Metabolic stress and neuroinflammation are associated with depression, but the mechanisms connecting peripheral metabolic dysfunction to reward-related circuit alterations remain incompletely understood. ATP-sensitive potassium (KATP) channels couple cellular energy state to neuronal excitability and may link metabolic and neuroimmune signaling. Here, we used female mice exposed to post-weaning isolation combined with a high-fat diet to model convergent psychosocial and metabolic stress. We tested whether KATP channel modulation is associated with behavioral, inflammatory, and dopaminergic-marker changes under this combined stress condition. Peripheral KATP channel modulation was achieved by interscapular brown adipose tissue infusion of glibenclamide, and dopaminergic neuron-specific Kir6.2 conditional knockout mice were used to assess the contribution of neuronal KATP channel signaling. Combined stress induced obesity, hyperglycemia, depression-like behavioral alterations, peripheral cytokine imbalance, increased inflammatory markers, and reduced dopaminergic activity markers in the mesolimbic pathway. Glibenclamide improved glucose tolerance, attenuated stress-associated behavioral and inflammatory-marker changes, and increased Fos expression under stress conditions, while enhancing SUR1 maturation and surface localization. Kir6.2 deletion attenuated stress-associated behavioral alterations and reduced nucleus accumbens Iba1-positive cell accumulation, whereas effects on ventral tegmental area tyrosine hydroxylase-positive cell density were more modest. Together, these findings support KATP channel functional state as a candidate link between metabolic stress, neuroimmune alterations, and dopaminergic circuit adaptations in female mice, and suggest KATP channel modulation as a potential therapeutic strategy for metabolic-associated depression.

Depression frequently co-occurs with metabolic disorders, yet the mechanisms linking metabolic dysfunction to depression remain incompletely understood. Using a chronic high-fat diet (HFD) feeding mouse model of metabolic disorder-related depression, we previously demonstrated that downregulation of astrocytic glutamate transporters in the ventral hippocampus drives depression-like behaviors through hyperactivation of ventral hippocampal glutamatergic projections to the nucleus accumbens. Although pharmacological restoration of these transporters rescued depression-like phenotypes, systemic glutamatergic modulation was associated with substantial mortality in chow-fed controls, highlighting the need for safer non-pharmacological strategies. Here, we showed that, compared with mice maintained on HFD for 12 weeks, switching from HFD to normal chow at week 9 ameliorated most metabolic abnormalities and anhedonia but failed to restore insulin sensitivity or alleviate behavioral despair. In contrast, initiation of mild-intensity treadmill running exercise at week 9 prevented further weight gain without improving metabolic dysfunction or depression-like behaviors. Neither intervention restored ventral hippocampal glutamate transporter expression, astrocytic structural integrity, nor hyperactivity within the ventral hippocampus-nucleus accumbens circuit. Notably, behavioral despair was strongly associated with systemic insulin resistance, but not overweight or corticosterone levels, implicating impaired insulin signaling as a key pathogenic factor and potential biomarker of this depression subtype. In parallel, we identified a distinct gut microbiota signature associated with HFD-induced depressive behaviors and astrocytic dysfunction. Together, these findings suggest that HFD-induced depression is driven by insulin resistance-linked astrocytic and circuit-level pathology and identify metabolic and microbial biomarkers with translational relevance for metabolic disorder-related depression.

BACKGROUND:Brain metastases are a major clinical challenge with poor prognosis, particularly in patients with a history of smoking. While neurons are abundant in the brain and capable of synaptic interaction with tumor cells, their role in brain metastasis remains poorly understood. Emerging evidence suggests that neuronal activity may contribute to metastatic progression, yet the mechanisms by which smoking alters the brain microenvironment to promote tumor growth are unclear. METHODS:We examined the impact of nicotine exposure on microglia-neuron-tumor interactions in brain metastasis models using in vivo and ex vivo approaches. We analyzed patient-derived brain metastatic tissues, performed molecular and metabolic profiling, and utilized pharmacologic inhibition strategies to dissect the underlying mechanisms of tumor-neuron communication. RESULTS:Our findings reveal a significant association between smoking history and perineural invasion in brain metastases. Nicotine exposure stimulates microglia to release exosomal miR-32-3p, which activates GABAergic neurons and enhances GABA release. GABA acts as a metabolic substrate in the tumor microenvironment, fueling tumor growth through the GABA shunt pathway. Pharmacological inhibition of GABA uptake with FDA-approved GABA transporter (GAT) inhibitors Tiagabine and NO-711 significantly suppress brain metastatic progression in vivo. CONCLUSIONS:This study identifies a novel GABAergic neuron-microglia-tumor signaling axis by which smoking promotes brain metastasis via GABAergic metabolic reprogramming. Targeting GABA uptake on tumor cells using repurposed anticonvulsant drugs offers a promising therapeutic strategy, particularly for patients with smoking-associated brain metastases.

Alzheimer’s disease (AD) progression is closely linked to the accumulation of amyloid- (A ), with impaired clearance mechanisms playing a key role. The meningeal lymphatic (mLym) system, which drains cerebrospinal fluid (CSF) and waste from the brain to peripheral lymph nodes, has emerged as a critical pathway for A removal. While physical exercise is known to improve cognitive function and reduce AD risk, its effect on the mLym system and downstream AD pathology have not been fully elucidated. Three-month-old 5xFAD mice underwent a 3-month wheel-running exercise regimen. The function of the mLym system was assessed before and after exercise using high-frequency ultrasound imaging with nanoparticle tracers to monitor CSF drainage to deep cervical lymph nodes. The study evaluated changes in mLym vessel structure, A deposition, and cognitive performance. Additionally, the effects of serum and extracellular vesicles (EVs) from exercised rats on the expression of lymphatic vessel-related genes (LYVE-1, VEGFR3, and VEGF-C) were examined in lymphatic endothelial and microglial cell lines. Compared to 3-month-old 5xFAD mice and age-matched wild-type controls, 6-month-old 5xFAD mice displayed progressive decline in mLym function, reduced vessel integrity, and increased amyloid plaque burden, accompanied by impaired learning and memory. These changes were associated with decreased expression of LYVE-1 and VEGFR3 in the meninges and VEGF-C in the brain. Exercise intervention reversed these deficits, restoring mLym function and vessel structure, enhancing A clearance, and improving cognitive performance. Surgical ligation of mLym vessels accelerated amyloid accumulation and removed the exercise-induced benefits, underscoring the system’s importance in A removal. In vitro, A oligomers suppressed VEGFR3 and VEGF-C expression, while serum and EVs from exercised rats counteracted this effect. Proteomic analysis of EVs from exercised animals revealed upregulation of CD9, suggesting a link to VEGFR3 signaling. This study demonstrates that A oligomers impair mLym function, exacerbating amyloid pathology. Exercise preserves the structure and function of the mLym system, promoting A clearance and mitigating AD progression. These findings highlight the therapeutic potential of targeting the meningeal lymphatic system to slow or prevent AD.

Excessive microglial activation and neuroinflammation are pivotal contributors to the progression of neurodegenerative diseases. Physical activity has emerged as a complementary therapy recognized for its anti-inflammatory effects. Long-term treadmill-induced mandatory physical activity (TMPA), a rodent paradigm modeling exercise with controllable intensity, has been shown to reduce age-related microglial activation, dopaminergic neuron degeneration in the substantia nigra, and motor impairments in mice. However, the mechanisms underlying these effects remain unclear. Given the role of physical activity-induced exerkines in modulating anti-inflammatory responses, this study investigated the effects of plasma-derived extracellular vesicles (EVs) from TMPA-treated animals on inflammagen-induced microglial activation in both in vitro and in vivo models. We showed that plasma from TMPA-treated rats suppressed lipopolysaccharide (LPS)-induced inflammatory signaling pathways in BV2 microglia cell line. Within 2 h, over 60% of BV2 microglia internalized EVs, and EVs from rats significantly inhibited LPS-induced microglial activation. In vivo, DiI-labeled EVs from TMPA-treated rats, delivered via tail vein injection, were detected in the brain parenchyma of recipient mice within one day. LPS-treated mice receiving EVs from TMPA-treated rats exhibited significantly lower microglial activation in the substantia nigra compared to those receiving EVs from sedentary rats. These findings demonstrate that physical activity-derived EVs effectively suppress inflammagen-induced microglial activation, providing new insights into their anti-neuroinflammatory properties and potential as therapeutic agents for neuroinflammation-related diseases.

This review aims to elucidate the positive effects of exercise on cognitive function and explore the underlying mechanisms. Extensive evidence supports the assertion that exercise positively influences neuroplasticity, learning and memory, and mitigates cognitive decline. Nevertheless, comprehending the intricate factors influencing the efficacy of exercise in cognitive improvement remains challenging. Further investigations are imperative to determine the optimal personalized exercise regimen, including the frequency, intensity, type, dosage, and duration, as a non-pharmacological, safe, and cost-effective approach to maximize cognitive benefits. This pursuit holds significant promise for advancing our understanding of exercise as a practical intervention to promote cognitive well-being.

Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders. Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation. This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.

Background This study was designed to examine how glucocorticoids (GCs) induced by a long-term ingestion of high-fat diet (HFD) mediate the HFD-induced adipose expansion and obesity. Material and methods To address this goal, we used a unique L/L mouse model that fails to induce its corticosterone (CORT) level, a major type of GCs in rodents, after prolonged exposure to an HFD. Results We found that, after receiving a 12-week HFD feeding, the L/L mice show less weight gain, milder adipose expansion, and higher plasma levels of triglycerides than the wild-type mice. These changes were reversed by replenishing CORT to L/L mice. When examining the expression levels of various molecules linked to lipid uptake and de novo lipogenesis in CORT-induced adipose expansion, we observed a reduction in the expression of adipose preadipocyte factor 1 (Pref-1), a key regulator in adipogenesis. In 3T3-L1 preadipocyte-like cells, dexamethasone, an agonist of the glucocorticoid receptor, also reduced expressions of Pref-1 and facilitated intracellular accumulation of lipids. Conclusions Our results suggest that fat ingestion-induced release of CORT contributes to adipose expansion and development of obesity and highlight the pathogenic role of CORT-mediated downregulation of adipose Pref-1 in diet-induced obesity.

Abstract Background Polymorphonuclear neutrophils (PMN) activation by monosodium urate crystals (MSU) is crucial to acute gouty arthritis and subsequent spontaneous remission within 7–10 days. Activated PMNs release neutrophil extracellular traps (NETs) that entrap MSU crystals, forming NET-MSU aggregates. Whether NET-MSU aggregates contribute to the resolution of acute inflammation remains to be elucidated. This study uses a cell-based approach to unveil their molecular bases. Methods All-trans retinoic acid-differentiated HL-60 cells (dHL-60) served as surrogate PMNs. NET release from MSU-activated dHL-60 was confirmed by detecting DNA, neutrophil elastase, and citrullinated histone 3, forming large NET-MSU aggregates. NET area was measured with Fiji software after SYTOX Green staining. Released pro-inflammatory cytokines IL-8 and TNF-α, and the anti-inflammatory cytokine IL-1RA in culture supernatants were quantified to calculate the estimate inflammation score (EIS). Cellular redox state was determined by a FRET-based sensor. Expression of intracellular positive (ERK1/2) and negative (SHP-1 and SHIP-1) cytokine signaling regulators was detected by western blot. qPCR detected mRNA expressions of CISH and SOCS1–SOCS7. Flow cytometry measured neutrophil N1 (CD54) and N2 (CD182) surface markers after staining with fluorescent-conjugated antibodies. Results Incubating dHL-60 with MSU for 4 h maximized NET-MSU aggregate formation and acute inflammation with an EIS of 11.6. Prolonging the incubation of dHL-60 + MSU to 22 h gradually raised the EIS to 19.40 without increasing NET area, due to reduced cellular redox capacity. Adding both new dHL-60 and new MSU crystals to the culture, mimicking the clinical scenario, increased NET area but conversely suppressed EIS to 1.53, indicating acute inflammation resolution. The resolution of acute inflammation following prolonged incubation was attributed to decreases in P-ERK and increases in P-SHP-1, SOCS2, SOCS3, and CISH gene expressions, which may suppress pro-inflammatory and enhance anti-inflammatory cytokine production. Moreover, the large NET-MSU aggregates facilitated N1 to N2 polarization, crucial for accelerating inflammation resolution. Conclusion We explored the potential molecular basis for the spontaneous resolution of MSU induced acute inflammation using a cell-based model in that huge NET-MSU aggregates frustrate the transformation of newly entering PMNs to the N2 phenotype, enhancing the production of the anti-inflammatory cytokine IL-1RA.

Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of “inflamm-aging” became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.

Oxytocin (OXT), a neuropeptide originating from the hypothalamus and traditionally associated with peripheral functions in parturition and lactation, has emerged as a pivotal player in the central regulation of the autonomic nervous system (ANS). This comprehensive ANS, comprising sympathetic, parasympathetic, and enteric components, intricately combines sympathetic and parasympathetic influences to provide unified control. The central oversight of sympathetic and parasympathetic outputs involves a network of interconnected regions spanning the neuroaxis, playing a pivotal role in the real-time regulation of visceral function, homeostasis, and adaptation to challenges. This review unveils the significant involvement of the central OXT system in modulating autonomic functions, shedding light on diverse subpopulations of OXT neurons within the paraventricular nucleus of the hypothalamus and their intricate projections. The narrative progresses from the basics of central ANS regulation to a detailed discussion of the central controls of sympathetic and parasympathetic outflows. The subsequent segment focuses specifically on the central OXT system, providing a foundation for exploring the central role of OXT in ANS regulation. This review synthesizes current knowledge, paving the way for future research endeavors to unravel the full scope of autonomic control and understand multifaceted impact of OXT on physiological outcomes.

Neutrophil extracellular traps (NETs) play a role in innate pathogen defense and also trigger B-cell response by providing antigens. NETs have been linked to vaccine-induced thrombotic thrombocytopenia. We postulated a potential link between NET biomarkers, NET-promoting autoantibodies, and adverse events (AEs) after COVID-19 vaccine boosters. Healthy donors (HDs) who received ChAdOx1-S (A), mRNA-1273 (M), or recombinant protein (MVC-COV1901) vaccines at the National Taiwan University Hospital between 2021 and 2022 were recruited. We measured serial NET-associated biomarkers, citrullinated-histone3 (citH3), and myeloperoxidase (MPO)-DNA. Serum citH3 and MPO-DNA were significantly or numerically higher in HDs who reported AEs (n=100, booster Day 0/Day 30, p=0.01/p=0.03 and p=0.30/p=0.35, respectively). We also observed a positive correlation between rash occurrence in online diaries and elevated citH3. A linear mixed model also revealed significantly higher citH3 levels in mRNA-1273/ChAdOx1-S recipients than MVC-COV1901 recipients. Significant positive correlations were observed between the ratios of anti-heparin platelet factor 4 and citH3 levels on Booster Day 0 and naive and between the ratios of anti-NET IgM and citH3 on Booster Day 30/Day 0 in the AA-M and MM-M group, respectively. The increased levels of citH3/MPO-DNA accompanied by NET-promoting autoantibodies suggest a potential connection between mRNA-1273/ChAdOx1-S vaccines and cardiovascular complications. These findings provide insights for risk assessments of future vaccines.

Hair emerged as a biospecimen for long-term investigation of endogenous metabolic perturbations, reflecting the chemical composition circulating in the blood over the past months. Despite its potential, the use of human hair for metabolomics in Alzheimer's disease (AD) research remains limited. Here, we performed both untargeted and targeted metabolomic approaches to profile the key metabolic pathways in the hair of 5xFAD mice, a widely used AD mouse model. Furthermore, we applied the discovered metabolites to human subjects. Hair samples were collected from 6-month-old 5xFAD mice, a stage marked by widespread accumulation of amyloid plaques in the brain, followed by sample preparation and high-resolution mass spectrometry analysis. Forty-five discriminatory metabolites were discovered in the hair of 6-month-old 5xFAD mice compared to wild-type control mice. Enrichment analysis revealed three key metabolic pathways: arachidonic acid metabolism, sphingolipid metabolism, and alanine, aspartate, and glutamate metabolism. Among these pathways, six metabolites demonstrated significant differences in the hair of 2-month-old 5xFAD mice, a stage prior to the onset of amyloid plaque deposition. These findings suggest their potential involvement in the early stages of AD pathogenesis. When evaluating 45 discriminatory metabolites for distinguishing patients with AD from nondemented controls, a combination of l-valine and arachidonic acid significantly differentiated these two groups, achieving a 0.88 area under the curve. Taken together, these findings highlight the potential of hair metabolomics in identifying disease-specific metabolic alterations and developing biomarkers for improving disease detection and monitoring.

Introduction: Insulin, the key hormone for glucose regulation, has garnered attention for its role as an immune modulator. Impaired insulin signaling in the central nervous system is linked to neuroinflammation and neurodegenerative diseases. Microglia, the resident macrophage-like immune cells in the brain, are key regulators of neuroinflammation. However, the mechanisms by which insulin influences microglial immune responses remain relatively unknown. Methods: This study aimed to assess the effects of post-treatment with insulin [30 minutes after lipopolysaccharide (LPS) exposure] on LPS-induced inflammatory responses in BV2 microglial cells. Results: Post-treatment with insulin potentiated LPS-induced production of nitric oxide and pro-inflammatory cytokines, such as TNF and IL-6, through activation of the Akt/NF-kappa B pathway. Insulin also enhanced the ability of BV2 cells to phagocytose bacteria particles and beta-amyloid fibrils. Conversely, insulin inhibited activation of NADPH oxidase and reduced intracellular levels of reactive oxygen species in LPS-treated BV2 cells. Conclusion: Insulin enhances microglial immune competence when challenged by endotoxins but mitigates oxidative stress in these cells.

High-fat diet (HFD)-induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal-striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress-induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity-induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100 beta+ astrocytes and Iba1+ microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP+ astrocytes and Iba1+ microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase-3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC)+ oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin-4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high-dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow.image Chronic high-fat diet (HFD)-induced obesity is linked to significant gliosis in the corpus callosum and the frontal-striatal (FS) circuit areas, including the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC). It also induces meningeal inflammation, as evidenced by immune cell accumulation in the meninges of obese mice. Additionally, there is a loss of oligodendrocytes (OL) in the corpus callosum, along with increased active caspase-3+ cells and decreased AQP4 levels in the FS regions. Furthermore, in vitro studies demonstrated that exposure to ciliary neurotrophic factor (CNTF) resulted in OL damage in cultures, suggesting that CNTF upregulation in the CPu and PFC might impact OL survival in the corpus callosum of obese mice. Therefore, these pathological interactions between the FS connectivity and the corpus callosum may contribute to obesity-associated depression. The figure was created with BioRender.com.image

Background The meningeal lymphatic (mLym) system is a route for waste clearance from the brain to the periphery that has been implicated in the pathogenesis of Alzheimer’s disease (AD). While exercise has been linked to enhanced cognition and delay of AD progression, the effects of exercise on the mLym system have remain largely undescribed. Methods Three-month-old 5xFAD transgenic mice were subjected to a 3-month period of wheel running exercise. Before and after the exercise period, mLym function (i.e., bulk flow of cerebrospinal fluid from the lateral ventricles to the deep cervical lymph nodes) was monitored in real time using high-frequency ultrasound imaging with a nanoparticle contrast agent. The relationships between mLym structure and function, amyloidosis, and learning and memory were examined. Additionally, serum and extracellular vesicles (EVs) were obtained from exercised animals and used to treat lymphatic endothelial cells (HDLECs). Expression of lymphatic vessel-related genes (LYVE-1 and VEGFR3) was monitored. Results Compared to 3-month-old 5xFAD mice (without significant amyloidosis) and age-matched wild-type mice, 6-month-old 5xFAD mice (with robust amyloid plaque deposition in the brain) exhibited decreased mLym function, deterioration of mLym vessels, and impaired learning and memory performance. Reductions were observed in the expression of lymphatic vessel-related genes (LYVE-1 and VEGFR3) in the meninges and VEGF-C in the brain of 6-month-old 5xFAD mice. Subjecting 3-month-old 5xFAD mice to 3 months of running exercise improved mLym vessel structure and function, reduced amyloidosis, and enhanced learning and memory performance compared to non-exercised controls. Conversely, ligating mLym vessels accelerated amyloidosis in 3-month-old 5xFAD mice. Exercise also upregulated the expression levels of LYVE-1 and VEGFR3 in the meninges and VEGF-C in the brain. Further in vitro studies showed that Aβ oligomers decreased VEGFR3 gene expression in HDLECs, while serum and EVs from exercised mice antagonized this effect. Conclusions This study reveals beneficial effects of running exercise on the mLym system, suggesting a non-pharmacological strategy to improve Aβ clearance from the brain, delay AD progression, and enhance cognitive function.

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vascul-opathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 degrees C in 5% CO2 incubator for 0-180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incu-bation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 & mu;g/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated 0-galactosidase (SA-0gal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but sup-pressed SA-0gal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-0gal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-0, or TNF-& alpha; in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

Monocytes are a major population of circulating immune cells that play a crucial role in producing pro-inflammatory cytokines in the body. The actions of monocytes are known to be influenced by the combinations and concentrations of certain fatty acids (FAs) in blood and dietary fats. However, systemic comparisons of the effects of FAs on cytokine secretion by monocytes have not be performed. In this study, we compared how six saturated FAs (SFAs), two monounsaturated FAs (MUFAs), and seven polyunsaturated FAs (PUFAs) modulate human THP-1 monocyte secretion of TNF, IL-1β, and IL-6 in the absence or presence of lipopolysaccharide. SFAs generally stimulated resting THP-1 cells to secrete pro-inflammatory cytokines, with stearic acid being the most potent species. In contrast, MUFAs and PUFAs inhibited lipopolysaccharide-induced secretion of pro-inflammatory cytokines. Interestingly, the inhibitory potentials of MUFAs and PUFAs followed U-shaped (TNF and IL-1β) or inverted U-shaped (IL-6) dose–response curves. Among the MUFAs and PUFAs that were analyzed, docosahexaenoic acid (C22:6 n-3) exhibited the largest number of double bonds and was found to be the most potent anti-inflammatory compound. Together, our findings reveal that the chemical compositions and concentrations of dietary FAs are key factors in the intricate regulation of monocyte-mediated inflammation.

Aims: Epidemiological evidence suggests that comorbidity of obesity and depression is extremely common and continues to grow in prevalence. However, the mechanisms connecting these two conditions are unknown. In this study, we explored how treatment with KATP channel blocker glibenclamide (GB) or the well-known metabolic regulator FGF21 impact male mice with high-fat diet (HFD)-induced obesity and depressive-like behaviors. Materials and methods: Mice were fed with HFD for 12 weeks and then treated with recombinant FGF21 protein by infusion for 2 weeks, followed by intraperitoneal injection of 3 mg/kg recombinant FGF21 once per day for 4 days. Measurements were made of catecholamine levels, energy expenditure, biochemical endpoints and behavior tests, including sucrose preference and forced swim tests were. Alternatively, animals were infused with GB into brown adipose tissue (BAT). The WT-1 brown adipocyte cell line was used for molecular studies. Key findings: Compared to HFD controls, HFD + FGF21 mice exhibited less severe metabolic disorder symptoms, improved depressive-like behaviors, and more extensive mesolimbic dopamine projections. FGF21 treatment also rescued HFD-induced dysregulation of FGF21 receptors (FGFR1 and co-receptor & beta;-klotho) in the ventral tegmental area (VTA), and it altered dopaminergic neuron activity and morphology in HFD-fed mice. Importantly, we also found that FGF21 mRNA level and FGF21 release were increased in BAT after administration of GB, and GB treatment to BAT reversed HFD-induced dysregulation of FGF21 receptors in the VTA. Significance: GB administration to BAT stimulates FGF21 production in BAT, corrects HFD-induced dysregulation of FGF21 receptor dimers in VTA dopaminergic neurons, and attenuates depression-like symptoms.