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We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Cross-sectional analyses revealed nominal associations between inflammatory markers and cognitive performance, with plasma IL-6 and IP-10 at baseline, and CSF TNFα at week 24 showing the strongest correlations (p < 0.05, uncorrected); however, none survived correction for multiple comparisons. Conversely, higher CSF Aβ42 and plasma BDNF were positively associated with memory and executive function. Longitudinally, biomarker changes did not significantly predict change in global cognition (ΔNPZ-8); the strongest trend (p-Tau217, ρ = -0.12, p = 0.38) was not statistically significant, and multivariate models failed to identify robust predictors (R These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts. Show less

Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Show less

This review aims to elucidate the molecular mechanisms underlying the neuroprotective effects of acupuncture in preclinical models of Parkinson's disease (PD). In PD animal models, acupuncture inhibits oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) and lipid peroxidation. It regulates autophagy either independently of mammalian target of rapamycin (mTOR) or via mTOR activation, promoting alpha-synuclein (α-synuclein) clearance. Acupuncture also suppresses apoptosis (modulating Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2)) and pyroptosis (inhibiting NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD)). It enhances neurogenesis through brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and glial cell line-derived neurotrophic factor (GDNF) signaling, promoting neural stem cell proliferation and differentiation. Furthermore, acupuncture reduces neuroinflammation by decreasing microglial activation, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It also modulates gut microbiota composition (e.g., increasing butyrate-producing bacteria like Butyricimonas and reducing pro-inflammatory Erysipelotrichaceae and Bacteroides) and influences lipid metabolism, thereby mitigating dopaminergic neuron loss and motor deficits. Preclinical evidence demonstrates that acupuncture exerts multi-target neuroprotective effects against PD through pathways involving oxidative stress, autophagy, apoptosis/pyroptosis, neurogenesis, neuroinflammation, and gut microbiota-lipid metabolism crosstalk. However, limitations include a focus on preventive rather than reversal effects, lack of long-term efficacy data, and heterogeneity in acupoint selection. Further mechanistic and standardization studies are warranted. Show less

Stress plays a pivotal role in anxiety-like disorders and cognitive decline. The present study investigated the potential effects of prior royal jelly supplementation and environmental enrichment against stress-induced anxiety-like behaviors, serum corticosterone, hippocampal brain-derived neurotrophic factor (BDNF) levels, and cognitive performance deficits in stressed rats. Male Wistar rats were randomly devised into 8 experimental groups. Rats were subjected to royal jelly (200 mg/kg) via oral gavage, standard environmental enrichment, or combination all for 14 days and control rats received saline in the same period of time. Stress induction was done on the 7th day of treatments by exposure to the restrainer under 10°C. Then open field, elevated plus maze, and inhibitory passive avoidance memory tests were used to explore emotional-cognitive behaviour. Also, corticosterone levels, and hippocampal BDNF expression were measured. Stress resulted in an increase in the serum corticosterone levels, anxiety-like behaviors, and decreased hippocampal BDNF expression which reversed by environmental enrichment and royal jelly treatments. Remarkably, the combined treatment exerts a more pronounced effect on the aforementioned outcomes. Our study strongly proposes a novel emerging therapeutic approach through nutritional interventions, emphasizing the potential of these treatments to mitigate stress-induced anxiety and memory impairments prior to stress exposure. Show less

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Show less

This comprehensive review examines the synergistic effects of physical exercise and polyphenolic compounds, such as flavonoids, curcumin, and resveratrol, on spatial learning and memory. The interplay between these interventions highlights their potential to enhance cognitive function by promoting neurogenesis, synaptic plasticity, and resilience against oxidative stress and inflammation. Mechanistic insights reveal that exercise and polyphenols activate complementary neuroprotective pathways, including the upregulation of BDNF and CREB, as well as the modulation of antioxidant defenses via Nrf2. Evidence from both animal and human studies demonstrates significant improvements in spatial memory and hippocampal function when these strategies are combined. Despite promising findings, challenges related to bioavailability, dosing, and long-term efficacy remain, underscoring the need for further investigation. This review emphasizes the potential clinical applications of these combined approaches for preventing cognitive decline and promoting brain health during aging and in neurodegenerative conditions. Show less

Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely symptomatic, with limited efficacy and significant side effects. Microglia act as pivotal mediators of DNP through RAGE/TLR4/NLRP3-driven IL-1β and BDNF release that amplifies spinal pain signaling. Microglia respond directly to hyperglycemia-induced cues such as advanced glycation end-products, reactive oxygen species, ATP, and pro-inflammatory signals, becoming activated and releasing cytokines, chemokines, and neuromodulators including BDNF that amplify spinal pain signaling. This review synthesizes recent insights into the molecular triggers of microglial activation such as RAGE, TLRs, purinergic receptors, and inflammasomes and the downstream intracellular pathways including NF-κB, MAPK, PI3K/Akt, and BDNF-TrkB that drive neuroinflammation. We further examine neuroimmune crosstalk, including bidirectional microglia-neuron and microglia-astrocyte signaling, which sustains central sensitization. Translational studies linking these pathways to human DNP are evaluated, along with novel technologies that illuminate microglial phenotypes. Emerging therapeutic strategies focus on inhibition of these pathways, including RAGE antagonists and purinergic receptor blockers. However, a critical translational gap persists owing to insufficient human validation of microglial biomarkers and the limited fidelity of current animal models. By integrating basic and clinical findings, we underscore the promise of microglia-focused interventions to complement traditional analgesics and ultimately improve outcomes in DNP patients. Show less

To compare two 16-week high-load, velocity-intentional resistance training programs-elastic bands (HL-VIRT-EB) vs. water-based (HL-VIRT-AQ)-combined with creatine or placebo supplementation on neuroplasticity, oxidative stress, inflammation, strength, physical function, cognition, and quality of life in older adults. In a randomized controlled trial, 103 community-dwelling older adults (57 women, 46 men; 68.2 ± 4.6 y) were assigned to HL-VIRT-EB + Creatine, HL-VIRT-EB + Placebo, HL-VIRT-AQ + Creatine, HL-VIRT-AQ + Placebo, Control+Creatine, or Control+Placebo. Training was performed 3×/week (60 min). Creatine was consumed daily (3 g). Outcomes included brain-derived neurotrophic factor, F2-isoprostanes (F2-iso), glutathione peroxidase (GPx), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), isokinetic strength (knee/elbow, 60°·s Both training modalities produced significant improvements in neurocognitive biomarkers, oxidative/inflammatory profiles, strength, functional performance and quality of life (p < 0.05). HL-VIRT-AQ yielded greater reductions in F2-iso and TNF-α and larger gains in functional tests compared to HL-VIRT-EB (d = 0.12-1.18), which elicited superior upper-limb strength gains. Creatine provided additional benefits, increasing GPx, reducing IL-6/TNF-α and improving strength and function when combined with exercise modalities. Creatine alone reduced F2-iso and TNF-α and improved perceived health versus placebo. High-load, velocity-intentional resistance training-on land or in water-effectively improves neurocognition, oxidative balance, inflammation, strength, function, and quality of life in older adults. Aquatic training is particularly effective for attenuating oxidative stress and inflammation. Creatine supplementation confers complementary, modality-specific benefits and supports their use in combination to high-speed resistance exercise to promote healthy aging. NCT06620666 (ClinicalTrials.gov). Show less

Glyphosate (GLY) is a widely used herbicide, particularly in agriculture, and its residues in plants and soil can induce toxic effects in various organisms, including humans, with the brain being especially vulnerable. Eugenol (EU), a natural antioxidant found in cloves, has demonstrated protective effects against different toxic substances. This experimental study explored whether eugenol could mitigate neurological damage triggered by glyphosate exposure in rats. A total of forty male Sprague-Dawley rats were allocated into five experimental groups consisting of control, eugenol (100 mg/kg), glyphosate (150 mg/kg), EU50 combined with glyphosate (50 mg/kg + 150 mg/kg), and EU100 combined with glyphosate (100 mg/kg + 150 mg/kg). Animals received the respective treatments by oral gavage for a period of seven days. Motor and anxiety-related behaviors were evaluated using behaviour tests, after which brain tissues were processed for histopathological analysis. Biochemical analyses included ELISA assessment of oxidative stress markers (MDA, SOD1, GSH, and GPx1), RT-PCR analysis of endoplasmic reticulum (ER) stress- and apoptosis-related genes (GRP78, ATF4, CHOP, PI3K/AKT/mTOR, BAX, and Bcl-2), Western blot evaluation of inflammatory and antioxidant signaling pathways (TLR4/NF-κB and Nrf2/HO-1/SIRT1), and immunohistochemical and immunofluorescence analyses of neuroplasticity, circadian rhythm, and autophagy markers (BDNF, BMAL1, CLOCK, Beclin-1, and LC3A/B). GLY exposure significantly increased lipid peroxidation (MDA), ER stress markers (GRP78 and CHOP), pro-inflammatory mediators (TLR4, NF-κB, TNF-α, and IL-1β), apoptotic signaling (BAX and caspase-3), and autophagy-related proteins, while suppressing antioxidant pathway components. Glyphosate exposure induced behavioral impairments accompanied by increased oxidative stress, inflammatory activation, endoplasmic reticulum stress, apoptosis, and dysregulated autophagy in cerebral cortex tissue. EU treatment dose-dependently attenuated these molecular and histopathological alterations, restored antioxidant and cellular stress responses, and significantly improved behavioral performance, indicating a protective role against GLY-induced neurotoxicity. Overall, EU may represent a promising therapeutic candidate for mitigating herbicide-induced brain injury. Show less

Paclitaxel (PTX) is a potent taxane widely used in the treatment of solid tumors and can cause dose-limiting peripheral neuropathy. This study evaluated the therapeutic potential of selenium in a paclitaxel-induced peripheral neuropathy model. A total of 30 male Sprague-Dawley rats were divided into five groups (n=6): Control, SE1, PTX, PTX+SE0.5, and PTX+SE1. PTX (2mg/kg, i.p., days 1-5) was administered followed by SE (0.5 or 1mg/kg, i.g., days 6-15); sciatic nerve tissues were analyzed on day 16. In addition to molecular and histopathological analyses, behavioral assessments were performed to evaluate mechanical nociception, locomotor activity, and anxiety-like behavior. PTX significantly reduced mechanical pain threshold, impaired locomotor performance, and decreased exploratory behavior. At the molecular level, PTX increased oxidative stress by elevating MDA levels while decreasing SOD and GSH; it also increased TNF-α, IL-1β, and IL-6, and reduced IL-10 levels. Histopathologically, marked axonal degeneration and demyelination, along with reduced myelin fiber area, were observed. SE treatment, particularly at 1mg/kg, restored mechanical pain threshold, improved locomotor parameters, and attenuated anxiety-like behavior. SE also brought oxidative stress markers closer to control levels, suppressed pro-inflammatory cytokines, increased IL-10, reduced histopathological damage, and improved myelin integrity. Immunostaining revealed that SE attenuated PTX-induced increases in BAX, caspase-3, and 8-OHdG, while partially reversing the decrease in Bcl-2. In qPCR analyses, PTX decreased BDNF and increased GFAP expression, which were normalized by SE. SE suppressed the PTX-induced increase in Keap-1 and enhanced Nrf-2 expression. In addition, SE treatment partially restored HO-1 expression, with statistically significant increases observed compared to the PTX group, although levels did not fully return to control values. Show less

Heart failure (HF) is a complex systemic syndrome with major neuropsychiatric consequences. Cognitive impairment (e.g., dementia) and depression are common among HF patients, worsening prognosis, increasing hospital admissions, and impairing quality of life. Despite their prevalence, the neurobiological basis of these comorbidities is not yet fully understood. This review uniquely discusses converging neuroendocrine, inflammatory, and neuroplastic mechanisms linking HF, depression, and dementia inside an integrative heart-brain axis highlighting brain-derived neurotrophic factor (BDNF) as an important modulator of synaptic plasticity, neurogenesis, and stress resilience. Understanding the interactions between HF-induced hypothalamic-pituitary-adrenal axis activation, systemic inflammation, and impaired BDNF signaling may contribute to the development of novel multimodal therapeutic strategies targeting neurotrophic pathways and improving cognitive and mental health outcomes in HF. Show less

This study aimed to elucidate the sedative-hypnotic effects of a stem-derived bioactive fraction from Syringa oblata Lindl. (ZDX) and to reveal its underlying mechanisms, thereby providing a theoretical and practical basis for the development of new sleep aid drugs. ZDX was prepared by optimizing the extraction and purification procedures. Using UPLC-Q-TOF-MS, the prototype compounds absorbed into the brain of insomnia mice were analyzed, and 15 bioactive compounds were identified or predicted, including Dihydrocubebin, (-)-Cubebin, Isoguamarol, and others. Its efficacy and mechanisms were investigated using network pharmacology, transcriptomics, metabolomics, and molecular docking, complemented by in vivo pharmacodynamic and molecular analyses. In an insomnia mouse model, ZDX significantly increased body weight, reduced sleep latency, and prolonged total sleep duration, while alleviating anxiety and depression-like behaviors and improving histopathological damage in the hippocampus and hypothalamus, showing significant sedative-hypnotic effects. Mechanistically, ZDX modulated key genes and proteins involved in the cAMP signaling pathway, enhanced superoxide dismutase activity, reduced malondialdehyde levels, decreased inflammatory cytokines (IL-6, IL-1β, and TNF-α), and restored neurotransmitter homeostasis in the brain. Collectively, ZDX exerts sedative-hypnotic effects, at least in part, by activating the cAMP/PKA-CREB-BDNF axis and coordinately regulating neurotransmission, oxidative stress, and inflammation. Show less

Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effects of fermented red quinoa (FRQ) in an alcohol-exposed mouse model, with a focus on cognitive function. Male C57BL/6J mice were randomized into three groups for a 28-day study: a normal control, an alcohol-treated group gavaged with ethanol (1 mL/100 g·BW), and a group receiving the same ethanol dose co-administered with FRQ powder (human equivalent dose: 9 g/60 kg·BW). Our results demonstrated that fermentation with Lactobacillus kisonensis significantly increased the content of phenolic compounds (e.g., quercetin and veratric acid) in FRQ. FRQ intervention improved cognitive function, ameliorated synaptic structural impairment and blood-brain barrier disruption, and attenuated hepatic steatosis. The protective mechanisms involved three pathways: 1) The specific phenolic compounds in FRQ promoted alcohol metabolism by regulating ADH/ALDH activity, leading to reduced acetaldehyde levels. As a primary initiating pathway, this metabolic enhancement dominantly attenuated subsequent oxidative stress and inflammation, mitigating injury in the liver, brain, and colon. 2) It directly modulated AP-1 subunits (ΔFOSB/JUND), restored BDNF, and rebalanced the glutamate/GABA systems. 3) It regulated the gut-liver-brain axis by remodeling the gut microbiota (e.g., enriching butyrate-producing Butyricicoccus), reinforcing intestinal barrier integrity, and thereby suppressing systemic LPS translocation and inflammation. In conclusion, FRQ mitigates alcohol-induced cognitive and hepatic damage via multiple mechanisms, highlighting its promise as an integrative dietary intervention. Show less

Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-drugs that linked two active molecules into a single compound and released the drugs after administration, which offering improved efficacy and tolerability than individual drug mixtures or monotherapy. In this work, five new co-drugs ODV-NSAIDs were synthesized from O-desmethylvenlafaxine (ODV) with non-steroidal anti-inflammatory drugs (NSAIDs) to achieve synergistic antidepression and anxiolytic effects. In vitro stability studies exhibited that these co-drugs can be metabolized into two single drugs within 60 min in simulated intestinal fluid. In both acute and chronic LPS-induced models, co-drug ODV-NAP significantly ameliorated depressive-like behaviors, evidenced by increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swim test (FST), and enhanced locomotion in the open field test (OFT). Furthermore, ODV-NAP decreased brain levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and malondialdehyde (MDA), while elevating serotonin (5-HT), norepinephrine (NE), and superoxide dismutase (SOD) activity. Nissl staining confirmed ODV-NAP significantly attenuated hippocampal neuronal damage. Moreover, western blotting revealed ODV-NAP inhibited the TLR4/NF-κB signaling pathway and upregulated BDNF and p-TrkB protein expression. ODV-NAP also inhibited LPS-induced p65 nuclear translocation in BV-2 microglia in vitro, and caused no toxicity in histology. Thus, co-drug ODV-NAP represented a promising novel candidate for treating depression and anxiety. Show less

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS. Show less

Yoga is increasingly incorporated into clinical practice for managing a wide range of mental and physical health conditions, especially those related to stress, and has shown beneficial effects on inflammatory processes and neuroendocrine regulation. Its influence on cytokines such as interleukin-6 and tumor necrosis factor-α, as well as its modulatory action on the hypothalamic pituitary adrenal axis, suggests a potential role in reducing systemic inflammation and improving stress resilience. Despite these promising indications, there is limited scientific evidence from India evaluating yoga's impact on biological markers of stress and inflammation. The present study was undertaken to assess the effects of a structured yoga program on selected biomarkers in 60 adult volunteers who underwent evaluations before and after 3 months of practice. The intervention consisted of a daily 1-h yoga session conducted 6 days a week and included postures, breathing practices, and relaxation techniques. Assessments focused on brain-derived neurotrophic factor, interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein, cortisol, and perceived stress levels. Findings indicated an increase in brain-derived neurotrophic factor and reductions in inflammatory markers, cortisol, and perceived stress. These outcomes suggest that regular yoga practice can positively influence neurotrophic activity, reduce inflammation, and lower stress, supporting its value as a complementary approach to improving overall health and well-being. Show less

Mental illness conditions and neurodegenerative diseases are an emerging worldwide burden, with depression affecting over 300 million people and dementia cases projected to triple by 2050. Oxidative stress and inflammation are central mechanisms for neuronal injury and cognitive impairment. This review discusses the neurotherapeutic promise of egg-derived antioxidants. Importantly, yolk in polypeptide complex (isolated from egg yolk with immunoglobulin Y) enhances cognitive function by upregulating brain-derived neurotrophic factor via cAMP/PKA and PI3K/Akt signaling. We discuss their molecular modes of action such as reactive oxygen species scavenging, regulation of inflammatory cytokines, maintenance of mitochondrial function, and promotion of neurogenesis and synaptic plasticity. Further, bioavailability, allergenicity, and targeted delivery issues across the blood-brain barrier are addressed in light of progress in nanocarrier systems and encapsulation methods. Comparative observations with other diet-based antioxidants like curcumin, polyphenols, and omega-3 fatty acids are presented to put egg-derived compounds into perspective within the overall nutraceutical regime. Lastly, future directions highlight the importance of targeted clinical trials, regulatory factors, and inclusion in public health initiatives designed to prevent cognitive degeneration and mental illness through accessible nutritional interventions. This review highlights the promising potential of antioxidants derived from eggs as adjunctive neuroprotective therapy and indicates the need for interdisciplinary investigations to extend these findings into the clinic. © 2026 Society of Chemical Industry. Show less

Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca Show less

This study aims to investigate the radioprotective effects of melatonin (MEL) against oxidative damage that may be caused by flattening filter (FF) and flattening filter-free (FFF) beam in the cerebrum and cerebellum of rat using various genetic markers. Forty female Wistar albino rats were randomly assigned to five groups. The control group received no intervention. The FF group received a single 16 Gy fraction at 600 MU/min. The FF+MEL group received the same FF protocol, preceded by melatonin (50 mg/kg, intraperitoneal) administered 15 min before irradiation. The FFF group received a single dose of 16 Gy at 2,400 MU/min. The FFF+MEL group received the same FFF protocol with melatonin administered as above. After treatment, cerebrum and cerebellum tissues were harvested, and mRNA expression levels of BDNF, CREB, BAX, BCL2 and IL6 were measured. Both FF and FFF radiotherapy treatments significantly increased BDNF, CREB, IL6, and BAX gene expression in cerebrum and cerebellum tissues, while decreasing BCL2 levels (P < 0.05). Melatonin treatment increased BDNF and CREB expression, significantly attenuated radiation-induced increases in IL6 and BAX, and partially reversed the decrease in BCL2 (P < 0.05). The increase in the BAX/BCL2 ratio after radiotherapy was significantly attenuated by melatonin treatment. Overall, FFF irradiation induced a stronger oxidative, inflammatory, and pro-apoptotic response than FF, whereas melatonin exhibited potent neuroprotective and anti-apoptotic effects. In conclusion, MEL demonstrates potential as a protective agent for healthy tissues during irradiations, owing to its antiapoptotic, anti-inflammatory, and neurotrophic properties. Show less

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

BackgroundCognitive decline represents a major challenge in aging populations. Probiotics have been proposed to influence cognitive function through gut-brain interactions, but clinical findings remain inconsistent.ObjectiveThis study evaluated the effects of probiotic supplementation on cognitive function as the primary outcome, and on BDNF levels, inflammatory markers, and oxidative stress biomarkers as secondary outcomes in adults aged 50 years and older.MethodsA systematic search of PubMed, EBSCO, ProQuest, and Google Scholar was conducted through 1 May 2024 using predefined search terms related to probiotics, cognitive function, BDNF, inflammation, and antioxidant activity. Study quality was assessed using the RoB 2 tool. Meta-analyses were performed using random-effects models, and publication bias was explored using Egger's test where study counts permitted.ResultsSixteen studies demonstrated significant improvement in cognitive function among participants receiving probiotics compared to placebo. Cognitive function, measured using the Mini-Mental State Examination (MMSE), yielded a standardized mean difference (SMD) of 0.747 (95% CI 0.307-1.186) which corresponds to moderate-to-large effects. In comparison, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) showed significant results with an SMD of 0.340 (95% CI 0.032-1.366) which corresponds to small-to-moderate effects. Probiotics also led to significant changes in several biochemical parameters, including BDNF, TNF-α, 8-OHdG, IL-6, IL-10, MDA, TAC, and GSH. Multi-strain probiotics showed better results compared to single-strain.ConclusionsProbiotic supplementation may offer modest cognitive benefits in aging populations, particularly in studies enrolling cognitively impaired individuals, but substantial heterogeneity and limited biomarker evidence restrict the certainty of these findings. Larger, longer-duration, and standardized trials are needed to clarify the clinical relevance and potential biological pathways underlying probiotic effects on cognition. Show less

The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR. This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway. In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro. SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression. SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment. Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1 mg/kg/day) starting from 5 weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration. Show less

Type 2 diabetes has been linked to oxidative stress, inflammation, and an imbalance in the gut microbiota, all of which contribute to neuroinflammation and cognitive decline. Gut microbiota influence inflammation and produce various substances, including butyrate, a short-chain fatty acid that promotes brain-derived neurotrophic factor (BDNF), which is essential for memory. This study investigated whether prebiotics, probiotics, or a combination of both (symbiotics) could improve memory in diabetic rats. Male Wistar rats were divided into five groups: control; diabetic and obese (induced by a high-fat diet and streptozotocin); diabetic and obese with prebiotics (inulin); diabetic and obese with probiotics (Lactobacillus acidophilus); and diabetic and obese with symbiotics (inulin + L. acidophilus). Treatments lasted 42 d. Memory performance was evaluated using the Morris water maze (spatial memory) and the Eight-arm radial maze (working memory). After testing, hippocampal tissue was analyzed for inflammatory markers (TNF-α, IL-10), BDNF, and butyric acid. Diabetes impaired memory and increased neuroinflammatory markers. All supplemented groups showed improved memory. The symbiotic group exhibited the most pronounced benefits, with higher levels of BDNF, IL-10, and butyric acid, and reduced TNF-α. Electrophysiological recordings revealed that diabetes reduced the firing frequency of CA1 pyramidal cells and decreased the synaptic strength in the hippocampus. Symbiotic supplementation preserved these neuronal and synaptic functions. Symbiotic treatment effectively countered diabetes-induced cognitive deficits by reducing neuroinflammation, increasing neurotrophic support, and maintaining synaptic plasticity. These results imply that altering the gut microbiota through symbiotic supplementation may be an effective approach to prevent or mitigate diabetes-associated cognitive decline. Show less

To evaluate the relationship between the levels of interleukin (IL)-6 (a marker of inflammation), cortisol (a marker of the hypothalamic-pituitary-adrenal axis functioning), and brain-derived neurotrophic factor (BDNF, a key neurotrophic factor) in acute and long-term (after 1 month) periods of traumatic brain injury (TBI) with trauma characteristics, as well as neurological and mental disorders. Analysis of data from a cohort longitudinal prospective study. Changes over time in IL-6, cortisol, and BDNF levels during the 1 month after injury were described: IL-6 and cortisol decreased, while BDNF increased, reflecting mechanisms of primary injury and secondary recovery processes. In the acute period, levels of IL-6, cortisol, and BDNF correlated with the severity of the patient's condition: low BDNF and high IL-6 and cortisol levels were associated with a more severe injury, as assessed by the Glasgow Coma Scale. An association between these markers and the presence of amnesia and abnormal EEG changes in the acute period of TBI was found. IL-6, cortisol, and BDNF are important pathophysiological markers of TBI associated with both immediate features of TBI and its complications. Show less

The present study investigated the effect of perinatal programming combined with exposure to a western diet on gene expression related to inflammation, neurodegeneration, and synaptic plasticity in the hippocampus of adult rats. Male rats from mothers fed either a standard diet or a western diet during gestation and lactation were used. All pups received only the standard chow diet from the 25th postnatal day (PND), and their body weight was analysed. Rats from the two groups fed the maternal diet were then divided on the 195 Adult rats submitted to a western diet during pregnancy and lactation showed signs of metabolic programming. In addition, glucose and total protein were found to have increased in the serum. The effect of acute exposure to a western diet is increased cholesterol. The western diet decreased gene expression of inflammatory factors ( Acute exposure to a western diet in adulthood alters pre-translational pathways ( Show less