Crocin alleviates cognitive impairment associated with atherosclerosis via improving neuroinflammation in LDLR-/- mice fed a high-fat/cholesterol diet.

Crocin has been extensively investigated in treating neurodegenerative diseases. However, its effect on cognitive impairment associated with atherosclerosis remains unknown. The present study aimed to explore the potential mechanism of crocin on cognitive impairment in a mouse model of atherosclerosis. LDLR-/- mice fed a high-fat/cholesterol diet were administered variable-dose crocin for 56 days through gavage. Biochemical tests showed that serum triglycerides and circulating lipopolysaccharide decreased in mice treated with crocin. Behavioral tests indicated that crocin alleviated cognitive impairment by reducing latency to the platform and increasing the swimming distance in the target quadrant. This mechanism might be associated with crocin inhibiting Aß deposition by decreasing Aß1-42 and tau phosphorylation. Crocin improved neuroinflammation by inhibiting the increase in reactive microglia and astrocytes, weakening NLRP3 inflammasome activation accompanied by a reduction in Caspase-1 and IL-1ß, and blocking TLR4 signaling accompanied by a decrease in NF-kB p65 and MyD88. In addition, crocin raised the protein expression of ZO-1 and occludin. These findings provide experimental support that crocin attenuates cognitive impairment associated with atherosclerosis by repressing neuroinflammation, which is attributed to its suppression on the activation of microglia and astrocytes, and the production of inflammatory cytokines via targeting the NLRP3 inflammasome and TLR4 signaling.

Magnetic, Fluorescence and Transition Metal Ion Response Properties of 2,6-Diaminopyridine Modified Silica-Coated Fe3O4 Nanoparticles.

Multi-functional nanoparticles possessing magnetic, fluorescence and transition metal ion response properties were prepared and characterized. The particles have a core/shell structure that consists of silica-coated magnetic Fe3O4 and 2,6-diaminopyridine anchored on the silica surface via organic linker molecules. The resultant nanoparticles were found by transmission electron microscopy to be well-dispersed spherical particles with an average diameter of 10-12 nm. X-ray diffraction analysis suggested the existence of Fe3O4 and silica in/on the particle. Fourier transform infrared spectra revealed that 2,6-diaminopyridine molecules were successfully covalently bonded to the surface of magnetic composite nanoparticles. The prepared particles possessed an emission peak at 364 nm with an excitation wavelength of 307 nm and have a strong reversible response property for some transition metal ions such as Cu(2+) and Zn(2+). This new material holds considerable promise in selective magneto separation and optical determination applications.

Apple Polyphenol Extract Ameliorates Atherosclerosis and Associated Cognitive Impairment through Alleviating Neuroinflammation by Weakening TLR4 Signaling and NLRP3 Inflammasome in High-Fat/Cholesterol Diet-Fed LDLR-/- Male Mice.

Although studies have supported the beneficial effects of the ingredients of apple polyphenol extract (APE), a polyphenol mixture being extracted from whole fresh apples, on neurodegenerative diseases, the role of APE in atherosclerosis-related cognitive impairment remains unclear. To clarify the role of APE in regulating cognitive dysfunction in mice with atherosclerosis and the underlying mechanisms, high-fat/cholesterol diet-fed male LDLR-/- mice were gavaged with 125 or 500 mg/(kg·bw·d) APE solution or sterile double-distilled water for consecutive 8 weeks, and age-matched C57BL/6 male mice were employed as normal control. APE intervention increased the serum concentration of high-density apolipoprotein cholesterol, improved atherosclerosis, and ameliorated cognitive function of mice by inhibiting the phosphorylation of tau protein, supporting with significantly reduced platform latency and obviously increased swimming distance in the target quadrant according to the Morris water maze test. APE intervention alleviated neuroinflammation by attenuating the activation of microglia and astrocytes and inhibiting TLR4 signaling with reduced protein expression of NF-κB, MyD88, TRIF, and IKKß. Meanwhile, APE intervention inactivated NLRP3 inflammasome with downregulated protein expression of caspase-1, IL-18, and IL-1ß. Additionally, APE intervention improved the damaged brain barrier structure by upregulating the protein expression of ZO-1 and occludin. Therefore, our research supplemented new data, supporting the potential of APE as an effective dietary bioactive ingredient to improve atherosclerosis and associated cognitive impairment.

Effect of Probiotics Supplementation on Heart Rate: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Background and Aims: Probiotics consumption lowers the risk of cardiovascular disease, but whether it affects heart rate (HR) remains controversial. Therefore, our study aimed to assess the chronotropic effects of probiotics on heartbeat via a meta-analysis of randomized clinical trials. Methods: Relevant studies were identified by searching PubMed, Cochrane library, and Clinical Trials databases up to October 2021. Either a fixed-effects or a random-effects model was used to calculate the pooled effect sizes and 95% confidence intervals (CIs). Results: This meta-analysis included 13 studies involving 16 interventional trial arms and 931 participants according to inclusion criteria. The overall pooled estimate showed that probiotics supplementation had a slight, but no significant reduction of 0.28 bpm (95% CI: -1.17, 0.60) on HR. Relatively high heterogeneity was observed among included trials (I 2 = 80.8%, P heterogeneity < 0.001). Subgroup analysis displayed that probiotics supplementation significantly reduced HR by 2.94 bpm (95% CI: -5.06, -0.82) among participants with baseline HR ≥ 75 bpm, by 1.17 bpm (95% CI: -2.34, -0.00) with probiotics dose ≥1 × 1010 CFU/day, and by 1.43 bpm (95% CI: -2.69, -0.17) with multiple-strain intervention. Meta-regression analysis showed that baseline HR was a major potential effect modifier of probiotics supplementation on lowering HR. Conclusion: Hitherto, the overall evidence in the literature was insufficient to support the notion that probiotics supplementation has a class effect on HR reduction. However, in subgroup analysis, probiotics reduced HR significantly in those who had higher baseline HR, received a higher dose or multiple strains of probiotics.

Oat fiber supplementation alleviates intestinal inflammation and ameliorates intestinal mucosal barrier via acting on gut microbiota-derived metabolites in LDLR-/- mice.

OBJECTIVE: Gut microbiota-derived metabolites are involved in intestinal inflammation, which can affect the development of atherosclerotic plaques. Previous studies have shown that oat fiber can delay the progression of atherosclerosis via improving lipid metabolism. The aim of this study was to evaluate how oat fiber acted on gut microbiota-derived metabolites, inhibited intestinal inflammation, and protected the intestinal mucosal barrier. METHODS: Male low-density lipoprotein receptor knock-out (LDLR-/-) mice were fed a high-fat/cholesterol diet with or without oat fiber for 14 wk. Histopathology of the aorta was detected by Oil Red O staining, and the small intestine mucosal pathology was measured through hematoxylin and eosin staining. Non-targeted metabolomics of feces was performed using liquid chromatography-mass spectrometry. Western blot method was used to assess the relative levels of the proteins involved in the toll-like receptor (TLR)4 signal pathway and intestinal mucosal barrier in interest tissues. RESULTS: Pathologically, oat fiber reversed the increment of the atherosclerotic lesion and ameliorated intestinal mucosal barrier in LDLR-/- mice. Oat fiber regulated the levels of gut microbiota-derived metabolites along with a decrease in isobutyrylcarnitine, valerylcarnitine, 1-methylguanosine, and 2-methylguanosine, and an increase in l-tyrosine and niacinamide. Notably, oat fiber blocked the TLR4 signal pathway and decreased the expression of nuclear factor-κB p65 in both the aorta and gut tissues. Also, oat fiber raised the expression of tight junction proteins including ZO-1 and occludin. CONCLUSION: Taken together, the present study revealed that oat fiber feeding effectively attenuated the development of atherosclerosis, at least partly via affecting gut microbiota-derived metabolites, inhibiting the intestinal inflammatory response, and maintaining the integrity of the intestinal mucosal barrier.

Oat Fiber Modulates Hepatic Circadian Clock via Promoting Gut Microbiota-Derived Short Chain Fatty Acids.

The biological alteration of circadian rhythm was found to be related to the development of metabolic disorders. Our previous studies reported that impaired lipid metabolism caused by a high-fat diet was improved by oat fiber, but did not attempt to answer whether the improvement is mechanistically linked to circadian rhythm. By focusing on circadian alteration, the present study aimed to elucidate the effect of gut microbiota-derived short chain fatty acids (SCFAs) on circadian rhythm in a high-fat diet experimental paradigm with and without dietary oat fiber feeding. The results showed that oat fiber prevented the production of obesity and dyslipidemia caused by a high-fat diet in C57BL/6 mice. From a circadian perspective specifically, a high-fat diet disrupted the hepatic circadian protein expressions of the liver clock genes, which were in parallel with the altered oscillation of serum triglycerides, low-density lipoprotein cholesterol, fasting insulin, and the homeostasis model assessment-insulin resistance index. Oat fiber, by contrast, reversed these disrupted diurnal oscillations. Most interestingly, what a high-fat diet induced and what oat fiber prevented were dictated in a close oscillation pattern resembling that of SCFA production facilitated by the intestinal microbiome. Given the results from the present study and from others that demonstrated the role played by SCFAs in regulating circadian rhythm, we conclude that the beneficial effects of oat fiber are likely mediated by complex processes involving multiple mechanisms including a signal transduction pathway of gut microbiota-derived SCFAs to hepatic circadian protein expression to lipid and other metabolic oscillations. The latter warrants more investigation to further determine whether the circadian rhythm pathway has any major and causal significance for the outcome measures in the prevention and treatment of metabolic disorders in humans.

Effects of Oat Fiber Intervention on Cognitive Behavior in LDLR-/- Mice Modeling Atherosclerosis by Targeting the Microbiome-Gut-Brain Axis.

It is known that cardiovascular disease can result in cognitive impairment. However, whether oat fiber improves cognitive behavior through a cardiovascular-related mechanism remains unclear. The present work was aimed to elucidate the potential of oat fiber on cognitive behavior by targeting the neuroinflammation signal and microbiome-gut-brain axis in a mouse model of atherosclerosis. Male low-density lipoprotein receptor knock-out (LDLR-/-) mice were treated with a high fat/cholesterol diet without or with 0.8% oat fiber for 14 weeks. Behavioral tests indicated that LDLR-/- mice exhibited a significant cognitive impairment; however, oat fiber can improve cognitive behavior by reducing latency to the platform and increasing the number of crossing and swimming distance in the target quadrant. Oat fiber can inhibit Aß plaque processing in both the cortex and hippocampus via decreasing the relative protein expression of GFAP and IBα1. Notably, oat fiber inhibited the nod-like receptor family pyrin domain-containing 3 inflammasome activation and blocked the toll-like receptor 4 signal pathway in both the cortex and hippocampus, accompanied by a reduction of circulating serum lipopolysaccharide. In addition, oat fiber raised the expressions of short-chain fatty acid (SCFA) receptors and tight junction proteins (zonula occludens-1 and occludin) and improved intestinal microbiota diversity via increasing the contents of gut metabolites SCFAs. In summary, the present study provided experimental evidence that dietary oat fiber retarded the progression of cognitive impairment in a mouse model of atherosclerosis. Mechanistically, the neuroprotective potential was related to oat fiber and its metabolites SCFAs on the diversity and abundance of gut microbiota that produced anti-inflammatory metabolites, leading to repressed neuroinflammation and reduced gut permeability through the microbiome-gut-brain axis.

Melatonin represses oral squamous cell carcinoma metastasis by inhibiting tumor-associated neutrophils.

Tumor-associated neutrophils (TANs) promote metastasis of multiple cancers, including oral squamous cell carcinoma (OSCC). Melatonin (Mel) reportedly exerts anti-metastatic effects on OSCC. However, little is known about the anti-OSCC effects of Mel involved in TANs. In this study, intensive infiltration of TANs was positively associated with advanced stage, lymphatic metastasis, and poor prognosis of OSCC. Moreover, Mel reduced the survival and migration of OSCC-associated neutrophils. Mechanistically, Mel suppressed the TAN release of C-X-C motif chemokine ligand 8, C-C motif chemokine ligand 2 (CCL2), CCL4, and matrix metalloproteinase-9 by blockage of p38 MAPK and Akt signaling. Mel-fostered TANs decreased the migration and invasion of OSCC cells and reduced tube formation in vitro. Additionally, Mel-hampered pro-motility and pro-angiogenesis effects of TANs were dependent on MMP-9 suppression in OSCC. Overall, The beneficial roles of melatonin in retarding OSCC metastasis were implicated with inhibition of TANs.