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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.

Alterations of microbiota-gut-brain axis have been invoked in the pathogenesis of autism spectrum disorders (ASD). Mouse models could represent an excellent tool to understand how gut dysbiosis and related alterations may contribute to autistic phenotype. In this study we paralleled gut microbiota (GM) profiles, behavioral characteristics, intestinal integrity and immunological features of colon tissues in BTBR T + tf/J (BTBR) inbred mice, a well established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Results showed that BTBR mice of both sexes presented a marked intestinal dysbiosis, alterations of behavior, gut permeability and immunological state with respect to prosocial C57BL/6j (C57) strain. Noticeably, sex-related differences were clearly detected. We identified Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with selected pathological traits. Taken together, our findings indicate that alteration of GM in BTBR mice shows relevant sex-associated differences and supports the use of BTBR mouse model to dissect autism associated microbiota-gut-brain axis alteration.

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.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and children. It is characterized by an aberrant lipid storage in hepatocytes, named hepatic steatosis. Simple steatosis remains a benign process in most affected patients, while some of them develop superimposed necroinflammatory activity with a non-specific inflammatory infiltrate and a progression to non-alcoholic steatohepatitis with or without fibrosis. Deep similarity and interconnections between innate immune cells and those of liver parenchyma have been highlighted and showed to play a key role in the development of chronic liver disease. The liver can be considered as an \"immune organ\" because it hosts non-lymphoid cells, such as macrophage Kupffer cells, stellate and dendritic cells, and lymphoid cells. Many of these cells are components of the classic innate immune system, enabling the liver to play a major role in response to pathogens. Although the liver provides a \"tolerogenic\" environment, aberrant activation of innate immune signaling may trigger \"harmful\" inflammation that contributes to tissue injury, fibrosis, and carcinogenesis. Pathogen recognition receptors, such as toll-like receptors and nucleotide oligomerization domain-like receptors, are responsible for the recognition of immunogenic signals, and represent the major conduit for sensing hepatic and non-hepatic noxious stimuli. A pivotal role in liver inflammation is also played by cytokines, which can initiate or have a part in immune response, triggering hepatic intracellular signaling pathways. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic alteration traits: insulin resistance, obesity, diabetes, hyperlipidemia, and their compounded combined effects. In this review, we discuss the relevant role of innate immune cell activation in relation to NAFLD, the metabolic complications associated to this pathology, and the possible pharmacological tools.

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.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD). After weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined. Evaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation. Our results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance.

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.

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.

Omega (ω)-3 polyunsaturated fatty acids (PUFA) are dietary compounds able to attenuate insulin resistance. Anyway, the precise actions of ω-3PUFAs in skeletal muscle are overlooked. We hypothesized that PUFAs, modulating mitochondrial function and efficiency, would ameliorate pro-inflammatory and pro-oxidant signs of nutritionally induced obesity. To this aim, rats were fed a control diet (CD) or isocaloric high fat diets containing either ω-3 PUFA (FD) or lard (LD) for 6 weeks. FD rats showed lower weight, lipid gain and energy efficiency compared to LD-fed animals, showing higher energy expenditure and O2 consumption/CO2 production. Serum lipid profile and pro-inflammatory parameters in FD-fed animals were reduced compared to LD. Accordingly, FD rats exhibited a higher glucose tolerance revealed by an improved glucose and insulin tolerance tests compared to LD, accompanied by a restoration of insulin signalling in skeletal muscle. PUFAs increased lipid oxidation and reduced energy efficiency in subsarcolemmal mitochondria, and increase AMPK activation, reducing both endoplasmic reticulum and oxidative stress. Increased mitochondrial respiration was related to an increased mitochondriogenesis in FD skeletal muscle, as shown by the increase in PGC1-α and -β. our data strengthened the association of high dietary ω3-PUFA intake with reduced mitochondrial energy efficiency in the skeletal muscle.

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.