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Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavonoid with neuroprotective and vascular benefits, has limited bioavailability due to poor water solubility. Although enzymatic glycosylation improves its solubility, it contains multiple compounds with differing numbers of sugar units and is not a single compound. To address this, EubioQuercetin®, a novel water-soluble rutin (wsRutin) formulation, was developed using L-arginine and ascorbic acid, without enzymatic processing. Here, we evaluated the neuroprotective effects of quercetin and isorhamnetin, the major metabolites of rutin, and compared the cognitive effects of rutin suspension and wsRutin solution in mice. Quercetin and isorhamnetin suppressed glutamate-, menadione- and H Show less

Brain aging is a multifactorial process associated with oxidative stress, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to cognitive decline and increased susceptibility to neurodegenerative disorders. Epigallocatechin gallate (EGCG) is a potent antioxidant and anti-inflammatory agent, but its therapeutic potential is limited by poor stability and bioavailability. In this study, a dual nano delivery system was developed by loading chitosan-EGCG nanoparticles into mesenchymal stem cell-derived exosomes (Ex-Chit-EGCG NPs) and evaluated for neuroprotective efficacy in a D-galactose-induced brain aging model. Intranasal administration of Ex-Chit-EGCG NPs significantly improved cognitive and locomotor performance compared with exosomes alone, as evidenced by enhanced outcomes in Y-maze and open field tests. Biochemical analyses revealed that Ex-Chit-EGCG NPs effectively reduced lipid peroxidation, restored glutathione levels, and reactivated the LKB1/AMPK/SIRT1 signaling pathway. Molecular investigations demonstrated upregulation of Nrf2, BDNF, and SIRT1 together with suppression of NF-κB and Iba-1 expression, indicating attenuation of oxidative and inflammatory responses. Histopathological and immunohistochemical evaluations confirmed these findings, showing preservation of cortical and brain stem architecture with marked reductions in neuronal necrosis, gliosis, BAX, GFAP, and NLRP3 expression. Collectively, the results demonstrate that Ex-Chit-EGCG NPs exert superior neuroprotective effects compared with exosomes alone, highlighting the therapeutic advantage of combining EGCG with chitosan nanocarriers and exosomal delivery. This dual nanotherapeutic strategy offers a promising and non-invasive approach for mitigating brain aging and holds potential for translation into therapies targeting age-related neurodegenerative disorders. Show less

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4-1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM-SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (-62%) and Bacteroidaceae (-77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (-77% SNAC, -75% SEM-SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery. Show less

Docosahexaenoic acid (DHA) is indispensable for neurological health, yet its therapeutic potential is hampered by poor bioavailability and non-specific brain distribution. We hypothesized that co-administering DHA with specific molecular carriers - eicosapentaenoic acid (EPA) or phosphatidylserine (PS) - would exploit distinct cellular transport pathways to achieve region-specific brain enrichment and associated neuroprotection. By dietary intervention using C57BL/6J mice, we employed regional lipidomics, ELISA, and western blotting to assess brain fatty acid incorporation, neurotrophic factor levels, inflammatory signaling, and transporter expression following supplementation with DHA alone or in combination with EPA or PS. Lipidomic analyses revealed striking, carrier-dependent spatial modulation of DHA. Co-administration with EPA enriched the cortex and striatum, while PS co-administration preferentially targeted the hippocampus and cortex. Mechanistically, both carrier-DHA complexes enhanced the expression of the key blood-brain barrier (BBB) transporter MFSD2A. Functionally, this precision delivery activated distinct neuroprotective programs. PS + DHA robustly upregulated the CREB-BDNF neurotrophic pathway, while EPA + DHA uniquely suppressed the NF-κB pathway, demonstrating potent anti-inflammatory effects. These results demonstrate that the choice of molecular carrier dictates both the spatial distribution of DHA and the nature of the ensuing neuroprotective response. Our findings establish that dietary co-supplementation with specific lipid carriers enables precise spatial delivery of DHA by engaging specific transporters, thereby activating distinct neuroprotective programs in a region-specific manner. This work provides a mechanistic framework for a precision nutrition strategy, tailoring DHA formulations to target specific neuroanatomical and cellular vulnerabilities in neurological disorders. Show less

Ginsenoside Rd, a protopanaxadiol abundant in Panax ginseng and Panax notoginseng, possesses well-documented neuroprotective properties but suffers from low bioavailability. Here, we engineered nanoparticles from zein, chitosan-α-lipoic acid copolymer, and sodium alginate for the delivery of ginsenoside Rd (Rd) and evaluated their efficacy in alleviating scopolamine-induced memory impairment in a mouse model. The results demonstrated that the nanoparticles successfully encapsulated Rd, with an encapsulation efficiency of approximately 73.23 %, and exhibited a hollow spherical morphology. Additionally, the carrier exhibited exceptional stability under varying temperature and salt ion conditions, along with the ability to be readily redispersed. The incorporation of Rd into nanoparticles significantly improved its antioxidant efficacy, as well as its stability and sustained release profile in the gastrointestinal environment. In vivo experiments demonstrated that Rd-loaded nanoparticles significantly improved scopolamine-induced memory deficits, oxidative stress, cholinergic system dysfunction, and neuronal damage in the hippocampal region of mice, outperforming the effects of ginsenoside Rd alone. Western blot results indicated that Rd-loaded nanoparticles improved memory-impaired mice by upregulating p-CaMKII, p-CREB, and BDNF protein expression through modulating the long-term potentiation pathway. We further found that Rd-loaded nanoparticles treatment increased the richness and diversity of gut microbiota. This study provides a promising strategy for the effective treatment of improving learning memory. Show less