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Gut microbiota has a proven role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Oral bacteriotherapy thus has potential in the treatment of central nervous system-related pathologies, such as Alzheimer’s disease (AD). Current AD treatments aim to prevent onset, delay progression and ameliorate symptoms. In this work, 3xTg-AD mice in the early stage of AD were treated with SLAB51 probiotic formulation, thereby affecting the composition of gut microbiota and its metabolites. This influenced plasma concentration of inflammatory cytokines and key metabolic hormones considered therapeutic targets in neurodegeneration. Treated mice showed partial restoration of two impaired neuronal proteolytic pathways (the ubiquitin proteasome system and autophagy). Their cognitive decline was decreased compared with controls, due to a reduction in brain damage and reduced accumulation of amyloid beta aggregates. Collectively, our results clearly prove that modulation of the microbiota induces positive effects on neuronal pathways that are able to slow down the progression of Alzheimer’s disease.

Background: Insufficient sleep is a serious public health problem in modern society. It leads to increased risk of chronic diseases, and it has been frequently associated with cellular oxidative damage and widespread low-grade inflammation. Probiotics have been attracting increasing interest recently for their antioxidant and anti-inflammatory properties. Here, we tested the ability of probiotics to contrast oxidative stress and inflammation induced by sleep loss. Methods: We administered a multi-strain probiotic formulation (SLAB51) or water to normal sleeping mice and to mice exposed to 7 days of chronic sleep restriction (CSR). We quantified protein, lipid, and DNA oxidation as well as levels of gut–brain axis hormones and pro and anti-inflammatory cytokines in the brain and plasma. Furthermore, we carried out an evaluation of microglia morphology and density in the mouse cerebral cortex. Results: We found that CSR induced oxidative stress and inflammation and altered gut–brain axis hormones. SLAB51 oral administration boosted the antioxidant capacity of the brain, thus limiting the oxidative damage provoked by loss of sleep. Moreover, it positively regulated gut–brain axis hormones and reduced peripheral and brain inflammation induced by CSR. Conclusions: Probiotic supplementation can be a possible strategy to counteract oxidative stress and inflammation promoted by sleep loss.

γ-Oryzanol is a complex mixture of ferulic acid esters of phytosterols and triterpene alcohols predominantly found in rice bran. It exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, and lipid-lowering effects, as well as the ability to modulate cellular metabolic pathways in both in vitro and in vivo models. The composition and concentration of γ-oryzanol vary significantly among rice varieties and are influenced by genetic, environmental, and technological factors. Advances in extraction methods, including traditional solvent extraction and innovative approaches such as supercritical fluid extraction, have improved yield and purity, supporting its use in functional foods, nutraceuticals, and cosmetics. Current research in the biological, biomedical, and cosmetic fields is actively investigating γ-oryzanol’s mechanisms of action in metabolic regulation and inflammation, as well as developing advanced formulation strategies to enhance its antioxidant, skin-protective, and functional properties. These efforts aim to optimize its delivery and efficacy by addressing challenges related to poor water solubility and bioavailability, thereby expanding its role as a multifunctional bioactive compound. This review provides a comprehensive overview on γ-oryzanol, focusing on its extraction techniques, chemical characterization, and biological/pharmacological activities. Additionally, clinical trials investigating its efficacy and safety have been thoroughly dissected, offering valuable insights into its therapeutic potential in human populations.

Background Alzheimer’s disease (AD) is the major age-related form of dementia in which dysfunctional ubiquitin-proteasome system (UPS) and autophagy represent primary mechanisms leading to accumulation of misfolded proteins, dysfunction of astroglial cells, neuroinflammation and neurodegeneration. Alterations of the endoplasmic reticulum (ER)-mitochondria contact sites (MERCS), specifically the shortening of the distance between the organelles, was proposed as a key mechanism of cell dysfunction in AD. However, its link to the impairment of the proteolytic system in AD remains unexplored. Methods We used, as a model, hippocampal astrocytes from 3xTg-AD mice expressing either control plasmid or synthetic linkers stabilizing ER-mitochondrial interaction at 10 nm (10 nm-EML) or at 20 nm (20 nm-EML). Alternatively, astrocytes were treated with mitochondrial Ca 2+ uptake inhibitor benzethonium chloride or activator amorolfine. We used Western blot to assess protein expression and specific enzymatic activity tests for the analysis of proteasomal, autophagic and lysosomal activities. Single cell fluorescent Ca 2+ imaging, using 4mtD3cpv probe targeted to the mitochondrial matrix, was used to assess mitochondrial Ca 2+ uptake. Results Stabilization of MERCS at 20 nm (20 nm-MERCS), which promotes mitochondrial Ca 2+ uptake, rescued protein ubiquitination, UPS composition and activity. Immunoproteasome components β2i and β5i, upregulated in AD astrocytes, and INFγ, a master-regulator of UPS remodelling in inflammatory conditions, were also rescued. Autophagic markers beclin 1, LC3II and p62, and lysosome-related marker cathepsin B, all upregulated in AD astrocytes, were significantly reduced, while autophagic flux was rescued, by stabilizing 20 nm-MERCS. Furthermore, stabilization of 20 nm-MERCS fully rescued previously reported deficit of mitochondrial Ca 2+ uptake. Strikingly, application of a mitochondrial Ca 2+ uptake positive modulator, amorolfine, partially rescued pathological remodelling of UPS and autophagy, suggesting that both mitochondrial Ca 2+ -related and Ca 2+ -unrelated mechanisms play a role in the beneficial effect of 20 nm-MERCS stabilization on protein dyshomeostasis. Conclusions Our results suggest that disruption of ER-mitochondrial interaction is a key factor for AD-related dysregulation of protein degradation and provide a proof that stabilization of MERCS at a defined distance and/or pharmacological rescue of mitochondrial Ca 2+ uptake represent valuable strategies for the development of future anti-AD therapy.

Chickpeas are used as alternative protein sources in healthy snacks due to their bioactive compounds beneficial for gut health. Combining chickpeas with dark chocolate improves palatability and may enhance biological functionality, although mechanistic evidence is still limited. In this explorative research, we evaluate the nutrigenomic, antioxidant and anti-inflammatory properties of a chickpea and chocolate snack using in vitro Caco-2 (colon adenocarcinoma cells) and THP-1 (monocyte-derived macrophages) models. The total polyphenol content and antioxidant activity were measured after in vitro digestion (30.30 mg/mL to 1.9 mg/mL). Caco-2 epithelia and THP-1 were pre-treated for 4 days (2 h/day) with high (15.1 mg/mL) or low (3.8 mg/mL) concentrations of digests. Inflammation was induced for 3 h by LPS (Lipopolysaccharides) and IL-1β (Interleukin-1β). Transepithelial electrical resistance (TEER) was measured to assess barrier integrity. Gene expression related to tight junctions and inflammation was analysed using qPCR (quantitative polymerase chain reaction). Chocolate and snack digests showed the highest total polyphenol content and 2,2-diphenyl-1-picrylhydrazyl activity. Barrier integrity improved with all treatments. Chickpea upregulated tight junction gene expression. Chickpea and chocolate reduced IL-1β expression in both cell types. In THP-1, the chocolate and the snack upregulated CD206 (mannose receptor C-type 1) expression. IL-10 increased with all treatments. These results pave the way for future research that may support the potential use of this snack as a functional food with antioxidant, gut-protective and anti-inflammatory effects.

Hypoxia-inducible factor-1α (HIF-1α), a central player in maintaining gut-microbiota homeostasis, plays a pivotal role in inducing adaptive mechanisms to hypoxia and is negatively regulated by prolyl hydroxylase 2 (PHD2). HIF-1α is stabilized through PI3K/AKT signaling regardless of oxygen levels. Considering the crucial role of the HIF pathway in intestinal mucosal physiology and its relationships with gut microbiota, this study aimed to evaluate the ability of the lysate from the multi-strain probiotic formulation SLAB51 to affect the HIF pathway in a model of in vitro human intestinal epithelium (intestinal epithelial cells, IECs) and to protect from lipopolysaccharide (LPS) challenge. The exposure of IECs to SLAB51 lysate under normoxic conditions led to a dose-dependent increase in HIF-1α protein levels, which was associated with higher glycolytic metabolism and L-lactate production. Probiotic lysate significantly reduced PHD2 levels and HIF-1α hydroxylation, thus leading to HIF-1α stabilization. The ability of SLAB51 lysate to increase HIF-1α levels was also associated with the activation of the PI3K/AKT pathway and with the inhibition of NF-κB, nitric oxide synthase 2 (NOS2), and IL-1β increase elicited by LPS treatment. Our results suggest that the probiotic treatment, by stabilizing HIF-1α, can protect from an LPS-induced inflammatory response through a mechanism involving PI3K/AKT signaling.

Background: Breast cancer is the most diagnosed cancer among women, and its incidence and mortality are rapidly growing worldwide. In this regard, plant-derived natural compounds have been shown to be effective as chemotherapeutic and preventative agents. Apricot kernels are a rich source of nutrients including proteins, lipids, fibers, and phenolic compounds and contain the aromatic cyanogenic glycoside amygdalin that has been shown to exert a cytotoxic effect on cancer cells by affecting the cell cycle, inducing apoptosis, and regulating the immune function. Methods: Here, we describe a previously unexplored proapoptotic mechanism of action of amygdalin in breast cancer (MCF7) cells that involves the modulation of intracellular proteolysis. For comparative purposes, the same investigations were also conducted upon cell treatment with two apricot kernel aqueous extracts from Prunus armeniaca L. Results: We observed that both the 20S and 26S proteasome activities were downregulated in the MCF7 cells upon 24 h treatments. Simultaneously, the autophagy cascade resulted in being impaired due to cathepsin B and L inhibition that also contributed to a reduction in cancer cell migration. The inhibition of these proteolytic systems finally promoted the activation of apoptotic events in the MCF7 cells. Conclusion: Collectively, our data unveil a novel mechanism of the anticancer activity of amygdalin, prompting further investigations for potential application in cancer preventative strategies.

Beer is the most consumed alcoholic beverage worldwide. It is rich in nutrients, and with its microbial component it could play a role in gut microbiota modulation. Conflicting data are currently available regarding the consequences of alcohol and alcohol-containing beverages on dementia and age-associated disorders including Alzheimer’s disease (AD), a neurodegeneration characterized by protein aggregation, inflammatory processes and alterations of components of the gut–brain axis. The effects of an unfiltered and unpasteurized craft beer on AD molecular hallmarks, levels of gut hormones and composition of micro/mycobiota were dissected using 3xTg-AD mice. In addition, to better assess the role of yeasts, beer was enriched with the same Saccharomyces cerevisiae strain used for brewing. The treatment with the yeast-enriched beer ameliorated cognition and favored the reduction of Aβ(1-42) and pro-inflammatory molecules, also contributing to an increase in the concentration of anti-inflammatory cytokines. A significant improvement in the richness and presence of beneficial taxa in the gut bacterial population of the 3xTg-AD animals was observed. In addition, the fungal order, Sordariomycetes, associated with gut inflammatory conditions, noticeably decreased with beer treatments. These data demonstrate, for the first time, the beneficial effects of a yeast-enriched beer on AD signs, suggesting gut microbiota modulation as a mechanism of action.

Virtual screening techniques and in vitro binding/inhibitory assays were used to search within a set of more than 8,000 naturally occurring small ligands for candidate inhibitors of 8-hydroxy-5-deazaflavin:NADPH oxidoreductase (FNO) from Methanobrevibacter smithii , the enzyme that catalyses the bidirectional electron transfer between NADP + and F420H 2 during the intestinal production of CH 4 from CO 2 . In silico screening using molecular docking classified the ligand-enzyme complexes in the range between − 4.9 and − 10.5 kcal/mol. Molecular flexibility, the number of H-bond acceptors and donors, the extent of hydrophobic interactions, and the exposure to the solvent were the major discriminants in determining the affinity of the ligands for FNO. In vitro studies on a group of these ligands selected from the most populated/representative clusters provided quantitative kinetic, equilibrium, and structural information on ligands’ behaviour, in optimal agreement with the predictive computational results.

Alzheimer’s disease is a neurodegeneration with protein deposits, altered proteolysis, and inflammatory and oxidative processes as major hallmarks. Despite the continuous search for potential therapeutic treatments, no cure is available to date. The use of natural molecules as adjuvants in the treatment of Alzheimer’s disease is a very promising strategy. In this regard, ginsenosides from ginseng root show a variety of biological effects. Here, we dissected the role of ginsenosides Rg1 and Rg2 in modulating autophagy and oxidative stress in neuroblastoma cells overexpressing Aβ(1-42). Key hallmarks of these cellular processes were detected through immunomethods and fluorometric assays. Our findings indicate that ginsenosides are able to upregulate autophagy in neuronal cells as demonstrated by increased levels of LC3II and Beclin-1 proteins and decreased amounts of p62. Simultaneously, an activation of lysosomal hydrolases was observed. Furthermore, autophagy activation promoted the clearance of Aβ(1-42). Rg1 and Rg2 also reduced oxidative stress sources and macromolecule oxidation, promoting NRF2 nuclear translocation and the expression of antioxidant enzymes. Our data further clarify the mechanisms of action of Rg1 and Rg2, indicating new insights into their role in the management of disorders like Alzheimer’s disease.