ABSTRACT
BACKGROUND AND AIMS: NASH confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed the safety and efficacy of Meriva in NASH. APPROACH AND RESULTS: In this double-blind trial, 52 patients with biopsy-proven NASH (71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a chronic kidney disease) were randomized 1:1 to receive Meriva 2 g/d or placebo for 72 weeks. The primary endpoint was NASH resolution with no worsening of fibrosis. The secondary endpoints included a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant (ie, stage ≥F2) fibrosis and CKD; and improvement in renal, glucose, lipid, and inflammatory parameters. We also explored the treatment effect on hepatic activation of NF-kB, a key proinflammatory transcription factor and a major target of curcumin. Fifty-one patients (26 on Meriva and 25 on placebo) completed the trial. Sixteen (62%) patients on Meriva versus 3 (12%) patients on placebo had NASH resolution (RR = 5.33 [95% CI = 1.76-12.13]; p = 0.003). Thirteen (50%) patients on Meriva versus 2 (8%) patients on placebo had ≥1 stage fibrosis improvement (RR = 6.50 [1.63-21.20]; p = 0.008). Eleven (42%) patients on Meriva versus 0 (0%) on placebo had regression of significant liver fibrosis (RR = 18.01 [1.43-36.07]; p = 0.02). Hepatic NF-kB inhibition predicted NASH resolution (AUC = 0.90, 95% CI = 0.84-0.95) and fibrosis improvement (AUC = 0.89, 95% CI = 0.82-0.96). Thirteen (50%) patients on Meriva versus 0 (0%) on placebo had chronic kidney disease regression (RR = 10.71 [1.94-17.99)]; p = 0.004). Compared with placebo, Meriva improved eGFR (difference in adjusted eGFR change: +3.59 [2.96-4.11] mL/min/1.73 m 2 /y, p = 0.009), fasting glucose(-17 mg/dL; 95% CI = -22, -12), HbA1c (-0.62%; 95% CI = -0.87%, -0.37%), LDL-C (-39 mg/dL; 95% CI = -45, -33), triglycerides (-36 mg/dL, 95% CI = -46, -26), HDL-C (+10 mg/dL; 95% CI = +8, +11), and inflammatory markers. Adverse events were rare, mild, and evenly distributed. CONCLUSIONS: In patients with NASH, Meriva administration for 72 weeks was safe, well-tolerated, and improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.
ABSTRACT
BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death). METHODS AND FINDINGS: We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (ß = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (ß = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies. CONCLUSIONS: In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetic Ketoacidosis/chemically induced , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Adult , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/diagnosis , Diabetic Ketoacidosis/diagnosis , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors , Treatment Outcome , Young AdultABSTRACT
The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.
Subject(s)
Diabetes Mellitus/genetics , Non-alcoholic Fatty Liver Disease/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Adipokines/metabolism , Cohort Studies , Cross-Sectional Studies , Diabetes Mellitus/metabolism , Dietary Fats/metabolism , Female , Genetic Predisposition to Disease , Genetic Variation , Glucose/metabolism , Humans , Insulin Resistance/genetics , Leukocytes, Mononuclear/metabolism , Lipid Metabolism , Lipoproteins/genetics , Liver Cirrhosis/metabolism , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Polymorphism, Single Nucleotide , c-Mer Tyrosine KinaseABSTRACT
OBJECTIVES: Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. METHODS: We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. RESULTS: AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. DISCUSSION: AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.
Subject(s)
Dietary Fats/metabolism , Hypertension/genetics , Non-alcoholic Fatty Liver Disease/genetics , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , Biomarkers/metabolism , Cross-Sectional Studies , Female , Genotype , Glucose/metabolism , Humans , Hypertension/metabolism , Lipid Metabolism , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Risk Factors , Severity of Illness IndexABSTRACT
OBJECTIVES: Conjugated linoleic acid (CLA) isomers have been shown to possess anti-inflammatory activity in the central nervous system. In this study, we aimed to evaluate whether modulation of the fatty acid profile by the CLA isomers c9,t11 or t10,c12CLA was associated with changes in the expression of pro-inflammatory molecules in human astrocytes. METHODS: Cultured astrocytes were treated for 6 days with 100â µM fatty acids (c9,t11CLA or t10,c12CLA or oleic acid). Following the treatment, the fatty acid profile of the cell and pro-inflammatory molecule expression were assessed. RESULTS: Only the t10,c12CLA isomer induced a significant decrease in arachidonic acid and increased the ratio of docosahexaenoic acid/eicosapentaenoic acid, which constitutes indirect evidence of peroxisome proliferator-activated receptor alpha activation. Inhibition of tumour necrosis factor-α, interleukin-1ß, and RANTES expression was observed in astrocytes treated with c9,t11CLA and t10,c12CLA. DISCUSSION: Current data demonstrate that CLA isomers, particularly t10,c12, may affect neuroinflammation by reducing the pro-inflammatory molecules in cultured astrocytes, suggesting a potential nutritional role of CLA isomers in modulating the astrocyte inflammatory response.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Astrocytes/metabolism , Inflammation Mediators/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Linoleic Acids, Conjugated/administration & dosage , Biomarkers/metabolism , Cells, Cultured , Down-Regulation , Fatty Acids/administration & dosage , Fatty Acids/metabolism , Humans , RNA, Messenger/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Cirrhosis/metabolism , Liver Neoplasms/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Carcinoma, Hepatocellular/etiology , Cell Hypoxia , Disease Progression , Hedgehog Proteins/metabolism , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Humans , Integrins/metabolism , Liver Cirrhosis/complications , Liver Neoplasms/etiology , Non-alcoholic Fatty Liver Disease/complications , Signal TransductionABSTRACT
Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic ß-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.
Subject(s)
Glucose/metabolism , Homeostasis/genetics , Lipoproteins/metabolism , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Polymorphism, Single Nucleotide , Postprandial Period , Adult , Female , Humans , Male , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/physiopathologyABSTRACT
UNLABELLED: Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6-D2 -glucose and U-(13) C-glucose) in the basal state and during an oral glucose tolerance test. The best-performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test-derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61-0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63-0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45-0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). CONCLUSION: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD.
Subject(s)
Insulin Resistance , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/metabolism , Adult , Female , Humans , Liver Diseases/etiology , Male , Middle Aged , PrognosisABSTRACT
BACKGROUND: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. METHODS: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. RESULTS: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. CONCLUSIONS: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients.
Subject(s)
Diet, High-Fat , Fatty Acids, Nonesterified/blood , Non-alcoholic Fatty Liver Disease/pathology , Adult , Blood Glucose/analysis , Case-Control Studies , Cholesterol/blood , Chromatography, High Pressure Liquid , Colorimetry , Fatty Acids, Omega-3/analysis , Fatty Acids, Omega-6/analysis , Female , Humans , Insulin/blood , Insulin Resistance , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Triglycerides/bloodABSTRACT
BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasing at an alarming rate, and only 50% of patients with T2DM achieve or maintain adequate glycemic control with pharmacological therapies. Metabolic surgery demonstrated superior efficacy compared to medical therapy but is unfeasible for most patients with T2DM. Duodenal mucosal resurfacing (DMR) by hydrothermal mucosal ablation, recellularization via electroporation therapy (ReCET), and photodynamic therapy are novel endoscopic procedures that use thermal, electrical, and photochemical energy, respectively, to ablate and reset dysfunctional duodenal mucosa. We assessed the data on the effects of these techniques on glycemic control and nonalcoholic fatty liver disease (NAFLD). METHODS: We systematically searched independently and in duplicate English and non-English language publications through January 31st, 2024. Outcomes assessed were an improvement in different metabolic health parameters and the safety of duodenal mucosal ablation (DMA) procedures. Outcomes were presented descriptively. FINDINGS: We selected 12 reports reporting results from 3 randomized and 6 uncontrolled trials (seven evaluating DMR, two evaluating ReCET, all with a low risk of bias) for a total of 317 patients enrolled. DMA reduced HbA1c, fasting plasma glucose, and liver fat. When combined with newer antidiabetic drugs, it allowed insulin discontinuation in up to 86% patients. No major safety signal emerged. CONCLUSIONS: All DMA techniques improve glucose homeostasis; DMR and ReCET appear to be safe in patients with T2DM. If confirmed by future randomized trials and by trials with histological endpoints in NAFLD, then DMA appears to be a promising alternative or complement option to medications for T2DM and NAFLD treatment. FUNDING: This study received no funding.
Subject(s)
Diabetes Mellitus, Type 2 , Duodenum , Intestinal Mucosa , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/surgery , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/therapy , Diabetes Mellitus, Type 2/surgery , Diabetes Mellitus, Type 2/drug therapy , Duodenum/surgery , Duodenum/pathology , Intestinal Mucosa/surgery , Intestinal Mucosa/pathology , Ablation Techniques/methodsABSTRACT
Various cells types, including stem and progenitor cells, can exchange complex information via plasma membrane-derived vesicles, which can carry signals both in their limiting membrane and lumen. Astrocytes, traditionally regarded as mere supportive cells, play previously unrecognized functions in neuronal modulation and are capable of releasing signalling molecules of different functional significance. In the present study, we provide direct evidence that human fetal astrocytes in culture, expressing the same feature as immature and reactive astrocytes, release membrane vesicles larger than the microvesicles described up to now. We found that these large vesicles, ranging from 1-5 to 8 µm in diameter and expressing on their surface ß1-integrin proteins, contain mitochondria and lipid droplets together with ATP. We documented vesicle content with fluorescent-specific dyes and with the immunocytochemistry technique we confirmed that mitochondria and lipid droplets were co-localized in the same vesicle. Scanning electron microscopy and transmission electron microscopy confirmed that astrocytes shed from surface membrane vesicles of the same size as the ones detected by fluorescence microscopy. Our results report for the first time that cultured astrocytes, activated by repetitive stimulation of ATP released from neighboring cells, shed from their surface large membrane vesicles containing mitochondria and lipid droplets.
Subject(s)
Adenosine Triphosphate/metabolism , Astrocytes/cytology , Cell Membrane/metabolism , Cytoplasmic Vesicles/chemistry , Cytoplasmic Vesicles/metabolism , Lipids/chemistry , Mitochondria/metabolism , Astrocytes/metabolism , Cells, Cultured , Humans , Particle SizeABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/therapy , Non-alcoholic Fatty Liver Disease/metabolism , Lipidomics , Liver/metabolism , Liver Cirrhosis/complications , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Fibrosis , Inflammation/metabolism , Lipids , Disease ProgressionABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition characterized by insulin resistance, oxidative stress, chronic low-grade inflammation, and sometimes fibrosis. To date, no effective pharmacological therapy has been approved for the treatment of metabolic-associated steatohepatitis (MASH), the progressive form of MASLD. Recently, numerous in vitro and in vivo studies have described the efficacy of nutraceutical compounds in the diet has been tested. Among them, curcumin is the most widely used polyphenol in the diet showing potent anti-inflammatory and antifibrotic activities. This review aims to summarize the most important basic studies (in vitro and animal models studies), describing the molecular mechanisms by which curcumin acts in the context of MASLD, providing the rationale for its effective translational use in humans.
Subject(s)
Curcumin , Fatty Liver , Animals , Humans , Curcumin/pharmacology , Curcumin/therapeutic use , Oxidative Stress , Dietary Supplements , Fatty Liver/drug therapy , InflammationABSTRACT
Hodgkin lymphoma (HL) is today one of the most curable pediatric cancers. Despite survival rates now exceeding 90%, survivors of pediatric HL are still at higher risk to develop late effects of cancer therapy. Premature aging has been proposed as a paradigm to explain the onset of long-term complications in these subjects. High levels of advanced glycation end products (AGEs), together with chronic inflammation and oxidative unbalance, have been shown to be among the main factors contributing to aging. The present study aims to evaluate glycoxydation, inflammatory status, and oxidative stress in plasma and peripheral blood mononuclear cells (PBMC) obtained from 20 adult survivors of pediatric HL and 40 age- and sex-matched healthy controls. After the isolation of PBMC and the collection of plasma, we performed the analyses of gene expression by qRT-PCR and measured inflammatory and oxidative-stress markers. AGEs plasma levels, expressed as Nϵ-carboxymethyl-lysine and methylglyoxal hydroimidazolone, were markedly higher in HL survivors than in healthy subjects. HL survivors also showed a condition of higher oxidative stress, as demonstrated by an increased expression of NADPH oxidase on PBMC. Antioxidant defenses, evaluated in terms of alpha-tocopherol, GSSG/GSH ratio and catalase plasma levels, were strongly impaired in survivors. This pro-oxidative condition led to the over-expression of both NLRP3 and NFkB genes in PBMC and, consequently, to increased plasma levels of interleukin(IL)-1ß and IL-6. Finally, the expression of the receptors for AGEs in PBMC confirmed the dysregulated AGE pathways. Data show AGEs accumulation in survivors of pediatric HL. The consequent activation of the receptor for AGEs leads to the persistent activation of intracellular signaling toward inflammation. These results suggest that the co-existence of AGEs accumulation, unbalanced oxidative status, and inflammation could play a role in the onset of late complications in HL survivors.
Subject(s)
Glycation End Products, Advanced , Hodgkin Disease , Glycation End Products, Advanced/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Oxidative Stress , Receptor for Advanced Glycation End Products/metabolism , SurvivorsABSTRACT
Several recent studies have expanded our conception of the role of astrocytes in neurogenesis, proposing that these cells may contribute to this phenomenon not only as a source of trophic substances, but also as stem cells themselves. We recently observed in vitro that human mature astrocytes can be induced to differentiate into cells with a neuronal phenotype. Antidepressant drugs have been shown to increase neurogenesis in the adult rodent hippocampus. In order to better understand the role of astroglia in antidepressant-induced neurogenesis, primary astrocyte cultures were treated with the antidepressant imipramine. Cell morphology was rapidly modified by treatment. In fact, whereas untreated astrocytes showed large, flat morphology, after a few hours of treatment cells exhibited a round-shaped cell body with long, thin processes. The expression of neuronal markers was analysed by immunocytochemistry, Western Blot and RT-PCR at different treatment times. Results showed an increase in neuronal markers such as neurofilament and neuron-specific enolase (NSE), whereas glial fibrillary acidic protein (GFAP) and nestin expression were not significantly modified by treatment. Similar results were obtained with fluoxetine and venlafaxine. Hes1 mRNA significantly increased after 2 h of treatment, suggesting involvement of this transcription factor in this process. These results confirm the role of astrocytes in neurogenesis and suggest that these cells may represent one of the targets of antidepressants.
Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Astrocytes/cytology , Cell Differentiation/drug effects , Imipramine/pharmacology , Neurons/cytology , Phenotype , Astrocytes/chemistry , Astrocytes/drug effects , Cell Differentiation/physiology , Cells, Cultured , Fetus , Glial Fibrillary Acidic Protein/analysis , Humans , Neurogenesis/drug effects , Neurogenesis/physiology , Neurons/chemistry , Neurons/drug effects , Stem Cells/chemistry , Stem Cells/cytology , Stem Cells/drug effectsABSTRACT
Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferator-activated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium.
Subject(s)
Fatty Liver/epidemiology , Kidney Failure, Chronic/epidemiology , Non-alcoholic Fatty Liver Disease/epidemiology , Renal Insufficiency, Chronic/epidemiology , Diet , Epigenesis, Genetic , Fatty Liver/complications , Fibrosis , Fructose/administration & dosage , Humans , Inflammation , Kidney Failure, Chronic/complications , Lipid Metabolism , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , Peroxisome Proliferator-Activated Receptors/genetics , Peroxisome Proliferator-Activated Receptors/metabolism , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/complications , Risk Factors , Vitamin D/administration & dosageABSTRACT
Mounting evidence connects non-alcoholic fatty liver disease (NAFLD) to chronic kidney disease (CKD). We review emerging mechanistic links between NAFLD and CKD, including altered activation of angiotensin converting enzyme (ACE)-2, nutrient/energy sensors sirtuin-1 and AMP-activated kinase, as well as impaired antioxidant defense mediated by nuclear factor erythroid 2-related factor-2 (Nrf2). Dietary fructose excess may also contribute to NAFLD and CKD. NAFLD affects renal injury through lipoprotein dysmetabolism and altered secretion of the hepatokines fibroblast growth factor-21, fetuin-A, insulin-like growth factor-1, and syndecan-1. CKD may mutually aggravate NAFLD and associated metabolic disturbances through altered intestinal barrier function and microbiota composition, the accumulation of uremic toxic metabolites, and alterations in pre-receptor glucocorticoid metabolism. We conclude by discussing the implications of these findings for the treatment of NAFLD and CKD.
Subject(s)
Non-alcoholic Fatty Liver Disease/etiology , Renal Insufficiency, Chronic/etiology , Animals , Humans , Non-alcoholic Fatty Liver Disease/complications , Renal Insufficiency, Chronic/complicationsABSTRACT
S100B is a Ca(2+)-binding protein expressed in the nervous system. Increased levels of S100B in the extracellular space have been detected in several neurological disorders. We investigated the response of human astrocytes to micromolar chronic concentrations of this protein measuring the expression of some costimulatory molecules, such as CD137, CD137-L, CD40, CD40-L, the chemokine RANTES and two growth factors FGF-2 and TGF-ß2. Our findings suggest that high levels of S100B in the brain parenchyma may modulate the activation status of astrocytes decreasing their neuroprotective role and modifying their interaction with microglia and other inflammatory cells. This effect may contribute to evolution of some neurological disorders.