PMID: 

Phytother Res. 2018 Jan ;32(1):115-124. Epub 2017 Oct 18. PMID: 29044703

Abstract Title: 

A comparative study on the effect of promoting the osteogenic function of osteoblasts using isoflavones from Radix Astragalus.

Abstract: 

Radix Astragalus has been shown to exert beneficial effects regarding the prevention postmenopausal osteoporosis. However, its mechanism of action remains to be investigated. Calycosin, formononetin, and calycosin-7-O-β-d-glucoside are the main isoflavone constituents of Astragalus. In this study, the abilities of these 3 compounds to promote osteogenic function of osteoblasts were compared, and the structure-activity relationships of these osteotrophic isoflavones were determined. Calycosin exhibited a greatereffect than formononetin and calycosin-7-O-β-d-glucoside regarding improvements in osteogenic function of osteoblasts, as demonstrated by cell proliferation, alkaline phosphatase activity, collagen I and osteocalcin secretion, and the number and area of mineralized bone nodules. This suggests thatcalycosin may be better than formononetin and calycosin-7-O-β-d-glucoside at preserving bone mass. In addition, calycosin, formononetin, and calycosin-7-O-β-d-glucoside stimulate the expression of bone morphogenetic protein 2 and runt-related transcription factor 2 proteins, which indicates that all 3 agents may promote the osteogenesis of osteoblasts via regulation of bone morphogenetic protein 2 expression. In conclusion, calycosin may be the best candidate, with higher osteogenic activity than formononetin and calycosin-7-O-β-d-glucoside. The higher osteogenic activity of calycosin couldbe attributable to the superiority of its chemical structure (a hydroxyl group at position C3 of Ring B and no glucosyl group).

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PMID: 

Curr Drug Targets. 2016 ;17(12):1331-40. PMID: 26343107

Abstract Title: 

The Antioxidant Effects of Radix Astragali (Astragalus membranaceus and Related Species) in Protecting Tissues from Injury and Disease.

Abstract: 

Oxidative stress plays a key role in the pathogenesis of various diseases. Antioxidants protect the cells and tissues from oxidative stress by scavenging free radicals and reactive oxygen species. These antioxidants may be endogenous or exogenous. Plants are considered as potential and powerful exogenous source of antioxidants. Astragalus species (spp.), especially Astragalus membranaceus, have a long history of medicinal use in traditional Chinese medicine. Specifically, constituents of the dried roots of Astragalus spp. (Radix Astragali) provide significant protection against heart, brain, kidney, intestine, liver and lung injury in various models of oxidative stress-related disease. Different isolated constituents of Astragalus spp., such as astragalosides, flavonoids and polysaccharides also displayed significant prevention of tissue injury via antioxidant mechanisms. In this article, the antioxidant benefits of Astragalus spp. and its isolated components in protecting tissues from injury are reviewed, along with identification of the various constituents that possess antioxidant activity.

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PMID: 

Int J Biol Macromol. 2020 Feb 26 ;153:349-356. Epub 2020 Feb 26. PMID: 32112840

Abstract Title: 

Astragalus polysaccharide exerts anti-Parkinson via activating the PI3K/AKT/mTOR pathway to increase cellular autophagy level in vitro.

Abstract: 

Astragalus polysaccharide (APS) is a bioactive macromolecule, which has been used to alleviate the development of Parkinson's disease (PD), while its mechanism is still unresolved. As is generally accepted that autophagy has an important link with PD, thus it is reasonable to hypothesize that APS was involved in autophagy pathway for the presence of anti-PD. To verify this hypothesis, PD model was induced by 100 μM 6-hydroxydopamine (6-HODA) in PC12 cells and then treated with different concentration of APS. Results showed that APS could increase cell viability and the level of autophagy, improve the formation of autophagosome, promote the conversion of LC3-I to LC3-II, showing APS could improve autophagy level. Moreover, APS could down-regulate the expression of pAKT and pmTOR, and up-regulate the expression of PTEN. While these proteins are involved in PI3K/AKT/mTOR pathway, we then knocked down (KD) endogenous PI3K protein (the PI3K/AKT/mTOR pathway receptor protein) in PC12 cells. Results showed that these events regulated by APS were reversed in PI3K KD cells, shown that APS activated autophagy through PI3K/AKT/mTOR pathway for treating PD. Altogether, APS has the role of increasing autophagy, and this event was responsible for inhibiting PI3K protein to activate PI3K/AKT/mTOR pathway.

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PMID: 

Crit Rev Food Sci Nutr. 2019 Oct 31:1-11. Epub 2019 Oct 31. PMID: 31670973

Abstract Title: 

Effect of bergamot on lipid profile in humans: A systematic review.

Abstract: 

Dyslipidemia is a well-established modifiable cardiovascular risk. Although statins can reduce LDLc by 50-60%, less than 20% of patients with high risk of CVD achieve LDL targets. The aim of this systematic review is to evaluate the effect of the nutraceutical, bergamot (), on lipid parameters in humans. PubMed, Embase, Cochrane Library, and Google Scholar databases were searched for interventional and observational studies investigating the effect of bergamot on lipid profile in humans. This systematic review retrieved a total of 442 studies of which 12 articles fulfilled the eligibility criteria and were included in the qualitative synthesis. Based on data, 75% of studies showed a significant decrease in total cholesterol, triglycerides and LDLc. The decrease in total cholesterol varied from 12.3% to 31.3%, from 7.6% to 40.8% in LDLc and from 11.5% to 39.5% in triglycerides. Eight trials reported HDLc increase after intervention with bergamot. Overall, a dose-dependent and possible synergistic effect when administering with statins can be deducted from these trials. It is essential to point out that studies had heterogeneous designs and scientific quality of studies was quite limited. Promising findings reveal an alternative therapeutic option in dyslipidemia management with bergamot supplementation, especially in subjects with statins intolerance.

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PMID: 

Front Pharmacol. 2019 ;10:575. Epub 2019 May 21. PMID: 31164827

Abstract Title: 

Effect of Grape Pomace Polyphenols With or Without Pectin on TMAO Serum Levels Assessed by LC/MS-Based Assay: A Preliminary Clinical Study on Overweight/Obese Subjects.

Abstract: 

Growing evidence suggests that trimethylamine N-oxide (TMAO) is recognized as a biomarker of increased cardiovascular risk. So far, the evaluation of TMAO serum levels in the clinical practice is limited due to the lack of developing new facile methods with reduced limitations. However, few approaches were achieved to determine TMAO in serum by using mass spectrometry-based technique, some limitations were reported including the use of internal standards. Therefore, in this work, a liquid chromatography-mass spectrometry (LC/MS) based-assay was developed to evaluate the effect of grape pomace extract (Taurisolo, group A) or Taurisolo+pectin (group B) on TMAO serum levels in a cohort of overweight/obese subjects. The serum levels of TMAO have been assessed before and after treatment, through LC/MS analysis. After 8-week treatment, in both intervention groups TMAO serum levels significantly decreased (-78.58%= 0.006 and -76.76%= 0.001, group A and group B, respectively). Moreover, we performed several analyses aimed to validate the LC/MS method we used. The method has high precision (% C.V = from 12.12 to 3.92% and from 8.25 to 1.07% for intraday and interday, respectively) and accuracy (% bias = from -5.52 to 0.5% and from -1.42 to 3.08% for intraday and interday, respectively). TMAO recoveries from serum ranged from 99 to 97%; LOD: 2 ng/ml and LOQ: 6 ng/ml. In conclusion, we demonstrated the efficacy of a novel nutraceutical formulation in reducing TMAO serum levels in high cardiovascular risk-subjects, and proposed a useful, versatile and rapid LC/MS method for identification and quantization of TMAO, without the use of marked/isotopic internal standards. It, thus, may represent a novel and practical method with applications in clinical practice and nutraceutical research.This study is listed on the ISRCTN registry with ID ISRCTN10794277 (doi: 10.1186/ISRCTN10794277).

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PMID: 

Nutrients. 2019 Jan 10 ;11(1). Epub 2019 Jan 10. PMID: 30634687

Abstract Title: 

Effects of Grape Pomace Polyphenolic Extract (Taurisolo) in Reducing TMAO Serum Levels in Humans: Preliminary Results from a Randomized, Placebo-Controlled, Cross-Over Study.

Abstract: 

Trimethylamine N-oxide (TMAO) is considered a novel risk factor for cardiovascular diseases. Several studies demonstrated that polyphenols are able to inhibit the growth of TMA-producing bacterial strains, and resveratrol (RSV) reduced TMAO levels in mice. In the present study, we evaluated the TMAO-reducing effect of a novel nutraceutical formulation containing grape pomace extract in humans (Taurisolo). The Taurisolopolyphenol content was evaluated by a High Performance Liquid Chromatography-diode-array detector (HPLC-DAD) method, and RSV was monitored as an indicative marker. After in vitro GI digestion, intestinal bioaccessibility of RSV was 92.3%. A randomized, placebo-controlled, cross-over trial was carried out to evaluate the TMAO-reducing effect of Taurisolo. In acute, the maximum levels of RSV were detected both in serum and whole blood 60 min after the administration of Taurisolo; in chronic, a significant increase of RSV was detected in serum after the 4-week treatment. After 4 weeks, the levels of TMAO were significantly decreased in the treatment group compared to placebo (63.6% vs. 0.54%, respectively,

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PMID: 

Food Funct. 2018 Dec 13 ;9(12):6470-6483. PMID: 30465688

Abstract Title: 

An in vitro exploratory study of dietary strategies based on polyphenol-rich beverages, fruit juices and oils to control trimethylamine production in the colon.

Abstract: 

Trimethylamine-N-oxide (TMAO) has been described as a new biomarker of cardiovascular disease (CVD), derived from gut microbial biotransformation of dietary choline and l-carnitine into trimethylamine (TMA) and subsequent hepatic oxidation. (Poly)phenols are among the dietary factors able to interfere with microbial enzymatic activity, possibly modulating TMA biotransformation at the gut level. The aim of this work was to investigate the in vitro biotransformation of choline and carnitine using faecal starters obtained from omnivorous and vegetarian subjects and the effect of (poly)phenol-rich foods on TMA production. Choline and l-carnitine were fermented with vegetarian or omnivorous faecal slurries, alone or in combination with 10 (poly)phenol-rich food items. TMA production from carnitine, but not from choline, was significantly lower when vegetarian faecal starters were used and, among the tested food items, blonde orange juice significantly reduced TMA formation during faecal biotransformation. Consequently, the main compounds of orange juice, namely phenolic compounds, terpenes, limonoids, organic acids and sugars, were tested individually. Sugars exerted the highest inhibitory effect on TMA production. Despite some limitations deriving from the applied in vitro model, this is the first work describing a possible role of some (poly)phenol-rich dietary products on the modulation of TMA colonic production. Free sugars were the main factor responsible for TMA inhibition, suggesting a potential beneficial role of colonic fermentation of carbohydrates in reducing TMA formation from its precursor molecules. This work opens new research directions to evaluate the effect of dietary fermentable fibre on TMA production and, potentially, on circulating TMAO levels.

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PMID: 

mBio. 2016 Apr 5 ;7(2):e02210-15. Epub 2016 Apr 5. PMID: 27048804

Abstract Title: 

Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.

Abstract: 

UNLABELLED: The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE(-/-) mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.IMPORTANCE: Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV's anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.

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PMID: 

Nutrients. 2019 Jan 16 ;11(1). Epub 2019 Jan 16. PMID: 30654453

Abstract Title: 

Effects of Lifestyle Intervention on Plasma Trimethylamine N-Oxide in Obese Adults.

Abstract: 

Accumulating evidence linking trimethylamine N-oxide (TMAO) to cardiovascular disease (CVD) risk has prompted interest in developing therapeutic strategies to reduce its production. We compared two lifestyle intervention approaches: hypocaloric versus eucaloric diet, combined with exercise, on TMAO levels in relation to CVD risk factors. Sixteen obese adults (66.1± 4.4 years, BMI (body mass index): 35.9 ± 5.3 kg/m², fasting glucose: 106 ± 16 mg/dL, 2-h PPG (postprandial glucose): 168 ± 37 mg/dL) were randomly assigned to 12 weeks of exercise (5 days/week, 80⁻85% HR(maximal heart rate)) plus either a hypocaloric (HYPO) (-500 kcal) or a eucaloric (EU) diet. Outcomes included plasma TMAO, glucose metabolism (oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamps for glucose disposal rates (GDR)), exercise capacity (VO, maximal oxygen consumption), abdominal adiposity (computed tomography scans), cholesterol, and triglycerides. Results showed that body composition (body weight, subcutaneous adiposity), insulin sensitivity, VO, and cholesterol all improved (

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PMID: 

Sci Rep. 2017 05 3 ;7(1):1445. Epub 2017 May 3. PMID: 28469156

Abstract Title: 

Impaired renal function and dysbiosis of gut microbiota contribute to increased trimethylamine-N-oxide in chronic kidney disease patients.

Abstract: 

Chronic kidney disease (CKD) patients have an increased risk of cardiovascular diseases (CVDs). The present study aimed to investigate the gut microbiota and blood trimethylamine-N-oxide concentration (TMAO) in Chinese CKD patients and explore the underlying explanations through the animal experiment. The median plasma TMAO level was 30.33 μmol/L in the CKD patients, which was significantly higher than the 2.08 μmol/L concentration measured in the healthy controls. Next-generation sequence revealed obvious dysbiosis of the gut microbiome in CKD patients, with reduced bacterial diversity and biased community constitutions. CKD patients had higher percentages of opportunistic pathogens from gamma-Proteobacteria and reduced percentages of beneficial microbes, such as Roseburia, Coprococcus, and Ruminococcaceae. The PICRUSt analysis demonstrated that eight genes involved in choline, betaine, L-carnitine and trimethylamine (TMA) metabolism were changed in the CKD patients. Moreover, we transferred faecal samples from CKD patients and healthy controls into antibiotic-treated C57BL/6 mice and found that the mice that received gut microbes from the CKD patients had significantly higher plasma TMAO levels and different composition of gut microbiota than did the comparative mouse group. Our present study demonstrated that CKD patients had increased plasma TMAO levels due to contributions from both impaired renal functions and dysbiosis of the gut microbiota.

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