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International Journal of Molecular... Jun 2024Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin...
Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG ( < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG ( < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG ( < 0.05). Bosentan treatment in diabetic, atherosclerotic mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.
Topics: Animals; Bosentan; Atorvastatin; Mice; Male; Atherosclerosis; Endothelin Receptor Antagonists; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Collagen; Diet, High-Fat; Chemokine CCL2; Tumor Necrosis Factor-alpha; Plaque, Atherosclerotic; Mice, Knockout; Tissue Inhibitor of Metalloproteinase-1
PubMed: 38928320
DOI: 10.3390/ijms25126614 -
International Journal of Molecular... Jun 2024Atopic dermatitis (AD) is a chronic inflammatory skin condition with a high prevalence worldwide. AD pathogenesis is complex and consists of immune system dysregulation... (Review)
Review
Atopic dermatitis (AD) is a chronic inflammatory skin condition with a high prevalence worldwide. AD pathogenesis is complex and consists of immune system dysregulation and impaired skin barrier, influenced by genetic and environmental factors. The purpose of the review is to show the complex interplay between atopic dermatitis and the microbiota. Human microbiota plays an important role in AD pathogenesis and the course of the disease. Dysbiosis is an important factor contributing to the development of atopic diseases, including atopic dermatitis. The gut microbiota can influence the composition of the skin microbiota, strengthening the skin barrier and regulating the immune response via the involvement of bacterial metabolites, particularly short-chain fatty acids, in signaling pathways of the gut-skin axis. AD can be modulated by antibiotic intake, dietary adjustments, hygiene, and living conditions. One of the promising strategies for modulating the course of AD is probiotics. This review offers a summary of how the microbiota influences the development and treatment of AD, highlighting aspects that warrant additional investigation.
Topics: Dermatitis, Atopic; Humans; Dysbiosis; Gastrointestinal Microbiome; Probiotics; Microbiota; Skin; Animals
PubMed: 38928245
DOI: 10.3390/ijms25126539 -
Genes Jun 2024Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid...
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
Topics: Alzheimer Disease; Animals; Fatty Acids, Omega-3; Mice; Frontal Lobe; Female; Disease Models, Animal; Amyloid beta-Protein Precursor; Estrogens; Mice, Transgenic; Presenilin-1; Lipid Metabolism; Humans
PubMed: 38927745
DOI: 10.3390/genes15060810 -
Biomolecules May 2024Metabolic syndrome (MetS) is a cluster of metabolic abnormalities affecting ~25% of adults and is linked to chronic diseases such as cardiovascular disease, cancer, and...
Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose-Response Study.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities affecting ~25% of adults and is linked to chronic diseases such as cardiovascular disease, cancer, and neurodegenerative diseases. Oxidative stress and inflammation are key drivers of MetS. Hesperidin, a citrus bioflavonoid, has demonstrated antioxidant and anti-inflammatory properties; however, its effects on MetS are not fully established. We aimed to determine the optimal dose of hesperidin required to improve oxidative stress, systemic inflammation, and glycemic control in a novel mouse model of MetS. Male 5-week-old C57BL/6 mice were fed a high-fat, high-salt, high-sugar diet (HFSS; 42% kcal fat content in food and drinking water with 0.9% saline and 10% high fructose corn syrup) for 16 weeks. After 6 weeks of HFSS, mice were randomly allocated to either the placebo group or low- (70 mg/kg/day), mid- (140 mg/kg/day), or high-dose (280 mg/kg/day) hesperidin supplementation for 12 weeks. The HFSS diet induced significant metabolic disturbances. HFSS + placebo mice gained almost twice the weight of control mice ( < 0.0001). Fasting blood glucose (FBG) increased by 40% ( < 0.0001), plasma insulin by 100% ( < 0.05), and HOMA-IR by 150% ( < 0.0004), indicating insulin resistance. Hesperidin supplementation reduced plasma insulin by 40% at 140 mg/kg/day ( < 0.0001) and 50% at 280 mg/kg/day ( < 0.005). HOMA-IR decreased by 45% at both doses ( < 0.0001). Plasma hesperidin levels significantly increased in all hesperidin groups ( < 0.0001). Oxidative stress, measured by 8-OHdG, was increased by 40% in HFSS diet mice ( < 0.001) and reduced by 20% with all hesperidin doses ( < 0.005). In conclusion, hesperidin supplementation reduced insulin resistance and oxidative stress in HFSS-fed mice, demonstrating its dose-dependent therapeutic potential in MetS.
Topics: Animals; Hesperidin; Oxidative Stress; Insulin Resistance; Metabolic Syndrome; Male; Mice; Citrus; Mice, Inbred C57BL; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Blood Glucose; Diet, High-Fat; Antioxidants
PubMed: 38927040
DOI: 10.3390/biom14060637 -
Biomolecules May 2024Ulcerative colitis (UC) is an autoimmune disease in which the immune system attacks the colon, leading to ulcer development, loss of colon function, and bloody diarrhea.... (Review)
Review
Ulcerative colitis (UC) is an autoimmune disease in which the immune system attacks the colon, leading to ulcer development, loss of colon function, and bloody diarrhea. The human gut ecosystem consists of almost 2000 different species of bacteria, forming a bioreactor fueled by dietary micronutrients to produce bioreactive compounds, which are absorbed by our body and signal to distant organs. Studies have shown that the Western diet, with fewer short-chain fatty acids (SCFAs), can alter the gut microbiome composition and cause the host's epigenetic reprogramming. Additionally, overproduction of HS from the gut microbiome due to changes in diet patterns can further activate pro-inflammatory signaling pathways in UC. This review discusses how the Western diet affects the microbiome's function and alters the host's physiological homeostasis and susceptibility to UC. This article also covers the epidemiology, prognosis, pathophysiology, and current treatment strategies for UC, and how they are linked to colorectal cancer.
Topics: Humans; Gastrointestinal Microbiome; Colitis, Ulcerative; Colorectal Neoplasms; Epigenesis, Genetic; Diet, Western; Animals
PubMed: 38927037
DOI: 10.3390/biom14060633 -
Biomolecules May 2024Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic...
Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered , a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of -induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems.
Topics: Uncoupling Protein 1; Thermogenesis; Animals; Obesity; Polyphenols; Mice; Diet, High-Fat; Adipose Tissue, Brown; Male; Mice, Inbred C57BL; Humans; Energy Metabolism
PubMed: 38927022
DOI: 10.3390/biom14060618 -
Lipids in Health and Disease Jun 2024Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here,... (Observational Study)
Observational Study
BACKGROUND
Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex.
METHODS
From 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out.
RESULTS
A total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup.
CONCLUSIONS
We present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men.
REGISTRATION
https://clinicaltrials.gov/ct2/show/NCT04936438 , Unique identifier: NCT04936438.
Topics: Aged; Female; Humans; Male; Middle Aged; Bile Acids and Salts; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Lipidomics; Sex Characteristics; Sex Factors; Tandem Mass Spectrometry; Triglycerides; Cohort Studies
PubMed: 38926753
DOI: 10.1186/s12944-024-02184-z -
Cardiovascular Diabetology Jun 2024Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals... (Review)
Review
Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i.
Topics: Humans; Peripheral Arterial Disease; Diabetes Mellitus, Type 2; Lower Extremity; Treatment Outcome; Hypoglycemic Agents; Risk Reduction Behavior; Blood Glucose; Predictive Value of Tests; Risk Factors; Risk Assessment; Biomarkers; Clinical Decision-Making
PubMed: 38926722
DOI: 10.1186/s12933-024-02325-9 -
Animal Models and Experimental Medicine Jun 2024Dihydrogen (H) is produced endogenously by the intestinal microbiota through the fermentation of diet carbohydrates. Over the past few years, numerous studies have...
BACKGROUND
Dihydrogen (H) is produced endogenously by the intestinal microbiota through the fermentation of diet carbohydrates. Over the past few years, numerous studies have demonstrated the significant therapeutic potential of H in various pathophysiological contexts, making the characterization of its production in laboratory species of major preclinical importance.
METHODS
This study proposes an innovative solution to accurately monitor H production in free-moving rodents while respecting animal welfare standards. The developed device consisted of a wire rodent cage placed inside an airtight chamber in which the air quality was maintained, and the H concentration was continuously analyzed. After the airtightness and efficiency of the systems used to control and maintain air quality in the chamber were checked, tests were carried out on rats and mice with different metabolic phenotypes, over 12 min to 1-h experiments and repeatedly. H production rates (HPR) were obtained using an easy calculation algorithm based on a first-order moving average.
RESULTS
HPR in hyperphagic Zucker rats was found to be twice as high as in control Wistar rats, respectively, 2.64 and 1.27 nmol.s per animal. In addition, the ingestion of inulin, a dietary fiber, stimulated H production in mice. HPRs were 0.46 nmol.s for animals under control diet and 1.99 nmol.s for animals under inulin diet.
CONCLUSIONS
The proposed device coupled with our algorithm enables fine analysis of the metabolic phenotype of laboratory rats or mice with regard to their endogenous H production.
PubMed: 38925626
DOI: 10.1002/ame2.12460 -
Complementary Therapies in Medicine Jun 2024Oxidative stress and inflammation play critical roles in the pathogenesis of many chronic diseases. Dark chocolate (DC)/cocoa, as a rich source of polyphenols like... (Review)
Review
Effect of dark chocolate/ cocoa consumption on oxidative stress and inflammation in adults: A GRADE-assessed systematic review and dose-response meta-analysis of controlled trials.
BACKGROUND
Oxidative stress and inflammation play critical roles in the pathogenesis of many chronic diseases. Dark chocolate (DC)/cocoa, as a rich source of polyphenols like flavonoids, has anti-inflammatory and antioxidant properties that may confer health benefits, but findings in this context are inconsistent.
OBJECTIVE
This systematic review and dose-response meta-analysis aimed to provide a comprehensive overview of the controlled trials (CTs) that have examined the effects of DC/cocoa on oxidative stress and inflammation biomarkers in adults.
SEARCH METHODS
Databases including PubMed, Web of Science, and Scopus, were searched for relevant studies through April 2024.
SELECTION CRITERIA
Studies assessed C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), nitric oxide (NO), P-selectin, E-selectin and thiobarbituric acid reactive substances (TBARS) in adults were included.
DATA ANALYSIS
Based on the random-effects model, we calculated WMDs, SMDs and 95 % confidence intervals (CIs). Sensitivity, sub-group, meta-regression and dose-response analyses were also conducted.
RESULTS
Thirty-three eligible CTs with 1379 participants were included. All studies reported the intervention types (cocoa powder, beverages and chocolate bars) and dosage. However, sixteen studies didn't do/report testing for purity and potency by independent groups. Also, none of the studies mentioned the risk of contamination with heavy metals. Another limitation was the lack of blinding assessment in studies. DC/cocoa significantly reduced MDA (SMD: -0.69, 95 %CI: -1.17, -0.2, p = 0.005) and increased NO levels (SMD: 2.43, 95 %CI: 1.11,3.75, p < 0.001); However, it has no significant effects on the other outcomes. Greater anti-inflammatory effects occurred at higher flavonoid doses (>450 mg/day) and for shorter durations (≤4 weeks) in the non-healthy participants. Non-linear dose-response relationships between cocoa dosage and CRP level and also between flavonoid dosage and IL-6 level were observed. Based on the GRADE evaluation, just CRP and MDA results were considered as high certainty evidence and the other outcomes results were categorized as very low to moderate certainty.
CONCLUSIONS
DC/cocoa may improve systemic oxidative status and inflammation in adults. However, further studies should be performed to determine its benefits.
PubMed: 38925412
DOI: 10.1016/j.ctim.2024.103061