Oleoylethanolamide attenuates acute-to-chronic kidney injury: in vivo and in vitro evidence of PPAR-α involvement.

Chronic kidney disease (CKD) development after acute kidney injury (AKI) involves multiple mechanisms, including inflammation, epithelial-mesenchymal transition (EMT), and extracellular matrix deposition, leading to progressive tubulointerstitial fibrosis. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in preserving kidney function during AKI. Among endogenous lipid mediators, oleoylethanolamide (OEA), a PPAR-α agonist, has been studied for its metabolic and anti-inflammatory effects. Here, we have investigated OEA effects on folic acid (FA)-induced kidney injury in mice and the underlying mechanisms. OEA improved kidney function, normalized urine output, and reduced serum BUN, creatinine, and albuminuria. Moreover, OEA attenuated tubular epithelial injury, as shown by histological analysis, and decreased expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Gene expression analysis of kidney tissue indicated that OEA limited immune cell infiltration and inflammation. Moreover, OEA significantly inhibited Wnt7b and Catnb1 gene transcription and α-smooth muscle actin expression, indicating suppression of EMT. Accordingly, OEA exhibited an anti-fibrotic effect, as shown by Masson staining and the reduced levels of transforming growth factor (TGF)-ß1, fibronectin, and collagen IV. Mechanistically, the nephroprotective effect of OEA was related to PPAR-α activation since OEA failed to exert its beneficial activity in FA-insulted PPAR-α-/- mice. PPAR-α involvement was also confirmed in HK2 cells where GW6471, a PPAR-α antagonist, blunted OEA activity on the TGF-ß1 signalling pathway and associated pro-inflammatory and fibrotic patterns. Our findings revealed that OEA counteracts kidney injury by controlling inflammation and fibrosis, making it an effective therapeutic tool for limiting AKI to CKD progression.

Vascular Function and Intima-Media Thickness in Children and Adolescents with Growth Hormone Deficiency: Results from a Prospective Case-Control Study.

INTRODUCTION: Growth hormone deficiency (GHD) may be associated with subtle cardiovascular abnormalities, reversible upon starting GH treatment. Data on vascular morphology and function in GHD children are scanty and inconclusive. The aim of our study was to evaluate the effects of GHD and GH treatment on endothelial function and intima-media thickness (IMT) in children and adolescents. METHODS: We enrolled 24 children with GHD (10.85 ± 2.71 years) and 24 age-, sex-, and BMI-matched controls. We evaluated anthropometry, lipid profile, asymmetric dimethylarginine (ADMA), brachial flow-mediated dilatation (FMD), and IMT of common (cIMT) and internal (iIMT) carotid artery at study entry in all subjects and after 12 months of treatment in GHD children. RESULTS: At baseline GHD, children had higher total cholesterol (163.17 ± 18.66 vs. 149.83 ± 20.68 mg/dL, p = 0.03), LDL cholesterol (91.18 ± 20.41 vs. 77.08 ± 19.73 mg/dL, p = 0.019), atherogenic index (AI) (2.94 ± 0.71 vs. 2.56 ± 0.4, p = 0.028), and ADMA (215.87 ± 109.15 vs. 164.10 ± 49.15 ng/mL, p < 0.001), compared to controls. GHD patients also exhibited increased higher waist-to-height ratio (WHtR) compared to controls (0.48 ± 0.05 vs. 0.45 ± 0.02 cm, p = 0.03). GH therapy resulted in a decrease in WHtR (0.44 ± 0.03 cm, p = 0.001), total (151.60 ± 15.23 mg/dL, p = 0.001) and LDL cholesterol (69.94 ± 14.40 mg/dL, p < 0.0001), AI (2.28 ± 0.35, p = 0.001), and ADMA (148.47 ± 102.43 ng/mL, p < 0.0001). GHD showed lower baseline FMD than controls (8.75 ± 2.44 vs. 11.85 ± 5.98%, p = 0.001), which improved after 1-year GH treatment (10.60 ± 1.69%, p = 0.001). Baseline cIMT and iIMT were comparable between the two groups, but slightly reduced in GHD patients after treatment. CONCLUSION: GHD children may exhibit endothelial dysfunction in addition to other early atherosclerotic markers like visceral adiposity, and altered lipids, which can be restored by GH treatment.

Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism.

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA) is an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.

Zooming into Gut Dysbiosis in Parkinson's Disease: New Insights from Functional Mapping.

Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson's disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies the neurodegenerative phenotype generated by striatal 6-hydroxydopamine (6-OHDA) injection in mice. Low GM diversity and the depletion of key gut colonizers and butyrate producers were the main signatures of GM alteration in this model. Here, we used the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) to unravel candidate pathways of cell-to-cell communication associated with dual-hit mice and potentially involved in PD progression. We focused our analysis on short-chain fatty acids (SCFAs) metabolism and quorum sensing (QS) signaling. Based on linear discriminant analysis, combined with the effect size results, we found increased functions linked to pyruvate utilization and a depletion of acetate and butyrate production in 6-OHDA+CFX mice. The specific arrangement of QS signaling as a possible result of the disrupted GM structure was also observed. With this exploratory study, we suggested a scenario in which SCFAs metabolism and QS signaling might represent the effectors of gut dysbiosis potentially involved in the designation of the functional outcomes that contribute to the exacerbation of the neurodegenerative phenotype in the dual-hit animal model of PD.

Impact of polystyrene microplastic exposure on gilthead seabream (Sparus aurata Linnaeus, 1758): Differential inflammatory and immune response between anterior and posterior intestine.

Plastics are the most widely discharged waste into the aquatic ecosystems, where they break down into microplastics (MPs) and nanoplastics (NPs). MPs are ingested by several marine organisms, including benthic and pelagic fish species, contributing to organ damage and bioaccumulation. This study aimed to assess the effects of MPs ingestion on gut innate immunity and barrier integrity in gilthead seabreams (Sparus aurataLinnaeus, 1758) fed for 21 days with a diet enriched with polystyrene (PS-MPs; 1-20 µm; 0, 25 or 250 mg /kg b.w./die). Physiological fish growth and health status were not impacted by PS-MPs treatments at the end of experimental period. Inflammation and immune alterations were revealed by molecular analyses in both anterior (AI) and posterior intestine (PI) and were confirmed by histological evaluation. PS-MPs triggered TLR-Myd88 signaling pathway with following impairment of cytokines release. Specifically, PS-MPs increased pro-inflammatory cytokines gene expression (i.e., IL-1ß, IL-6 and COX-2) and decreased anti-inflammatory ones (i.e., IL-10). Moreover, PS-MPs also induced an increase in other immune-associated genes, such as Lys, CSF1R and ALP. TLR-Myd88 signaling pathway may also lead to the mitogen-activated protein kinases (MAPK) signaling pathway activation. Here, MAPK (i.e., p38 and ERK) were activated by PS-MPs in PI, following the disruption of intestinal epithelial integrity, as evidenced by reduced gene expression of tight junctions (i.e. ZO-1, Cldn15, Occludin, and Tricellulin), integrins (i.e., Itgb6) and mucins (i.e., Muc2-like and Muc13-like). Thus, all the obtained results suggest that the subchronic oral exposure to PS-MPs induces inflammatory and immune alterations as well as an impact on intestinal functional integrity in gilthead seabream, with a more evident effect in PI.

The Hepatic Mitochondrial Alterations Exacerbate Meta-Inflammation in Autism Spectrum Disorders.

The role of the liver in autism spectrum disorders (ASD), developmental disabilities characterized by impairments in social interactions and repetitive behavioral patterns, has been poorly investigated. In ASD, it has been shown a dysregulation of gut-brain crosstalk, a communication system able to influence metabolic homeostasis, as well as brain development, mood and cognitive functions. The liver, with its key role in inflammatory and metabolic states, represents the crucial metabolic organ in this crosstalk. Indeed, through the portal vein, the liver receives not only nutrients but also numerous factors derived from the gut and visceral adipose tissue, which modulate metabolism and hepatic mitochondrial functions. Here, we investigated, in an animal model of ASD (BTBR mice), the involvement of hepatic mitochondria in the regulation of inflammatory state and liver damage. We observed increased inflammation and oxidative stress linked to hepatic mitochondrial dysfunction, steatotic hepatocytes, and marked mitochondrial fission in BTBR mice. Our preliminary study provides a better understanding of the pathophysiology of ASD and could open the way to identifying hepatic mitochondria as targets for innovative therapeutic strategies for the disease.

Dual-Hit Model of Parkinson's Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice-Neuroprotective and Anti-Inflammatory Effects of Butyrate.

Recent evidence highlights Parkinson's disease (PD) initiation in the gut as the prodromal phase of neurodegeneration. Gut impairment due to microbial dysbiosis could affect PD pathogenesis and progression. Here, we propose a two-hit model of PD through ceftriaxone (CFX)-induced dysbiosis and gut inflammation before the 6-hydroxydopamine (6-OHDA) intrastriatal injection to mimic dysfunctional gut-associated mechanisms preceding PD onset. Therefore, we showed that dysbiosis and gut damage amplified PD progression, worsening motor deficits induced by 6-OHDA up to 14 days post intrastriatal injection. This effect was accompanied by a significant increase in neuronal dopaminergic loss (reduced tyrosine hydroxylase expression and increased Bcl-2/Bax ratio). Notably, CFX pretreatment also enhanced systemic and colon inflammation of dual-hit subjected mice. The exacerbated inflammatory response ran in tandem with a worsening of colonic architecture and gut microbiota perturbation. Finally, we demonstrated the beneficial effect of post-biotic sodium butyrate in limiting at once motor deficits, neuroinflammation, and colon damage and re-shaping microbiota composition in this novel dual-hit model of PD. Taken together, the bidirectional communication of the microbiota-gut-brain axis and the recapitulation of PD prodromal/pathogenic features make this new paradigm a useful tool for testing or repurposing new multi-target compounds in the treatment of PD.

Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α.

The potential role of brown and beige adipose tissue against obesity has been recognized. Browning, or beiging of white adipose tissue (WAT) is associated with the remodeling of adipocytes and the improvement of their metabolic and secretory functions. Here, palmitoylethanolamide (PEA) restore the plasticity of brown and white adipocytes impaired in mice on a high-fat diet (HFD). Young male C57Bl/6J mice were fed with control (STD) diet or HFD for 12 weeks. Ultramicronized PEA (30 mg/kg/die p.o.) was administered for an additional 7 weeks, together with HFD. PEA recovered interscapular brown fat morphology and function, increasing UCP1 positivity, noradrenergic innervation, and inducing the mRNA transcription of several specialized thermogenic genes. PEA promotes the beige-conversion of the subcutaneous WAT, increasing thermogenic markers and restoring leptin signaling and tissue hormone sensitivity. The pivotal role of lipid-sensing peroxisome proliferator-activated receptor (PPAR)-α in PEA effects was determined in mature 3T3-L1. Moreover, PEA improved mitochondrial bioenergetics in mature adipocytes measured by a Seahorse analyzer and induced metabolic machinery via AMPK phosphorylation. All these outcomes were dampened by the receptor antagonist GW6471. Finally, PEA induced adipogenic differentiation and increased AMPK phosphorylation in human adipose-derived stromal cells (ASCs) obtained from subcutaneous WAT of normal-weight patients and patients with obesity. We identify PEA and PPAR-α activation as the main mechanism by which PEA can rewire energy-storing white into energy-consuming brown-like adipocytes via multiple and converging effects that restore WAT homeostasis and metabolic flexibility.

Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice.

High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level. Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice. PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1ß, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase ß2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood-brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects. Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.

The Pressing Issue of Micro- and Nanoplastic Contamination: Profiling the Reproductive Alterations Mediated by Oxidative Stress.

Micro- and nanoplastics (MPs/NPs) are among the most widely distributed pollutants in the environment. It has been suggested that exposure to MPs/NPs can trigger toxicity pathways among which inflammation and oxidative stress (OS) play a pivotal role. Once absorbed, MPs/NPs may act locally or access the bloodstream and, following the translocation process, reach several organs and tissues, including the gonads. Notably, MPs/NPs can bioaccumulate in human and murine placenta, opening new scenarios for toxicological evaluations. We review recent studies on the effects of MPs/NPs on the reproductive health in aquatic and terrestrial organisms of both sexes, focusing on the role of OS and the antioxidant defence system failure as the main underlying mechanisms. Alterations in gametogenesis, embryonic and offspring development, and survival have been shown in most studies and often related to a broken redox balance. All these detrimental effects are inversely related to particle size, whereas they are closely linked to shape, plastic polymer type, superficial functionalization, concentration, and time of exposure. To date, the studies provide insights into the health impacts, but no conclusions can be drawn for reproduction toxicity. The main implication of the few studies on antioxidant substances reveals their potential role in mitigating MP-induced toxic effects.

Transverse aortic constriction induces gut barrier alterations, microbiota remodeling and systemic inflammation.

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events.

Palmitoylethanolamide counteracts brain fog improving depressive-like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis.

BACKGROUND AND PURPOSE: High-fat diet (HFD)-induced obesity is accompanied by metabolic and neurochemical changes that have been associated with depression. Recent studies indicate that palmitoylethanolamide (PEA) exerts metabolic effects and holds neuroprotective potential. However, studies on HFD exposure in mice which investigate the effects of PEA on monoamine system and synaptic plasticity are limited. EXPERIMENTAL APPROACH: In C57Bl/6J male mice, obesity was established by HFD feeding for 12 weeks. Then, mice were treated with ultra-micronized PEA (30 mg·kg-1 daily p.o.) or vehicle for 7 weeks along with HFD. Mice receiving chow diet and vehicle served as controls. Thereafter, depressive-, anhedonic-like behaviour and cognitive performance were measured. Monoamine analyses were performed on brain areas (nucleus accumbens, Nac; prefrontal cortex, PFC; hippocampus), and markers of synaptic plasticity and neurogenesis were evaluated in hippocampus. KEY RESULTS: PEA limited depressive- and anhedonic-like behaviour, and cognitive deficits induced by HFD. PEA induced an increase in 5-HT levels in PFC, and a reduction of dopamine and 5-HT turnover in Nac and PFC, respectively. Moreover, PEA increased dopamine levels in the hippocampus and PFC. At a molecular level, PEA restored brain-derived neurotrophic factor signalling pathway in hippocampus and PFC, indicating an improvement of synaptic plasticity. In particular, PEA counteracted the reduction of glutamatergic synaptic density induced by HFD in the stratum radiatum of the CA1 of the hippocampus, where it also exhibited neurogenesis-promoting abilities. CONCLUSION AND IMPLICATIONS: PEA may represent an adjuvant therapy to limit depressive-like behaviours and memory deficit, affecting monoamine homeostasis, synaptic plasticity and neurogenesis. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.

Randomised Clinical Trial: Calorie Restriction Regimen with Tomato Juice Supplementation Ameliorates Oxidative Stress and Preserves a Proper Immune Surveillance Modulating Mitochondrial Bioenergetics of T-Lymphocytes in Obese Children Affected by Non-Alcoholic Fatty Liver Disease (NAFLD).

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child.

Autophagy and NLRP3 inflammasome crosstalk in neuroinflammation in aged bovine brains.

NLRP3 inflammasome is a multiprotein complex that can sense several stimuli such as autophagy dysregulation and increased reactive oxygen species production stimulating inflammation by priming the maturation of proinflammatory cytokines interleukin-1ß and interleukin-18 in their active form. In the aging brain, these cytokines can mediate the innate immunity response priming microglial activation. Here, we describe the results of immunohistochemical and molecular analysis carried out on bovine brains. Our results support the hypothesis that the age-related impairment in cellular housekeeping mechanisms and the increased oxidative stress can trigger the inflammatory danger sensor NLRP3. Moreover, according to the recent scientific literature, we demonstrate the presence of an age-related proinflammatory environment in aged brains consisting in an upregulation of interleukin-1ß, an increased microglial activation and increased NLRP3 expression. Finally, we suggest that bovine may potentially be a pivotal animal model for brain aging studies.

Butyrate prevents valproate-induced liver injury: In vitro and in vivo evidence.

Sodium valproate (VPA), an antiepileptic drug, may cause dose- and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations. Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment.

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet-induced obese mice.

Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice. Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload.

Nutraceuticals: An integrative approach to starve Parkinson's disease.

The therapeutic approach of multifactorial complex diseases is always a challenge; Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder triggered by genetic and environmental factors, contributing to its etiology. Indeed, several pathogenic mechanisms lead to selective dopaminergic neuronal injury, including oxidative stress, mitochondrial dysfunction, alteration of endoplasmic reticulum-to-Golgi protein trafficking, excitotoxicity, and neuroinflammation. Current treatment approaches include mainly dopamine replacement therapy or optimizing dopaminergic transmission; however, these strategies that do not counteract the pathogenic mechanisms underlying PD symptoms and often are less effective over time. Recently, there has been growing interest in the therapeutic use of nutraceuticals, that could represent an integrative approach to the pharmacological standard therapy and specifically affect one or more pathogenic pathways. The intake of nutraceuticals or nutritional modifications are generally safe and can be combined with current common drug therapy in most cases to improve the patient's quality of life and/or mitigate PD symptoms. The current review focuses on several key nutritional compounds and dietary modifications that are effective on several pathogenic pathways involved in PD onset and progression, and further highlights the rationale behind their potential use for the prevention and treatment of PD.

Effects of Histone Deacetylase Inhibitors on the Development of Epilepsy and Psychiatric Comorbidity in WAG/Rij Rats.

Epigenetic mechanisms, such as alterations in histone acetylation based on histone deacetylases (HDACs) activity, have been linked not only to normal brain function but also to several brain disorders including epilepsy and the epileptogenic process. In WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity, we investigated the effects of two HDAC inhibitors (HDACi), namely sodium butyrate (NaB), valproic acid (VPA) and their co-administration, on the development of absence seizures and related psychiatric/neurologic comorbidities following two different experimental paradigms. Treatment effects have been evaluated by EEG recordings (EEG) and behavioural tests at different time points. Prolonged and daily VPA and NaB treatment, started before absence seizure onset (P30), significantly reduced the development of absence epilepsy showing antiepileptogenic effects. These effects were enhanced by NaB/VPA co-administration. Furthermore, early-chronic HDACi treatment improved depressive-like behaviour and cognitive performance 1 month after treatment withdrawal. WAG/Rij rats of 7 months of age showed reduced acetylated levels of histone H3 and H4, analysed by Western Blotting of homogenized brain, in comparison to WAG/Rij before seizure onset (P30). The brain histone acetylation increased significantly during treatment with NaB or VPA alone and more markedly during co-administration. We also observed decreased expression of both HDAC1 and 3 following HDACi treatment compared to control group. Our results suggest that histone modifications may have a crucial role in the development of epilepsy and early treatment with HDACi might be a possible strategy for preventing epileptogenesis also affecting behavioural comorbidities.

High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction.

Brain mitochondrial dysfunction is involved in the development of neurological and neurodegenerative diseases. Mitochondria specifically located at synapses play a key role in providing energy to support synaptic functions and plasticity, thus their defects may lead to synaptic failure, which is a common hallmark of neurodegenerative diseases. High-Fat Diet (HFD) consumption increases brain oxidative stress and impairs brain mitochondrial functions, although the underlying mechanisms are not completely understood. The aim of our study is to analyze neuroinflammation and mitochondrial dysfunctions in brain cortex and synaptosomal fraction isolated from a mouse model of diet-induced obesity. Male C57Bl/6 mice were divided into two groups fed a standard diet or HFD for 18 weeks. At the end of the treatment, inflammation (detected by ELISA), antioxidant state (measured by enzymatic activity), mitochondrial functions and efficiency (detected by oxidative capacity and Seahorse analysis), and brain-derived neurotrophic factor (BDNF) pathway (analyzed by western blot) were determined in brain cortex and synaptosomal fraction. In HFD animals, we observed an increase in inflammatory parameters and oxidative stress and a decrease in mitochondrial oxidative capacity both in the brain cortex and synaptosomal fraction. These alterations parallel with modulation of BDNF, a brain key signaling molecule that is linking synaptic plasticity and energy metabolism. Neuroinflammation HFD-dependent negatively affects BDNF pathway and mitochondrial activity in the brain cortex. The effect is even more pronounced in the synaptic region, where the impaired energy supply may have a negative impact on neuronal plasticity.

N-(1-carbamoyl-2-phenylethyl) butyramide reduces antibiotic-induced intestinal injury, innate immune activation and modulates microbiota composition.

The use/misuse of antibiotics leads to pathological features referring to antibiotic-induced intestinal injury (AIJ), a clinical issue that plays a prominent role in the development of severe digestive disturbances. AIJ is characterized by loss of intestinal architecture and function, dysbiosis and bacterial translocation into the liver, triggering hepatic inflammation. This study aimed at determining the beneficial effect of N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), a butyrate releasing compound, in ceftriaxone-induced intestinal injury. To this purpose, mice receiving ceftriaxone (8 g∙kg-1/die, per os) for five days, were treated with FBA (212,5 mg∙kg-1/die, per os) for five or fifteen days. FBA modulated key players of innate immunity in antibiotic-injured gut tissues, reducing inflammatory process and improving the anti-inflammatory and resolving pattern. FBA also improved colonic architecture and intestinal integrity. Interestingly, we also observed a remodeling of gut microbiota composition related to an increase of metabolic pathways related to lactate and butyrate production. At mechanistic level, FBA induced histone acetylation and increased the expression of GPR43 and monocarboxylate transporter 1 in colon. Our data clearly demonstrated that FBA has multiple converging mechanisms in limiting intestinal and hepatic alterations to counteract AIJ.