The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo.

BACKGROUND AND AIMS: The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. METHODS: Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-ß1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. RESULTS: Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-ß1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. CONCLUSIONS: TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Properties of curcumin-loaded zein-tea saponin nanoparticles prepared by antisolvent co-precipitation and precipitation.

The properties of nutraceutical-loaded biopolymer nanoparticles fabricated by antisolvent co-precipitation (ASCP) and precipitation (ASP) were compared. Curcumin-loaded zein-tea saponin nanoparticles were fabricated using both methods and then their structural and physicochemical properties were characterized. The diameter of the nanoparticles prepared by ASCP were smaller (120-130 nm) than those prepared by ASP (140-160 nm). The encapsulation efficiency of the ASCP-nanoparticles (80.0%) was higher than the ASP-ones (71.0%) at a zein-to-curcumin mass ratio of 3:1, which was also higher than previous studies. The storage and light stability of curcumin was higher in zein-saponin nanoparticles than in zein nanoparticles. All nanoparticles had good water dispersibility after freeze-drying and rehydration. This study shows that nanoparticles produced by antisolvent co-precipitation have superior properties to those produced by antisolvent precipitation. The co-precipitation method leads to a higher encapsulation efficiency, smaller particle size, and greater storage stability, which may be advantageous for some applications.

Inhibition of the TLR/NF-κB Signaling Pathway and Improvement of Autophagy Mediates Neuroprotective Effects of Plumbagin in Parkinson's Disease.

A naphthoquinone molecule known as plumbagin (PL), which has a wide range of pharmacological properties including antitumor, antioxidation, anti-inflammation, and neuroprotective effects, is extracted from the roots of the medicinal herb Plumbago zeylanica L. Plumbagin has been studied for its potential to treat Parkinson's disease (PD). However, its effectiveness and mechanism are still unknown. This study intends to evaluate plumbagin's effectiveness against PD in vitro and in vivo. Plumbagin partially repaired the loss of dopaminergic neurons in the nigral substantia nigra and the resulting behavioural impairment caused by MPTP or MPTP/probenecid in mice. Furthermore, plumbagin treatment significantly inhibited the TLR/NF-κB pathways. It reduced the TNF-α, IL-6, and IL-1ß mRNA expression in PD mice induced by MPTP or MPTP/probenecid, which was consistent with the findings in the inflammatory model of BV2 cells induced by MPP+ or LPS. In addition, plumbagin treatment enhanced the microtubule-associated protein 1 light chain 3 beta (LC3) LC3-II/LC3-I levels while decreasing the p-mTOR and p62 protein accumulation in PD mice induced by MPTP or MPTP/probenecid, which was similar to the results obtained from the experiments in SH-SY5Y and PC12 cells induced by MPP+. Consequently, our results support the hypothesis that plumbagin, by promoting autophagy and inhibiting the activation of the TLR/NF-κB signaling pathway, is a promising treatment agent for treating Parkinson's disease (PD). However, to confirm plumbagin's anti-PD action more thoroughly, other animal and cell PD models must be used in future studies.

Interfacial characteristics and in vitro digestion of emulsion coated by single or mixed natural emulsifiers: lecithin and/or rice glutelin hydrolysates.

BACKGROUND: The interfacial characteristics and in vitro digestion of emulsion were related to emulsifier type. The mean droplet diameter, ζ-potential, microstructure, interfacial tension, Quartz crystal microbalance with dissipation (QCM-D) and in vitro gastrointestinal fate of emulsions stabilized by soybean lecithin, hydrolyzed rice glutelin (HRG) and their mixture were researched. RESULTS: The value of interfacial tension was much more dramatically declined for the sample containing 20 g kg-1 of HRG. For QCM-D, a rigid layer was formed for all the samples after rinsing. The layer thickness was 0.87 ± 0.20, 2.11 ± 0.31 and 2.63 ± 0.22 nm, and adsorbed mass was 87.17 ± 10.31, 210.56 ± 20.12 and 263.09 ± 23.23 ng cm-2 , for HRG, lecithin and HRG/lecithin, respectively, indicating both HRG and lecithin were adsorbed at the oil-water interface. Structural rearrangements at the interface occurred for HRG/lecithin. The kinetics and final amount of lipid digestion depended on emulsifier type: lecithin > HRG/lecithin > HRG. These differences in digestion rate were primarily due to differences in the aggregation state of the emulsifiers. CONCLUSION: The incorporation of lecithin into HRG emulsions had better interfacial properties comparing with HRG emulsion and facilitated lipid digestibility. These results provide important information for the rational design of plant-based functional food. © 2021 Society of Chemical Industry.

Comparison of Lutein Bioaccessibility from Dietary Supplement-Excipient Nanoemulsions and Nanoemulsion-Based Delivery Systems.

The impact of lutein-loaded nanoemulsions and excipient nanoemulsions mixed with lutein-based dietary supplements (capsules and soft gels) on the bioaccessibility of lutein was explored using a simulated gastrointestinal tract (GIT). The particle size, particle size distribution, ζ-potential, microstructure, lipid digestibility, and lutein bioaccessibility of all the samples were measured after they were exposed to different environments (stomach and small intestine environments) within a simulated GIT. As expected, the bioaccessibility of lutein from the capsules (1.5%) and soft gels (3.2%) was relatively low when they were administered alone. However, the co-administration of excipient nanoemulsions significantly increased the bioaccessibility of lutein from both the capsules (35.2%) and soft gels (28.7%). This phenomenon was attributed to the fast digestion of the small oil droplets in the excipient nanoemulsions and the further formation of mixed micelles to solubilize any lutein molecules released from the supplements. The lutein-loaded nanoemulsions exhibited a much higher lutein bioaccessibility (86.8%) than any of the supplements, which was attributed to the rapid release and solubilization of lutein when the lipid droplets were rapidly and extensively digested within the small intestine. This study indicates that the bioaccessibility of lutein is much higher in nanoemulsion droplets than that in dietary supplements. However, consuming dietary supplements in the presence of nanoemulsion droplets can greatly increase lutein bioavailability. The results of this study have important guiding significance for the design of more effective lutein supplements.

Effects of anionic polysaccharides on the digestion of fish oil-in-water emulsions stabilized by hydrolyzed rice glutelin.

The effects of two anionic polysaccharides (pectin and xanthan gum) on the in vitro lipid digestibility of fish oil-in-water emulsions stabilized by hydrolyzed rice glutelin (HRG) were determined. The emulsions were passed through a simulated gastrointestinal tract (GIT) consisting of mouth, stomach, and small intestine phases. The physicochemical properties of the colloidal particles in the gastrointestinal fluids (mean particle diameter, ξ-potential, and structural organization) were monitored throughout the GIT. In addition, the kinetics of lipid digestion was characterized in the small intestine phase. Interestingly, the addition of polysaccharide led to a marked increase in both the rate and extent of lipid digestion, with the effect depending on polysaccharide type. For instance, the initial rates of lipid digestion were 8.6 ±â€¯0.6, 13.3 ±â€¯0.4 and 16.1 ±â€¯0.6% free fatty acids (FFA) released min-1 for HRG emulsions containing no polysaccharides, pectin, and xanthan gum, respectively. Similarly, the calculated final extents of lipid digestion were 71.9 ±â€¯3.6, 97.7 ±â€¯3.2, and 100.0 ±â€¯3.8%, respectively. This was probably because the polysaccharides inhibited droplet flocculation, thereby increasing the surface area of lipids exposed to the digestive enzymes. Moreover, the polysaccharides may have interacted with other components involved in the lipid digestion process, such as enzymes, bile salts, and calcium ions. Our results may facilitate the design of plant-based functional foods and beverages that can control lipid digestion in the gastrointestinal tract.

Preparation of Bioactive Polysaccharide Nanoparticles with Enhanced Radical Scavenging Activity and Antimicrobial Activity.

Because of their biocompatibility and biodegradability in vivo, natural polysaccharides are effective nanocarriers for delivery of active ingredients or drugs. Moreover, bioactive polysaccharides, such as tea, Ganoderma lucidum, and Momordica charantia polysaccharides (TP, GLP, and MCP), have antibacterial, antioxidant, antitumor, and antiviral properties. In this study, tea, Ganoderma lucidum, and Momordica charantia polysaccharide nanoparticles (TP-NPs, GLP-NPs, and MCP-NPs) were prepared via the nanoprecipitation approach. When the ethanol to water ratio was 10:1, the diameter of the spherical polysaccharide nanoparticles was the smallest, and the mean particle size of the TP-NPs, GLP-NPs, and MCP-NPs was 99 ± 15, 95 ± 7, and 141 ± 9 nm, respectively. When exposed to heat, increased ionic strength and pH levels, the nanoparticles exhibited superior stability and higher activity than the corresponding polysaccharides. In physiological conditions (pH 7.4), the nanoparticles underwent different protein adsorption capacities in the following order: MCP-NPs> TP-NPs> GLP-NPs. Moreover, the 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical, and superoxide anion radical scavenging rates of the nanoparticles were increased by 9-25% as compared to the corresponding polysaccharides. Compared to the bioactive polysaccharides, the nanoparticles enhanced antimicrobial efficacy markedly and exhibited long-acting antibacterial activity.