater in those with aged 60 or less, low baseline HDL-C, AST reduction as well as in men. CONCLUSION: Our results showed that a new combination of bioactive molecules as nutraceutical was safe and effective in reducing liver fat content over 12 weeks in individuals with hepatic steatosis. Trial registration ISRCTN, ISRCTN70887063. Registered 03 August 2021-retrospectively registered, https://doi.org/10.1186/ISRCTN70887063.

Bending Resistance at Hip and Fractures Risk in Postmenopausal Women Independent of Bone Mineral Density.

Several studies suggest that aging loss of bone mass is not necessarily associated with reduced mechanical proprieties as bending resistance. Since postmenopausal women with fracture and without osteoporosis might have an impairment in the bending mechanisms at hip, our aim was to assess if women with and without fractures differ in the femoral parameters of resistance to bending, independent of the bone loss. In this cross-sectional study we enrolled 192 postmenopausal women who underwent X-ray absorptiometry scan to measure bone mineral density as well as cross-sectional geometry parameters at the hip (Hip structure analysis). Among women with osteoporosis, a higher odds ratio for fracture was found in the first tertile of NN-Dmax, a parameter linked to the resistance to bending forces in a cross-section (tertile I, OR = 6.7, p = 0.03; CI 1.19-38.01; reference tertile III). We also found a significantly higher risk for major fracture in the first tertile of NN-Dmax (tertile I, OR = 6.0, p = 0.02; CI 1.26-28.4; reference tertile III). Among women without osteoporosis, a significantly higher odds ratio for fracture was found in the first tertile of IT-CSA, a parameter of resistance to axial load (tertile I, OR = 7.2, p = 0.002; CI 2.04-25.9; reference tertile III). We also found a significantly higher risk for major fracture in the first tertile of IT-CSA (OR = 18.4, p = 0.001; CI 1.52-221.8; tertile III reference). We demonstrate that some hip structural parameters are independently associated to the fracture risk in postmenopausal women.

Citrus Bergamia and Cynara Cardunculus Reduce Serum Uric Acid in Individuals with Non-Alcoholic Fatty Liver Disease.

Background and Objectives: Hyperuricemia and liver steatosis are risk factors for cardiovascular diseases and mortality. The use of natural compounds could be a safe and effective alternative to drugs for the treatment of fatty liver and hyperuricemia. Polyphenolic fraction of Citrus Bergamia in association with the extract of Cynara Cardunculus, as nutraceutical, is able to reduce body weight, hepatic steatosis and markers of oxidative stress. Then, we performed a secondary analysis of a double-blind placebo-controlled trial to examine the effects of this nutraceutical on serum uric acid levels in adults with fatty liver. Materials and Methods: The study included 94 individuals with hepatic steatosis. For six weeks, the intervention group was given a nutraceutical (300 mg/day) comprising a Bergamot polyphenol fraction and Cynara Cardunculus extract. The control group received a daily pill of placebo. Serum uric acid, lipids, glucose and anthropometric parameters were assessed at baseline and after 6 weeks. Results: We found a greater reduction in serum uric acid in the participants taking the nutraceutical rather than placebo (−0.1 ± 0.7 mg/dL vs. 0.3 ± 0.7 mg/dL, p = 0.004), and especially in those with moderate/severe hepatic steatosis also after adjustment for confounding variables. In addition, we analysed the two groups according to tertiles of uric acid concentration. Among participants taking the nutraceutical, we found in those with the highest baseline serum uric acid (>5.4 mg/dL) the greater reduction compared to the lowest baseline uric acid (−7.8% vs. +4.9%; adjusted p = 0.04). The stepwise multivariable analysis confirmed the association between the absolute serum uric acid change and nutraceutical treatment (B = −0.43; p = 0.004). Conclusions: A nutraceutical containing bioactive components from bergamot and wild cardoon reduced serum uric acid during 6 weeks in adults with fatty liver. Future investigations are needed to evaluate the efficacy of this nutraceutical in the treatment of hyperuricaemia.

Mediterranean Diet a Potential Strategy against SARS-CoV-2 Infection: A Narrative Review.

Mediterranean Diet represents the traditional eating habits of populations living around the Mediterranean Sea, and it is associated with a lower risk of overall mortality and cancer incidence and cardiovascular diseases. Severe acute respiratory syndrome coronavirus 2 is a new pandemic, and represents a significant and critical threat to global human health. In this study, we aimed to review the possible effects of Mediterranean Diet against the risk of the coronavirus disease 2019. Several vitamins, minerals, fatty acids, and phytochemicals with their potential anti-COVID-19 activity are presented. Different risk factors may increase or reduce the probability of contracting the disease. Mediterranean Diet has also a positive action on inflammation and immune system and could have a protective effect against severe acute respiratory syndrome coronavirus 2. Further studies are needed to corroborate the benefits of the Mediterranean Diet protective role on infection with SARS-CoV-2.

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.

OBJECTIVE: Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant. DESIGN: We sequenced the hepatic transcriptome of 125 obese individuals. 'Severe NAFLD' was defined as the presence of steatohepatitis, NAFLD activity score ≥4 or fibrosis stage ≥2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA. RESULTS: Carriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10-6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10-5). CONCLUSION: Hepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.

Lycopene and bone: an in vitro investigation and a pilot prospective clinical study.

BACKGROUND: There are several effective therapies for osteoporosis but these agents might cause serious adverse events. Lycopene intake could prevent bone loss, however studies on its effects on bone are scarce. Our aim was to investigate the effects of lycopene on osteoblast cells as well as bone mineral density and bone turnover markers in postmenopausal women. METHODS: We investigated the effect of lycopene on the Wnt/ß-catenin and ERK 1/2 pathways, RUNX2, alkaline phosphatase, RANKL and COL1A of Saos-2. We also carried out a pilot controlled clinical study to verify the feasibility of an approach for bone loss prevention through the intake of a lycopene-rich tomato sauce in 39 postmenopausal women. RESULTS: Lycopene 10 µM resulted in higher ß-catenin and phERK1/2 protein Vs the vehicle (p = 0.04 and p = 0.006). RUNX2 and COL1A mRNA was induced by both 5 and 10 µM doses (p = 0.03; p = 0.03 and p = 0.03; p = 0.05) while RANKL mRNA was reduced (p < 0.05). A significant bone density loss was not detected in women taking the tomato sauce while the control group had bone loss (p = 0.002). Tomato sauce intake resulted in a greater bone alkaline phosphatase reduction than the control (18% vs 8.5%, p = 0.03). CONCLUSIONS: Lycopene activates the WNT/ß-catenin and ERK1/2 pathways, upregulates RUNX2, alkaline phosphatase, COL1A and downregulates RANKL Saos-2. These processes contributed to prevent bone loss in postmenopausal women.

Effects of C-Peptide Replacement Therapy on Bone Microarchitecture Parameters in Streptozotocin-Diabetic Rats.

C-peptide therapy protects against diabetic micro- and macrovascular damages and neuropatic complications. However, to date, the role of C-peptide in preventing diabetes-related bone loss has not been investigated. Our aim was to evaluate if C-peptide infusion improves bone quality in diabetic rats. Twenty-three male Wistar rats were randomly divided into three groups: normal control group; sham diabetic control group; diabetic plus C-peptide group. Diabetes was induced by streptozotocin injection and C-peptide was delivered subcutaneously for 6 weeks. We performed micro-CT and histological testing to assess several trabecular microarchitectural parameters. At the end, diabetic plus C-peptide rats had a higher serum C-peptide (p = 0.02) and calcium (p = 0.04) levels and tibia weight (p = 0.02) than the diabetic control group. The diabetic plus C-peptide group showed a higher trabecular thickness and cross-sectional thickness than the diabetic control group (p = 0.01 and p = 0.03). Both the normal control and diabetic plus C-peptide groups had more Runx-2 and PLIN1 positive cells in comparison with the diabetic control group (p = 0.045 and p = 0.034). Diabetic rats receiving C-peptide had higher quality of trabecular bone than diabetic rats not receiving this treatment. If confirmed, C-peptide could have a role in improving bone quality in diabetes.

3D culture models to study pathophysiology of steatotic liver disease.

Steatotic liver disease (SLD) refers to a spectrum of diseases caused by hepatic lipid accumulation. SLD has emerged as the leading cause of chronic liver disease worldwide. Despite this burden and many years, understanding the pathophysiology of this disease is challenging due to the inaccessibility to human liver specimens. Therefore, cell-based in vitro systems are widely used as models to investigate the pathophysiology of SLD. Culturing hepatic cells in monolayers causes the loss of their hepatocyte-specific phenotype and, consequently, tissue-specific function and architecture. Hence, three-dimensional (3D) culture models allow cells to mimic the in vivo microenvironment and spatial organization of the liver unit. The utilization of 3D in vitro models minimizes the drawbacks of two-dimensional (2D) cultures and aligns with the 3Rs principles to alleviate the number of in vivo experiments. This article provides an overview of liver 3D models highlighting advantages and limitations, and culminates by discussing their applications in pharmaceutical and biomedical research.

A nutraceutical with Citrus bergamia and Cynara cardunculus improves endothelial function in adults with non-alcoholic fatty liver disease.

OBJECTIVE: Polyphenol intake may prevent hepatic steatosis and cardiovascular disease by potentially improving endothelial function. The purposes of this study are to investigate the association between fatty liver disease and endothelial dysfunction and to test the effects of a nutraceutical containing extracts made from Citrus bergamia and Cynara cardunculus on peripheral vascular endothelial function in adults with liver steatosis. METHODS: We analyzed data from 32 individuals with hepatic steatosis and endothelial dysfunction (reactive hyperemia index ≤ 1.67). Sixteen subjects took 1 capsule/d (300 mg/d) containing Cynara cardunculus extract and bergamot polyphenol fraction, while the other 16 subjects matched for age, sex, and body mass index took 1 capsule/d of placebo (maltodextrin) for 12 wk. All anthropometric parameters were assessed at baseline and after 12 wk as were lipids, glucose, and reactive hyperemia index using an EndoPAT 2000. RESULTS: The mean age was 52 ± 9 y. The mean reactive hyperemia index was 1.15 ± 0.4. After 12 wk, we found a greater increase in reactive hyperemia index in the participants taking the nutraceutical rather than placebo (0.58 ± 0.5 versus 0.13 ± 0.5; P = 0.02, respectively). The stepwise multivariable analysis confirmed a positive association between reactive hyperemia index change and the nutraceutical treatment (B = 0.38; P = 0.025) and negative association with reactive hyperemia index values at baseline (B = -0.81; P < 0.001). No association was found between the reduction in the amount of intrahepatic fat and the improvement of endothelial function (B = 0.002; P = 0.56). CONCLUSIONS: A nutraceutical containing bergamot and artichoke extracts improves peripheral vascular endothelial function in adults with hepatic steatosis and early phase of atherosclerosis.

Therapeutic patient education and treatment intensification of diabetes and hypertension in subjects with newly diagnosed type 2 diabetes mellitus: a longitudinal study.

PURPOSE: The aim of this study is to prospectively evaluate whether individual and group Therapeutic Patient Education (TPE) can reduce the need to intensify treatment of diabetes and hypertension in newly diagnosed type 2 diabetic patients. METHODS: A total of 937 patients were recruited and followed-up for 42.7 ± 21.5 months. TPE was a structured comprehensive education delivered by trained nurses: 322 patients received individual TPE (ITPE), 291 underwent group TPE (GTPE), and 324 were in Usual Care (UC). The primary endpoints were intensification of diabetes treatment and intensification of hypertension treatment. RESULTS: The rate of diabetes treatment intensification was 40.1% in patients receiving ITPE, 47.8% in patients undergoing GTPE, and 64.2% in patients in UC (p < 0.001). The rate of hypertension treatment intensification was 24.2% in patients following ITPE, 31.3% in patients receiving GTPE, and 41.0% in patients in UC (p < 0.001). Multivariate analysis showed that both ITPE and GTPE were associated with reduced intensification of diabetes (ITPE: HR:0.51; 95% IC:0.40-0.64; p < 0.001 - GTPE: HR:0.46; 95% IC:0.44-0.70; p < 0.001) and hypertension medication (ITPE: HR:0.45; 95% IC:0.34-0.61; p < 0.001 - GTPE: HR:0.49; 95% IC:0.38-0.65; p < 0.001). The association was independent of age, sex, BMI, HbA1c, and presence of hypertension at baseline. CONCLUSIONS: TPE, delivered as both individual and group sessions, represents an effective tool to reduce the need to intensify treatment of both diabetes and hypertension. Therefore, it can ensure better control of diabetes and hypertension with fewer medications. This could reduce adverse effects and costs and improve quality of life and medication taking in patients with type 2 diabetes.

Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma.

Over the past 10 years, the biological role of lipid droplets (LDs) has gained significant attention in the context of both physiological and pathological conditions. Considerable progress has been made in elucidating key aspects of these organelles, yet much remains to be accomplished to fully comprehend the myriad functions they serve in the progression of hepatic tumors. Our current perception is that LDs are complex and active structures managed by a distinct set of cellular processes. This understanding represents a significant paradigm shift from earlier perspectives. In this review, we aim to recapitulate the function of LDs within the liver, highlighting their pivotal role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) (Hsu and Loomba, 2024) and their contribution to the progression towards more advanced pathological stages up to hepatocellular carcinoma (HC) (Farese and Walther, 2009). We are aware of the molecular complexity and changes occurring in the neoplastic evolution of the liver. Our attempt, however, is to summarize the most important and recent roles of LDs across both healthy and all pathological liver states, up to hepatocarcinoma. For more detailed insights, we direct readers to some of the many excellent reviews already available in the literature (Gluchowski et al., 2017; Hu et al., 2020; Seebacher et al., 2020; Paul et al., 2022).

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci, we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.

Poor accuracy and sustainability of the first-step FIB4 EASL pathway for stratifying steatotic liver disease risk in the general population.

BACKGROUND AND AIMS: The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first-step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met-ALD and ALD) and various age classes. METHODS: We analysed a total of 3372 individuals at risk of SLD from the 2017-2018 National Health and Nutrition Examination Survey (NHANES17-18), projected to 152.3 million U.S. adults, 300,329 from the UK Biobank (UKBB) and 57,644 from the Biobank Japan (BBJ). We assessed liver stiffness measurement (LSM) ≥8 kPa and liver-related events occurring within 3 and 10 years (3/10 year-LREs) as outcomes. We defined MASLD, MetALD, and ALD according to recent international recommendations. RESULTS: FIB4 sensitivity for LSM ≥ 8 kPa was low (27.7%), but it ranged approximately 80%-90% for 3-year LREs. Using FIB4, 22%-57% of subjects across the three cohorts were identified as candidates for vibration-controlled transient elastography (VCTE), which was mostly avoidable (positive predictive value of FIB4 ≥ 1.3 for LSM ≥ 8 kPa ranging 9.5%-13% across different SLD categories). Sensitivity for LSM ≥ 8 kPa and LREs increased with increasing alcohol intake (ALD>MetALD>MASLD) and age classes. For individuals aged ≥65 years, using the recommended age-adjusted FIB4 cut-off (≥2) substantially reduced sensitivity for LSM ≥ 8 kPa and LREs. CONCLUSIONS: The first-step FIB4 EASL CP is poorly accurate and feasible for individuals at risk of SLD in the general population. It is crucial to enhance the screening strategy with a first-step approach able to reduce unnecessary VCTEs and optimise their yield.

The Effects of Online Home-Based Pilates Combined with Diet on Body Composition in Women Affected by Obesity: A Preliminary Study.

Diet and exercise intervention are the first strategies to counteract obesity. An online home-based exercise program may be a feasible approach in an obese population. Therefore, this study aimed to investigate the effects of twelve weeks of online Pilates plus diet on body composition in individuals affected by obesity. Thirty-five females were randomly assigned to a home-based Pilates group (PG, n = 18) or a group without intervention (control group, CG, n = 17). All participants followed a Mediterranean diet. The PG followed a twelve-week online Pilates Matwork program (three times/week; 180 min/week), while the CG was not involved in any structured physical exercise program. Body composition and handgrip strength were evaluated at baseline (T0) and after the intervention (T1). A significant group × time interaction (p < 0.05) was found for the fat mass percentage (pFM). Specifically, the pFM was significantly lower at T1 than at T0 in the PG. Significant group × time interactions for fat-free mass (p < 0.05), appendicular skeletal muscle mass (p < 0.05), and skeletal muscle mass (p < 0.01) were found. All these variables were significantly higher at T1 than at T0 in the PG (p < 0.05). Home-based Pilates combined with diet intervention may represent an effective strategy to improve body composition in terms of fat mass reduction and muscle mass gain in adults affected by obesity.