The gut–brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.

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.

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.

BackgroundUlcerative colitis (UC) is characterized by persistent mucosal inflammation, epithelial-barrier injury, and disruption of intestinal microbial and metabolic homeostasis. Lemairamin (WGX50), a natural amide alkaloid from Sichuan pepper, has anti-inflammatory and redox-regulatory activity, but its pharmacology in mammalian colitis remains unclear.PurposeTo define the anti-colitic effects of WGX50 and the host signaling and multi-omics responses associated with its activity.MethodsLPS-stimulated RAW264.7 macrophages and NCM460 colonic epithelial cells were combined with a DSS-induced mouse colitis model. WGX50 (14, 28, or 56 mg/kg) was evaluated using disease indices, histology, barrier markers, cytokines, network pharmacology, molecular simulation, transcriptomics, Western blotting, shotgun metagenomics, and fecal metabolomics. AKT involvement was further examined by SC79-mediated pharmacological rescue in NCM460 cells.ResultsWGX50 attenuated inflammatory cytokines, COX-2, iNOS, and nitric oxide in RAW264.7 and NCM460 cells. In DSS-induced ulcetative colitis mouse model, WGX50 reduced disease activity and weight loss, preserved colon length and crypt architecture, restored goblet cells and ZO-1/occludin, and normalized cytokine profiles. Computational and transcriptomic analyses prioritized AKT1-related inflammatory signaling. WGX50 subsequently reduced colonic p-AKT1/AKT1, p-p65/p65, and p-IκBα/IκBα. Meanwhile, AKT activator SC79 partially restored AKT1 and p65 phosphorylation and attenuated the inhibitory effects of WGX50 on IL-6 and TNF-α. Metagenomics and metabolomics demonstrated concomitant remodeling of species-level microbial composition and tryptophan-, bile-acid-, sphingolipid-, purine-, and energy-related metabolism.ConclusionWGX50 alleviates DSS-induced colitis through suppression of AKT1/NF-κB-driven inflammation, reinforcement of the mucosal barrier, and coordinated recovery of the colonic transcriptional and gut microbiota–metabolome landscape.