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Adolescent Psychiatry (Hilversum,... 2023Adolescents and young adults may use cannabidiol (CBD) products in an attempt to reduce depression and anxiety symptoms, despite little research examining this use. This...
BACKGROUND
Adolescents and young adults may use cannabidiol (CBD) products in an attempt to reduce depression and anxiety symptoms, despite little research examining this use. This systematic review evaluated preclinical and clinical research on the effects of CBD on depressive and anxiety disorders in adolescence and young adulthood. To provide context, we discuss CBD's mechanism of action and neurodevelopmental effects.
METHODS
PubMed was searched for articles published through June 2022. Preclinical or clinical CBD administration studies with > 1 that examined depressive and/or anxiety disorders were eligible.
RESULTS
Initially, 224 publications were identified. After excluding duplicates and applying eligibility criteria, 6 preclinical (depression: ≈133; anxiety: ≈161) and 4 clinical (anxiety: =113) articles remained. Due to the low number of studies, results were synthesized qualitatively. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence were used to rate each study's evidence. The preclinical effects of CBD on depression-like behavior appear to differ by sex, early life stress, and duration of use. Despite no evidence that CBD exerts anxiolytic effects in preclinical adolescent models, CBD may reduce anxiety symptoms in human adolescents and young adults with anxiety disorders.
CONCLUSIONS
The existing evidence suggests that CBD may reduce symptoms of anxiety in adolescents and young adults. However, the evidence is sparse and limited by variations in samples and CBD dosing duration. Further research is needed to understand the potential benefits and/or harms of CBD for depression and anxiety disorders in this population. Implications for clinical practice and research are discussed.
PubMed: 38919887
DOI: 10.2174/0122106766233339230919143924 -
Experimental and Therapeutic Medicine Aug 2024(CF) is known for its anti-inflammatory, antioxidant and antibacterial activities. However, there is a lack of research on its other pharmacological properties. In the...
(CF) is known for its anti-inflammatory, antioxidant and antibacterial activities. However, there is a lack of research on its other pharmacological properties. In the present study, the bifunctional roles of CF in 3T3-L1 and RAW264.7 cells were investigated, focusing on its anti-obesity and immunostimulatory effects. In 3T3-L1 cells, CF effectively mitigated the accumulation of lipid droplets and triacylglycerol. Additionally, CF downregulated the peroxisome proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding protein α protein levels; however, this effect was impeded by the knockdown of β-catenin using β-catenin-specific small interfering RNA. Consequently, CF-mediated inhibition of lipid accumulation was also decreased. CF increased the protein levels of adipose triglyceride lipase and phosphorylated hormone-sensitive lipase, while decreasing those of perilipin-1. Moreover, CF elevated the protein levels of phosphorylated AMP-activated protein kinase and PPARγ coactivator 1-α. In RAW264.7 cells, CF enhanced the production of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, and increased their phagocytic capacities. Inhibition of Toll-like receptor (TLR)-4 significantly reduced the effects of CF on the production of pro-inflammatory mediators and phagocytosis, indicating its crucial role in facilitating these effects. CF-induced increase in the production of pro-inflammatory mediators was controlled by the activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-κB pathways, and TLR4 inhibition attenuated the phosphorylation of these kinases. The results of the pesent study suggested that CF inhibits lipid accumulation by suppressing adipogenesis and inducing lipolysis and thermogenesis in 3T3-L1 cells, while stimulating macrophage activation via the activation of JNK and NF-κB signaling pathways mediated by TLR4 in RAW264.7 cells. Therefore, CF simultaneously exerts both anti-obesity and immunostimulatory effects.
PubMed: 38911047
DOI: 10.3892/etm.2024.12604 -
Endocrine Journal Jun 2024Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent...
Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent DNA demethylation in the mouse liver via peroxisome proliferator-activated receptor (PPAR) α during the fetal to lactation periods. Furthermore, we found that the DNA methylation state of Fgf21 was involved in obesity in adult animals. In the present study, we analyzed the DNA methylation state of the FGF21 gene (FGF21) in obese patients using genomic DNA extracted from human monocytes and macrophages and investigated the pathophysiological significance of the FGF21 expression response to pemafibrate (PM), a PPARα ligand. We examined 67 patients with obesity stratified into in- and outpatient cohorts. A positive correlation was observed between serum FGF21 levels and triglyceride (TG) levels before PM administration. However, changes in serum FGF21 levels following PM administration did not correlate with the FGF21 DNA methylation rate, except at one CpG site. The body mass index (BMI) and serum TG levels positively correlated with the FGF21 DNA methylation rate, particularly at different CpG positions. A negative correlation was observed between absolute changes in serum FGF21 levels and the ratio of change in serum TG levels after PM administration. Collectively, these results indicate the potential of FGF21 DNA methylation as a surrogate indicator of BMI and serum TG levels, while absolute changes in serum FGF21 levels after PM administration may offer prognostic insights into the efficacy of reducing serum TG levels through PM administration.
PubMed: 38910123
DOI: 10.1507/endocrj.EJ23-0570 -
European Journal of Pharmacology Jun 2024Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is...
Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.
PubMed: 38909934
DOI: 10.1016/j.ejphar.2024.176767 -
Lipids in Health and Disease Jun 2024Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they...
BACKGROUND
Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community.
METHOD
This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes.
RESULTS
7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate.
CONCLUSION
In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.
Topics: Animals; Diet, High-Fat; Adipogenesis; Obesity; Mice; 3T3-L1 Cells; Adipocytes; Mice, Inbred C57BL; Male; PPAR gamma; Sterol Regulatory Element Binding Protein 1; Stearoyl-CoA Desaturase; Mice, Obese; Fatty Acid-Binding Proteins; Adipokines; Anti-Obesity Agents; Uncoupling Protein 1; Adipose Tissue, White; CCAAT-Enhancer-Binding Proteins
PubMed: 38909257
DOI: 10.1186/s12944-024-02175-0 -
Frontiers in Pharmacology 2024Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately...
INTRODUCTION
Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately 90% of all DM cases. Current medicines used in the treatment of DM have some adverse or undesirable effects on patients, necessitating the use of alternative medications.
METHODS
To overcome the low bioavailability of plant metabolites, all entities were first screened through pharmacokinetic, network pharmacology, and molecular docking predictions. Experiments were further conducted on a combination of antidiabetic phytoactive molecules (rosmarinic acid, RA; luteolin, Lut; resveratrol, RS), along with evaluation (α-amylase inhibition assay) and diabetic mice tests (oral glucose tolerance test, OGTT; oral starch tolerance test, OSTT) for maximal responses to validate starch digestion and glucose absorption while facilitating insulin sensitivity.
RESULTS
The results revealed that the combination of metabolites achieved all required criteria, including ADMET, drug likeness, and Lipinski rule. To determine the mechanisms underlying diabetic hyperglycemia and T2DM treatments, network pharmacology was used for regulatory network, PPI network, GO, and KEGG enrichment analyses. Furthermore, the combined metabolites showed adequate predictions (α-amylase, α-glucosidase, and pancreatic lipase for improving starch digestion; SGLT-2, AMPK, glucokinase, aldose reductase, acetylcholinesterase, and acetylcholine M2 receptor for mediating glucose absorption; GLP-1R, DPP-IV, and PPAR-γ for regulating insulin sensitivity), α-amylase inhibition, and efficacy (OSTT versus acarbose; OGTT versus metformin and insulin) as nutraceuticals against T2DM.
DISCUSSION
The results demonstrate that the combination of RA, Lut, and RS could be exploited for multitarget therapy as prospective antihyperglycemic phytopharmaceuticals that hinder starch digestion and glucose absorption while facilitating insulin sensitivity.
PubMed: 38903985
DOI: 10.3389/fphar.2024.1362150 -
Frontiers in Toxicology 2024Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and...
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (, , , -) and downregulation of lipid transport genes (, , ). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis () and bile acid synthesis () were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis () showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
PubMed: 38903859
DOI: 10.3389/ftox.2024.1390196 -
PPAR Research 2024Partial and full PPAR- agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study...
Partial and full PPAR- agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR- agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 g/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and and antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group ( < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR- agonists and adiponectin receptors.
PubMed: 38899161
DOI: 10.1155/2024/5868010 -
Physiological Reports Jun 2024This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three...
This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.
Topics: Animals; Male; Muscle, Skeletal; Mice; Physical Conditioning, Animal; Physical Endurance; Mice, Inbred C57BL; Hyperoxia; PPAR alpha; PPAR gamma; Phosphofructokinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors; DNA-Binding Proteins; Mitochondrial Proteins
PubMed: 38898524
DOI: 10.14814/phy2.16117 -
The American Journal of Pathology Jun 2024Bifidobacterium bifidum (BB) strain BB1 causes a strain-specific enhancement in intestinal epithelial tight junction (TJ) barrier. TNF-α induces an increase in...
Bifidobacterium bifidum strain BB1 inhibits TNF-α-induced increase in intestinal epithelial tight junction permeability via TLR-2/TLR-6 receptor complex-dependent stimulation of PPAR-γ and suppression of NF-kB p65.
Bifidobacterium bifidum (BB) strain BB1 causes a strain-specific enhancement in intestinal epithelial tight junction (TJ) barrier. TNF-α induces an increase in intestinal epithelial TJ permeability and promotes intestinal inflammation. The major purpose of this study was to delineate the protective effect of BB1 against the TNF-α induced increase in intestinal TJ permeability and to unravel the intracellular mechanisms involved. Previously reported, TNF-α produces an increase in intestinal epithelial TJ permeability in Caco-2 monolayers and in mice. The addition of BB1 inhibited the TNF-α increase in Caco-2 intestinal TJ permeability and mouse intestinal permeability in a strain-specific manner. BB1 inhibited the TNF-α induced increase in intestinal TJ permeability by interfering the with TNF-α induced enterocyte NF-κB p50/p65 and MLCK gene activation. The BB1 protective effect against the TNF-α induced increase in intestinal permeability was mediated by TLR-2/TLR-6 heterodimer complex activation of PPAR-γ and PPAR-γ pathway inhibition of TNF-α induced IKK-α activation, which in turn resulted in a step-wise inhibition of NF-κB p50/p65, MLCK gene, MLCK kinase activity, MLCK-induced opening of the TJ barrier. In conclusion, these studies unravel novel intracellular mechanisms of BB1 protection against the TNF-α induced increase in intestinal TJ permeability. Our data show that BB1 protects against the TNF-α induced increase in intestinal epithelial TJ permeability via a PPAR-γ dependent inhibition of NF-κB p50/p65 and MLCK gene activation.
PubMed: 38885924
DOI: 10.1016/j.ajpath.2024.05.012