Positive Effects of Exercise Intervention without Weight Loss and Dietary Changes in NAFLD-Related Clinical Parameters: A Systematic Review and Meta-Analysis

One of the focuses of non-alcoholic fatty liver disease (NAFLD) treatment is exercise. Randomized controlled trials investigating the effects of exercise without dietary changes on NAFLD-related clinical parameters (liver parameters, lipid metabolism, glucose metabolism, gut microbiota, and metabolites) were screened using the PubMed, Scopus, Web of Science, and Cochrane databases on 13 February 2020. Meta-analyses were performed on 10 studies with 316 individuals who had NAFLD across three exercise regimens: aerobic exercise, resistance training, and a combination of both. No studies investigating the role of gut microbiota and exercise in NAFLD were found. A quality assessment via the (RoB)2 tool was conducted and potential publication bias, statistical outliers, and influential cases were identified. Overall, exercise without significant weight loss significantly reduced the intrahepatic lipid (IHL) content (SMD: -0.76, 95% CI: -1.04, -0.48) and concentrations of alanine aminotransaminase (ALT) (SMD: -0.52, 95% CI: -0.90, -0.14), aspartate aminotransaminase (AST) (SMD: -0.68, 95% CI: -1.21, -0.15), low-density lipoprotein cholesterol (SMD: -0.34, 95% CI: -0.66, -0.02), and triglycerides (TG) (SMD: -0.59, 95% CI: -1.16, -0.02). The concentrations of high-density lipoprotein cholesterol, total cholesterol (TC), fasting glucose, fasting insulin, and glycated hemoglobin were non-significantly altered. Aerobic exercise alone significantly reduced IHL, ALT, and AST; resistance training alone significantly reduced TC and TG; a combination of both exercise types significantly reduced IHL. To conclude, exercise overall likely had a beneficial effect on alleviating NAFLD without significant weight loss. The study was registered at PROSPERO: CRD42020221168 and funded by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 813781

Effects of exercise on NAFLD using non-targeted metabolomics in adipose tissue, plasma, urine, and stool

The mechanisms by which exercise benefits patients with non-alcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, remain poorly understood. A non-targeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics analysis was used to identify metabolic changes associated with NAFLD in humans upon exercise intervention (without diet change) across four different sample types-adipose tissue (AT), plasma, urine, and stool. Altogether, 46 subjects with NAFLD participated in this randomized controlled intervention study. The intervention group (n = 21) performed high-intensity interval training (HIIT) for 12 weeks while the control group (n = 25) kept their sedentary lifestyle. The participants' clinical parameters and metabolic profiles were compared between baseline and endpoint. HIIT significantly decreased fasting plasma glucose concentration (p = 0.027) and waist circumference (p = 0.028); and increased maximum oxygen consumption rate and maximum achieved workload (p </p

Expression and Functional Contribution of Different Organic Cation Transporters to the Cellular Uptake of Doxorubicin into Human Breast Cancer and Cardiac Tissue

Doxorubicin is a frequently used anticancer drug to treat many types of tumors, such as breast cancer or bronchial carcinoma. The clinical use of doxorubicin is limited by its poorly predictable cardiotoxicity, the reasons of which are so far not fully understood. The drug is a substrate of several efflux transporters such as P-gp or BCRP and was recently reported to be a substrate of cation uptake transporters. To evaluate the potential role of transporter proteins in the accumulation of doxorubicin at its site of action (e.g., mammary carcinoma cells) or adverse effects (e.g., heart muscle cells), we studied the expression of important uptake and efflux transporters in human breast cancer and cardiac tissue, and investigated the affinity of doxorubicin to the identified transporters. The cellular uptake studies on doxorubicin were performed with OATP1A2*1, OATP1A2*2, and OATP1A2*3-overexpressing HEK293 cells, as well as OCT1-, OCT2-, and OCT3- overexpressing MDCKII cells. To assess the contribution of transporters to the cytotoxic effect of doxorubicin, we determined the cell viability in the presence and absence of transporter inhibitors in different cell lines. Several transporters, including P-gp, BCRP, OCT1, OCT3, and OATP1A2 were expressed in human heart and/or breast cancer tissue. Doxorubicin could be identified as a substrate of OCT1, OCT2, OCT3, and OATP1A2. The cellular uptake into cells expressing genetic OATP1A2 variants was markedly reduced and correlated well with the increased cellular viability. Inhibition of OATP1A2 (naringin) and OCT transporters (1-methyl-4-phenylpyridinium) resulted in a significant decrease of doxorubicin-mediated cytotoxicity in cell lines expressing the respective transporters. Similarly, the excipient Cremophor EL significantly inhibited the OCT1-3- and OATP1A2-mediated cellular uptake and attenuated the cytotoxicity of doxorubicin. In conclusion, genetic and environmental-related variability in the expression and function of these transporters may contribute to the substantial variability seen in terms of doxorubicin efficacy and toxicity

The Effect of Dietary Supplementations on Delaying the Progression of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

Purpose: Age-related macular degeneration (AMD) is a neurodegenerative ophthalmic disease. The purpose of this systematic review (SR) and meta-analysis was to evaluate if dietary supplementation alone or in combinations might delay the progression of any of the stages of AMD. Methods: A SR and meta-analysis identifying cohort studies and randomized controlled trials (RCTs) evaluating the effect of supplements in patients diagnosed with AMD. PubMed, Scopus, Web of Science, CINAHL, and Cochrane were searched through 8th October 2021. Results: Twenty studies, examining 5634 participants ranging from 55 to 80 years, were included in the SR. Eight studies were selected for meta-analysis (414 and 216 subjects in the intervention and control groups). Lutein and zeaxanthin plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) supplementation showed significant improvements in best-corrected visual acuity (BCVA) (SMD: &minus;1.99, 95% CI: &minus;3.33, &minus;0.65) compared to the control group. Multifocal electroretinogram results (mfERG) were significantly improved overall (SMD: 4.59, 95% CI: 1.75, 7.43) after lutein plus zeaxanthin supplementation. Conclusions: Combinations of lutein and zeaxanthin with n-3 LC-PUFA might be beneficial in preventing AMD progression and deterioration of visual function. Our results encourage initiating further studies with combinations of n-3 LC-PUFA, lutein, and zeaxanthin especially in early AMD patients

Dietary Interventions in Patients With Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Background: With no approved pharmacotherapy to date, the present therapeutic cornerstone for non-alcoholic fatty liver diseases (NAFLD) is a lifestyle intervention. Guidelines endorse weight loss through dietary modifications, physical exercise, or both. However, no consensus exists on the optimal dietary treatment. Objectives: The aim of our systematic review and meta-analysis was to summarize and assess the evidence for applied types of dietary interventions on the liver and metabolic outcomes in patients with NAFLD, aside from any effects of exercise intervention. Methods: This systematic review was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) statement guidelines. The search was conducted in PubMed, Scopus, and Cochrane databases in February 2020. Included were only dietary interventions without exercise. This study was registered at PROSPERO: CRD42020203573. Results: Eight randomized controlled trials, seven with endpoint reduction of hepatic steatosis, one with an assessment of endpoint fibrosis, were included in this systematic review, five of which were included in the meta-analysis. Mediterranean dietary interventions without energy restriction (n = 3) showed significant reduction of intrahepatic lipid content (IHL) (SDM: −0.57, 95% CI: −1.04, −0.10), but there was no significant change in alanine transaminase (ALT) (SDM: 0.59, 95% CI: −0.5, −1.68). Hypocaloric dietary interventions with foods high in unsaturated fatty acids (n = 2) led to a significant decrease in ALT (SDM: −1.09, 95% CI: −1.49, −0.69) and aspartate aminotransferase (AST) (SDM: −0.75, 95% CI: −1.27, 0.23); yet effects on steatosis could not be aggregated due to different assessment techniques. Mediterranean diet did not lead to significant changes in concentrations of gamma-glutamyl transpeptidase (γGT), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), fasting glucose or insulin, or homeostatic assessment for insulin resistance. Conclusions: In patients with NAFLD, Mediterranean and hypocaloric dietary interventions favoring unsaturated fatty acids result in improvements in IHL and transaminases. Since many dietary intervention studies are combined with exercise interventions and there is a paucity of ample-sized studies examining dietary interventions on the more advanced and clinically relevant stages of NAFLD, that is active and fibrotic NASH, with multiparametric imaging and liver histology as outcome measures, the optimal dietary invention in NAFLD remains to be defined

Twelve Weeks of High-Intensity Interval Training Alters Adipose Tissue Gene Expression but Not Oxylipin Levels in People with Non-Alcoholic Fatty Liver Disease

Lifestyle modifications, including increased physical activity and exercise, are recommended for non-alcoholic fatty liver disease (NAFLD). Inflamed adipose tissue (AT) contributes to the progression and development of NAFLD and oxylipins such as hydroxyeicosatetraenoic acids (HETE), hydroxydocosahexanenoic acids (HDHA), prostaglandins (PEG2), and isoprostanoids (IsoP), which all may play a role in AT homeostasis and inflammation. To investigate the role of exercise without weight loss on AT and plasma oxylipin concentrations in NAFLD subjects, we conducted a 12-week randomized controlled exercise intervention. Plasma samples from 39 subjects and abdominal subcutaneous AT biopsy samples from 19 subjects were collected both at the beginning and the end of the exercise intervention. In the AT of women, a significant reduction of gene expression of hemoglobin subunits (HBB, HBA1, HBA2) was observed within the intervention group during the 12-week intervention. Their expression levels were negatively associated with VO2max and maxW. In addition, pathways involved in adipocyte morphology alterations significantly increased, whereas pathways in fat metabolism, branched-chain amino acids degradation, and oxidative phosphorylation were suppressed in the intervention group (p < 0.05). Compared to the control group, in the intervention group, the ribosome pathway was activated, but lysosome, oxidative phosphorylation, and pathways of AT modification were suppressed (p < 0.05). Most of the oxylipins (HETE, HDHA, PEG2, and IsoP) in plasma did not change during the intervention compared to the control group. 15-F2t-IsoP significantly increased in the intervention group compared to the control group (p = 0.014). However, this oxylipin could not be detected in all samples. Exercise intervention without weight loss may influence the AT morphology and fat metabolism at the gene expression level in female NAFLD subjects