Cornuside Is a Potential Agent against Alzheimer’s Disease via Orchestration of Reactive Astrocytes

Cornuside is an iridoid glycoside from Cornus officinalis, with the activities of anti-inflammatory, antioxidant, anti-mitochondrial dysfunction, and neuroprotection. In the present research, a triple-transgenic mice model of AD (3 × Tg-AD) was used to explore the beneficial actions and potential mechanism of cornuside on the memory deficits. We found that cornuside prominently alleviated neuronal injuries, reduced amyloid plaque pathology, inhibited Tau phosphorylation, and repaired synaptic damage. Additionally, cornuside lowered the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), lowered the level of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and the level of glutathione peroxidase (GSH-Px). Cornuside also significantly reduced the activation of astrocytes and modulated A1/A2 phenotypes by the AKT/Nrf2/NF-κB signaling pathway. We further confirmed that LY294002 and Nrf2 silencing could block the cornuside-mediated phenotypic switch of C6 cells induced by microglia conditioned medium (MCM) in response to lipopolysaccharide (LPS), which indicated that the effects of cornuside in astrocyte activation are dependent on AKT/Nrf2/NF-κB signaling. In conclusion, cornuside may regulate the phenotypic conversion of astrocytes, inhibit neuroinflammation and oxidative stress, improve synaptic plasticity, and alleviate cognitive impairment in mice through the AKT/Nrf2/NF-κB axis. Our present work provides an experimental foundation for further research and development of cornuside as a candidate drug for AD management.     

Inosine Pretreatment Attenuates LPS-Induced Lung Injury through Regulating the TLR4/MyD88/NF-κB Signaling Pathway In Vivo

Inosine is a type of purine nucleoside, which is considered to a physiological energy source, and exerts a widely range of anti-inflammatory efficacy. The TLR4/MyD88/NF-κB signaling pathway is essential for preventing host oxidative stresses and inflammation, and represents a promising target for host-directed strategies to improve some forms of disease-related inflammation. In the present study, the results showed that inosine pre-intervention significantly suppressed the pulmonary elevation of pro-inflammatory cytokines (including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)), malondialdehyde (MDA), nitric oxide (NO), and reactive oxygen species (ROS) levels, and restored the pulmonary catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities (p < 0.05) in lipopolysaccharide (LPS)-treated mice. Simultaneously, inosine pre-intervention shifted the composition of the intestinal microbiota by decreasing the ratio of Firmicutes/Bacteroidetes, elevating the relative abundance of Tenericutes and Deferribacteres. Moreover, inosine pretreatment affected the TLR4/MyD88/NF-κB signaling pathway in the pulmonary inflammatory response, and then regulated the expression of pulmonary iNOS, COX2, Nrf2, HO-1, TNF-α, IL-1β, and IL-6 levels. These findings suggest that oral administration of inosine pretreatment attenuates LPS-induced pulmonary inflammatory response by regulating the TLR4/MyD88/NF-κB signaling pathway, and ameliorates intestinal microbiota disorder.     

Green Tea Extract Containing Piper retrofractum Fruit Ameliorates DSS-Induced Colitis via Modulating MicroRNA-21 Expression and NF-κB Activity

The aim of the present study was to examine the effect of green tea extract containing Piper retrofractum fruit (GTP) on dextran-sulfate-sodium (DSS)-induced colitis, the regulatory mechanisms of microRNA (miR)-21, and the nuclear factor-κB (NF-κB) pathway. Different doses of GTP (50, 100, and 200 mg/kg) were administered orally once daily for 14 days, followed by GTP with 3% DSS for 7 days. Compared with the DSS-treated control, GTP administration alleviated clinical symptoms, including the disease activity index (DAI), colon shortening, and the degree of histological damage. Moreover, GTP suppressed miR-21 expression and NF-κB activity in colon tissue of DSS-induced colitis mice. The mRNA levels of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were downregulated by GTP. Colonic nitric oxide (NO) and prostaglandin E2 (PGE2) production, and myeloperoxidase (MPO) activity were also lowered by GTP. Taken together, our results revealed that GTP inhibits DSS-induced colonic inflammation by suppressing miR-21 expression and NF-κB activity, suggesting that it may be used as a potential functional material for improving colitis.     

Protective effects of Acanthopanax divaricatus extract in mouse models of Alzheimer's disease

BACKGROUND

Acanthopanax divaricatus var. albeofructus (ADA) extract has been reported to have anti-oxidant, immunomodulatory, and anti-mutagenic activity.

MATERIALS/METHODS

We investigated the effects of ADA extract on two mouse models of Alzheimer''s disease (AD); intracerebroventricular injection of β-amyloid peptide (Aβ) and amyloid precursor protein/presenilin 1 (APP/PS1)-transgenic mice.

RESULTS

Intra-gastric administration of ADA stem extract (0.25 g/kg, every 12 hrs started from one day prior to injection of Aβ1-42 until evaluation) effectively blocked Aβ1-42-induced impairment in passive avoidance performance, and Aβ1-42-induced increase in immunoreactivities of glial fibrillary acidic protein and interleukin (IL)-1α in the hippocampus. In addition, it alleviated the Aβ1-42-induced decrease in acetylcholine and increase in malondialdehyde levels in the cortex. In APP/PS1-transgenic mice, chronic oral administration of ADA stem extract (0.1 or 0.5 g/kg/day for six months from the age of six to 12 months) resulted in significantly enhanced performance of the novel-object recognition task, and reduced amyloid deposition and IL-1β in the brain.

CONCLUSIONS

The results of this study suggest that ADA stem extract may be useful for prevention and treatment of AD.     

Effect of Cone of Pinus densiflora on DNCB-Induced Allergic Contact Dermatitis-Like Skin Lesion in Balb/c Mice

Cone of Pinus densiflora (CP), or Korean red pinecone, is a cluster of Pinus densiflora fruit. CP has also been verified in several studies to have anti-oxidation, anti-fungal, anti-bacterial, and anti-melanogenic effects. However, anti-inflammatory effects have not yet been confirmed in the inflammatory responses of pinecones to allergic contact dermatitis. The purpose of this study is to prove the anti-inflammatory effect of CP on allergic contact dermatitis (ACD) in vitro and in vivo. CP inhibited the expression of TSLP, TARC, MCP-1, TNF-α, and IL-6 in TNF-α/IFN-γ-stimulated HaCaT cells and MCP-1, GM-CSF, TNF-α, IL-6, and IL-8 in PMACI (phorbol-12-myristate-13-acetate plus A23187)-stimulated HMC-1 cells. CP inhibited the phosphorylation of mitogen-activated protein kinase (MAPKs), as well as the translocation of NF-κB on TNF-α/IFN-γ stimulated in HaCaT cells. In vivo, CP decreased major symptoms of ACD, levels of IL-6 in skin lesion, thickening of the epidermis and dermis, infiltration of eosinophils and mast cells, and the infiltration of CD4⁺ T cells and CD8⁺ T cells. This result suggests that CP represents a potential alternative medicine to ACD for diseases such as chronic skin inflammation.     

Alginate Oligosaccharides Ameliorate DSS-Induced Colitis through Modulation of AMPK/NF-κB Pathway and Intestinal Microbiota

Alginate oligosaccharides (AOS) are shown to have various biological activities of great value to medicine, food, and agriculture. However, little information is available about their beneficial effects and mechanisms on ulcerative colitis. In this study, AOS with a polymerization degree between 2 and 4 were found to possess anti-inflammatory effects in vitro and in vivo. AOS could decrease the levels of nitric oxide (NO), IL-1β, IL-6, and TNFα, and upregulate the levels of IL-10 in both RAW 264.7 and bone-marrow-derived macrophage (BMDM) cells under lipopolysaccharide (LPS) stimulation. Additionally, oral AOS administration could significantly prevent bodyweight loss, colonic shortening, and rectal bleeding in dextran sodium sulfate (DSS)-induced colitis mice. AOS pretreatment could also reduce disease activity index scores and histopathologic scores and downregulate proinflammatory cytokine levels. Importantly, AOS administration could reverse DSS-induced AMPK deactivation and NF-κB activation in colonic tissues, as evidenced by enhanced AMPK phosphorylation and p65 phosphorylation inhibition. AOS could also upregulate AMPK phosphorylation and inhibit NF-κB activation in vitro. Moreover, 16S rRNA gene sequencing of gut microbiota indicated that supplemental doses of AOS could affect overall gut microbiota structure to a varying extent and specifically change the abundance of some bacteria. Medium-dose AOS could be superior to low- or high-dose AOS in maintaining remission in DSS-induced colitis mice. In conclusion, AOS can play a protective role in colitis through modulation of gut microbiota and the AMPK/NF-kB pathway.     

Schisandrae Fructus ethanol extract attenuates particulate matter 2.5-induced inflammatory and oxidative responses by blocking the activation of the ROS-dependent NF-κB signaling pathway

BACKGROUND/OBJECTIVESSchisandrae Fructus, the fruit of Schisandra chinensis Baill., has traditionally been used as a medicinal herb for the treatment of various diseases, and has proven its various pharmacological effects, including anti-inflammatory and antioxidant activities. In this study, we investigated the inhibitory effect of Schisandrae Fructus ethanol extract (SF) on inflammatory and oxidative stress in particulate matter 2.5 (PM2.5)-treated RAW 264.7 macrophages.MATERIALS/METHODSTo investigate the anti-inflammatory and antioxidant effects of SF in PM2.5-stimulated RAW 264.7 cells, the levels of pro-inflammatory mediator such as nitric oxide (NO) and prostaglandin E₂ (PGE₂), cytokines including interleukin (IL)-6 and IL-1β, and reactive oxygen species (ROS) were measured. To elucidate the mechanism underlying the effect of SF, the expression of genes involved in the generation of inflammatory factors was also investigated. We further evaluated the anti-inflammatory and antioxidant efficacy of SF against PM2.5 in the zebrafish model.RESULTSThe results indicated that SF treatment significantly inhibited the PM2.5-induced release of NO and PGE₂, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. SF also attenuated the PM2.5-induced expression of IL-6 and IL-1β, reducing their extracellular secretion. Moreover, SF suppressed the PM2.5-mediated translocation of nuclear factor-kappa B (NF-κB) from the cytosol into nuclei and the degradation of inhibitor IκB-α, indicating that SF exhibited anti-inflammatory effects by inhibiting the NF-κB signaling pathway. In addition, SF abolished PM2.5-induced generation of ROS, similar to the pretreatment of a ROS scavenger, but not by an inhibitor of NF-κB activity. Furthermore, SF showed strong protective effects against NO and ROS production in PM2.5-treated zebrafish larvae.CONCLUSIONSOur findings suggest that SF exerts anti-inflammatory and antioxidant effects against PM2.5 through ROS-dependent down-regulating the NF-κB signaling pathway, and that SF can be a potential functional substance to prevent PM2.5-mediated inflammatory and oxidative damage.     

Allium hookeri Extracts Improve Scopolamine-Induced Cognitive Impairment via Activation of the Cholinergic System and Anti-Neuroinflammation in Mice

Allium hookeri (AH) is a medicinal food that has been used in Southeast Asia for various physiological activities. The objective of this study was to investigate the activation of the cholinergic system and the anti-neuroinflammation effects of AH on scopolamine-induced memory impairment in mice. Scopolamine (1 mg/kg body weight, i.p.) impaired the performance of the mice on the Y-maze test, passive avoidance test, and water maze test. However, the number of error actions was reduced in the AH groups supplemented with leaf and root extracts from AH. AH treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. AH significantly improved the cholinergic system by decreasing acetylcholinesterase activity, and increasing acetylcholine concentration. The serum inflammatory cytokines (IL-1β, IL-6, and IFN-γ) increased by scopolamine treatment were regulated by the administration of AH extracts. Overexpression of NF-κB signaling and cytokines in liver tissue due to scopolamine were controlled by administration of AH extracts. AH also significantly decreased Aβ and caspase-3 expression but increased NeuN and ChAT. The results suggest that AH extracts improve cognitive effects, and the root extracts are more effective in relieving the scopolamine-induced memory impairment. They have neuroprotective effects and reduce the development of neuroinflammation.     

Moringa Oleifera Alleviates Aβ Burden and Improves Synaptic Plasticity and Cognitive Impairments in APP/PS1 Mice

Alzheimer’s disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Moringa oleifera (MO) that have strong anti-oxidative, anti-inflammatory, anticholinesterase, and neuroprotective virtues. In this study, we treated APP/PS1 mice with a methanolic extract of MO for four months and evaluated its effect on AD-related pathology in these mice using a multitude of behavioral, biochemical, and histochemical tests. Our data revealed that MO improved behavioral deficits such as anxiety-like behavior and hyperactivity and cognitive, learning, and memory impairments. MO treatment abrogated the Aβ burden to wild-type control mice levels via decreasing BACE1 and AEP and upregulating IDE, NEP, and LRP1 protein levels. Moreover, MO improved synaptic plasticity by improving the decreased GluN2B phosphorylation, the synapse-related proteins PSD95 and synapsin1 levels, the quantity and quality of dendritic spines, and neurodegeneration in the treated mice. MO is a nutraceutical agent with promising therapeutic potential that can be used in the management of AD and other neurodegenerative diseases.     

Antioxidant and Anti-Inflammatory Properties of Rubber Seed Oil in Lipopolysaccharide-Induced RAW 267.4 Macrophages

Rubber seed oil (RSO) is a typical PUFA-enriched plant oil, but it has not been widely used as a healthy edible oil resource due to the lack of understanding of its nutritional values, health biological effects, and action mechanisms. This work was conducted to characterize the basic physicochemical properties, evaluate the antioxidant and anti-inflammatory properties, and explore the involved mechanisms of RSO in LPS-induced RAW 264.7 cells. In the present study, the basic physicochemical parameters of RSO indicated that RSO has good qualities as a potential edible plant oil resource. In LPS-induced macrophages, RSO supplementation displayed a significant antioxidant effect by decreasing ROS and MDA levels as well as elevating T-AOC. In addition, RSO supplementation showed an anti-inflammatory effect by reducing the production of NO, IL-1β, IL-6, and TNF-α while promoting the production of IL-10. Moreover, RSO supplementation decreased the mRNA expression of IL-6, IL-1β, TNF-α, iNOS, and MCP-1 genes while increasing the mRNA expression of the IL-10 gene. Furthermore, RSO supplementation increased Nrf2 protein expression and up-regulated antioxidant genes (HO-1 and NQO-1), which was accompanied by the decrease in TLR4 protein expression and NF-κB p65 phosphorylation as well as IκBα phosphorylation. This study provided some insight into the applications of RSO as a healthy edible oil resource.     

Probiotic Bifidobacterium breve MCC1274 Mitigates Alzheimer’s Disease-Related Pathologies in Wild-Type Mice

Probiotics improve brain function, including memory and cognition, via the microbiome–gut–brain axis. Oral administration of Bifidobacterium breve MCC1274 (B. breve MCC1274) improves cognitive function in App^NL-G-F mice and mild cognitive impairment (MCI) subjects, and mitigates Alzheimer’s disease (AD)-like pathologies. However, its effects on wild-type (WT) mice have not yet been explored. Thus, the effects of B. breve MCC1274 on AD-like pathologies in two-month-old WT mice were investigated, which were orally administered B. breve MCC1274 for four months. Aβ levels, amyloid precursor protein (APP), APP processing enzymes, phosphorylated tau, synaptic protein levels, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated. Data analysis was performed using Student’s t-test, and normality was tested using the Shapiro–Wilk test. Oral administration of B. breve MCC1274 in WT mice decreased soluble hippocampal Aβ42 levels by reducing presenilin1 protein levels, and reduced phosphorylated tau levels. It also activated the protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway, which may be responsible for the reduction in presenilin1 levels and inhibition of tau phosphorylation. B. breve MCC1274 supplementation attenuated microglial activation and elevated synaptic protein levels in the hippocampus. These findings suggest that B. breve MCC1274 may mitigate AD-like pathologies in WT mice by decreasing Aβ42 levels, inhibiting tau phosphorylation, attenuating neuroinflammation, and improving synaptic protein levels.     

Fucoxanthin alters the apelin-13/APJ pathway in certain organs of γ-irradiated mice

Apelin-13 and APJ are implicated in different key physiological processes. This work aims at exploring the radioprotective effect of fucoxanthin (FX) on γ-radiation (RAD)-induced changes in the apelin-13/APJ pathway, which causes damage in the liver, kidney, lung and spleen of mice. Mice were administered FX (10 mg kg^–1 day^–1, i.p) and exposed to γ-radiation (2.5 Gy week^–1) for four consecutive weeks. The treatment of irradiated mice by FX resulted in a significant amendment in protein expression of the apelin-13/APJ/NF-κB signalling pathway concurrently with reduced hypoxia (hypoxia-inducible factor-1α), suppressed oxidative stress marker (malondialdehyde), enhanced antioxidant defence mechanisms (reduced glutathione and glutathione peroxidase), a modulated inflammatory response [interleukin-6 (IL-6), monocyte chemoattractant protein-1, IL-10 and α-7-nicotinic acetylcholine receptor) and ameliorated angiogenic regulators [matrix metalloproteinase (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1), as well as the tissue damage indicator (lactate dehydrogenase) in organ tissues. In addition, there were significant improvement in serum inflammatory markers tumour necrosis factor-α, IL-10, IL-1β and C-reactive protein compared with irradiated mice. The histopathological investigation of the FX + RAD organ tissues support the biochemical findings where the improvements in the tissues’ architecture were obvious when compared with those of RAD. FX was thus shown to have a noticeable radioprotective action mediated through its regulatory effect on the apelin-13/APJ/NF-κB signalling pathway attributed to its antioxidant and anti-inflammatory activity that was reflected in different physiological processes. It could be recommended to use FX in cases of radiation exposure to protect normal tissues.     

Dietary Glycemic Load and Plasma Amyloid-β Biomarkers of Alzheimer’s Disease

Previous studies have highlighted links between a high-glycemic-load (GL) diet and Alzheimer’s disease in apolipoprotein E ε4 (APOE4) carriers. However, the impact of high-GL diet on plasma amyloid-β (Aβ), an Alzheimer’s disease hallmark that can be detected decades before clinical symptomatology, is unknown. This study examined the association between plasma Aβ peptides (Aβ₄₀, Aβ₄₂ concentration and Aβ₄₂/Aβ₄₀ ratio) and GL. The influence of the GL of four meal types (breakfast, lunch, afternoon snack, and dinner) was also determined. From the prospective Three-City study, 377 participants with plasma Aβ measurements, and who completed the Food Frequency Questionnaire, were selected. The association between plasma Aβ and GL was tested using an adjusted linear regression model. Lunch GL was associated with a lower plasma Aβ₄₂ concentration (β = −2.2 [CI = −4.27, −0.12], p = 0.038) and lower Aβ₄₂/Aβ₄₀ ratio (β = −0.009 [CI = −0.0172, −0.0007], p = 0.034) in the model adjusted for center, age, sex, education level, APOE4 status, energy intake, serum creatinine, total cholesterol, and Mediterranean-like diet. No significant association was found with the GL of the other meal types. These results suggest that dietary GL may independently modulate the plasma Aβ of the APOE4 status. The mechanism underlying diet, metabolic response, and Aβ peptide regulation must be elucidated.     

Casein Oligochitosan-Glycation by Transglutaminase Enhances the Anti-Inflammatory Potential of Casein Hydrolysates to the Lipopolysaccharide-Stimulated IEC-6 Cells

In this study, milk protein casein was glycated by oligochitosan through the catalysis of transglutaminase (TGase) and then hydrolyzed by trypsin. The obtained glycated casein hydrolysates (GCNH) were assessed for their anti-inflammatory activities, using the lipopolysaccharide (LPS)-stimulated rat intestinal epithelial cells (IEC-6) as cell models and the casein hydrolysates (CNH) without TGase catalysis as controls. The results showed that GCNH had oligochitosan incorporation and thus possessed a glucosamine content of 5.74 g/kg protein. In general, GCNH at dose levels of 25–100 μg/mL could elevate IEC-6 cell growth, and at dose levels of 25–50 μg/mL, they were also able to alleviate the LPS-induced cytotoxicity by increasing cell viability efficiently. Although LPS caused clear inflammation in the LPS-stimulated cells, GCNH were capable of reducing the secretion of three pro-inflammatory mediators including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, or promoting the secretion of two anti-inflammatory mediators like IL-10 and transforming growth factor-β, demonstrating their anti-inflammatory activities to the stimulated cells. Moreover, GCNH also could down-regulate the expression of three inflammation-related proteins including TLR4, p-p38, and p-p65 in the stimulated cells, and thus possessed a capacity to suppress the phosphorylation of p38 and p65 proteins as well as to inactivate the NF-κB and MAPK signaling pathways. Additionally, a higher GCNH dose level consistently led to higher anti-inflammatory effect in the cells, while GCNH were always more potent than CNH at performing anti-inflammatory function targets. It is thus suggested that the TGase-catalyzed casein oligochitosan-glycation could enhance the anti-inflammatory activities of casein hydrolysates efficiently. TGase-catalyzed protein glycation thus might enhance the healthcare function of protein ingredients in the body.     

Therapeutic Effect of Polysaccharide of Large Yellow Croaker Swim Bladder on Lupus Nephritis of Mice

The therapeutic effect of polysaccharide of large yellow croaker swim bladder (PLYCSB) on lupus nephritis has been studied in vivo. A high concentration (50 mg/kg dose) of PLYCSB reduced the levels of serum inflammatory cytokine levels of IL-6, IL-12, TNF-α and IFN-γ compared to a low concentration (25 mg/kg dose) and control mice. SCr, BUN, TC and TG serum levels of PLYCSB treated mice were lower than those of control mice, and TP and ALB serum levels were higher than control mice. Control mice tested ds-DNA positive at the 6th week, and 50 mg/kg treated mice tested at the 10th week after the experiment began. The output of urine protein of 50 mg/kg PLYCSB treated mice was most closely comparable to the normal mice. The glomerular number of 50 mg/kg PLYCSB treated mice was more than the 25 mg/kg dose and control groups, and the 50 mg/kg dose group showed the lowest glomerular sclerosis index in lupus nephritis mice. By RT-PCR and western blot assay, PLYCSB significantly induced inflammation in kidney tissues of mice by downregulating NF-κB-p65, TGF-β1, Fas, FasL and upregulating IκB-α. These results suggest that PLYCSB showed a potential curative effect on lupus nephritis as a drug or functional food.