Hippuric Acid Research Articles

Arteriovenous Fistulae in Chronic Kidney Disease and the Heart: Physiological, Histological, and Transcriptomic Characterization of a Novel Rat Model.

Background Arteriovenous fistulae (AVFs) are the gold standard for vascular access in those requiring hemodialysis but may put an extra hemodynamic stress on the cardiovascular system. The complex interactions between the heart, kidney, and AVFs remain incompletely understood. Methods and Results We characterized a novel rat model of five-sixths partial nephrectomy (NX) and AVFs. NX induced increases in urea, creatinine, and hippuric acid. The addition of an AVF (AVF+NX) further increased urea and a number of uremic toxins such as trimethylamine N-oxide and led to increases in cardiac index, left and right ventricular volumes, and right ventricular mass. Plasma levels of uremic toxins correlated well with ventricular morphology and function. Heart transcriptomes identified altered expression of 8 genes following NX and 894 genes following AVF+NX, whereas 290 and 1431 genes were altered in the kidney transcriptomes, respectively. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed gene expression changes related to cell division and immune activation in both organs, suppression of ribosomes and transcriptional activity in the heart, and altered renin-angiotensin signaling as well as chronodisruption in the kidney. All except the latter were worsened in AVF+NX compared with NX. Conclusions Inflammation and organ dysfunction in chronic kidney disease are exacerbated following AVF creation. Furthermore, our study provides important information for the discovery of novel biomarkers and therapeutic targets in the management of cardiorenal syndrome.

Citrate and hydroxycinnamate derivatives from Mume Fructus protect LPS-injured intestinal epithelial cells by regulating the FAK/PI3K/AKT signaling pathway

Ethnopharmacological relevanceMume Fructus (MF) is processed from the near-ripe fruit of Prunus mume (Siebold) Siebold & Zucc by drying at low temperature until the color turns black. MF is often used in Chinese medicine for the treatment of chronic diarrhea and dysentery. Previous studies have shown that the active components of MF against Crohn's disease (CD) are mainly citrate and hydroxycinnamate derivatives, which can alleviate the CD-induced inflammatory response and intestinal barrier damage. However, their molecular mechanisms on CD still need further elucidation. Aim of the studyTo investigate the protective effects and underlying mechanisms of citrate and hydroxycinnamate derivatives in MF on intestinal epithelial injury. Materials and methodsNetwork pharmacology technology was used to predict the anti-CD targets and molecular mechanisms of 4 citrate and 11 hydroxycinnamate derivative prototypes and 5 hydroxycinnamate derivative metabolites in the 40% ethanol fraction of MF (MFE40), the active anti-CD ingredient group of MF. Lipopolysaccharide (LPS)-treated IEC-6 cells were used to investigate the effects of the above components on the proliferation of damaged IEC-6 cells and to verify the molecular mechanism of their regulation on the FAK/PI3K/AKT signaling pathways for the promotion of the proliferation of IEC-6 cells. ResultsA “compound-target-pathway” network was constructed based on network pharmacology analysis, including 20 citrate and hydroxycinnamate derivatives that target 316 core proteins and 36 CD-related pathways, of which PI3K-AKT pathway and focal adhesion were the most enriched pathways. Further cell validation experiments showed that 1 citric acid (CA) compound and 10 hydroxycinnamate derivatives, including 3-O-caffeoylquinic acid (3CQA), 4-O-caffeoylquinic acid (4CQA), 5-O-caffeoylquinic acid (5CQA), caffeic acid (CFA), p-coumaric acid (PCMA), m-coumaric acid (MCMA), ferulic acid (FUA), isoferulic acid (IFUA), 3-hydroxyphenylpropionic acid (3HPPA) and hippuric acid (HPP), could promote the proliferation of IEC-6 cells and inhibit the damage of LPS to IEC-6 cells. Ethyl caffeate (ECFA), a hydroxycinnamic acid derivative, had no effect on promoting the proliferation of IEC-6 cells and was weak in inhibiting the damage of IEC-6 cells caused by LPS. Further mechanistic verification experiments showed that 7 citrate and hydroxycinnamate derivatives (CA, CFA, 3CQA, MCMA, FUA, 3HPPA, and HPP) could upregulate the expression of p-FAK, p-PI3K, and p-AKT proteins. Among them, CA had the better effect on activating the FAK-PI3K-AKT signaling pathway. ConclusionsCitrate and hydroxycinnamate derivatives in MF can ameliorate LPS-induced intestinal epithelial cell injury to demonstrate potential for Crohn's disease alleviation. This protective effect can be achieved by upregulating FAK/PI3K/AKT pathway.

A metabolic biomarker panel of restless legs syndrome in peritoneal dialysis patients.

Restless legs syndrome (RLS) is a neuromotor disorder, and dialysis patients are more likely to develop RLS. RLS often causes sleep disorders, anxiety and depression in patients. It will increase the risk of death and severely affect the life of patients. At present, RLS has not received enough recognition and attention, and the misdiagnosis rate can reach more than 10%. The discovery set selected 30 peritoneal dialysis (PD) patients and 27 peritoneal dialysis patients with RLS (PD-RLS). A metabolomics method based on ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometric method (UPLC-Q-TOF/MS) was used to analyze the differential metabolites of the two groups. 51 PD patients and 51 PD-RLS patients were included in the validation set. The receiver operating characteristic (ROC) analysis was used to evaluate the early diagnostic biomarkers, and the correlation between the differential metabolites and laboratory test indexes was analyzed to explore the biological function of the differential metabolites. Through the integrated analysis, four metabolites can be used as markers for the diagnosis of PD-RLS, including Hippuric acid, Phenylacetylglutamine, N,N,N-Trimethyl-L-alanyl-L-proline betaine and Threonic acid. Through ROC analysis, it is found that they can be used as a metabolic biomarker panel, and the area under the curve of this combination is more than 0.9, indicating that the panel has good diagnostic and predictive ability. Metabolomics based on UPLC-Q-TOF/MS technology can effectively identify the potential biomarkers, and provide a theoretical basis for the early diagnosis, prevention and treatment on PD-RLS.

Mitochondrial dysfunction: The pathological link between psoriasis and insulin resistance?

Psoriasis is strongly associated with insulin resistance (IR). Lipid profile disturbances and upregulation of enzymes crucial for fatty acid oxidation have been reported in patients with psoriasis. Mitochondrial ß-oxidation is altered in patients with IR. Common mitochondrial dysfunction may be involved in the origin of both diseases. This study aimed to evaluate mitochondrial ß-oxidation, intermediary metabolism, and mitochondrial content in psoriatic patients with or without IR and compare them to healthy controls. The participants were divided into three groups: (1) psoriasis and IR (n=26); (2) psoriasis without IR (n=17); and (3) healthy controls (n=17). Quantification of amino acids and acylcarnitines (AC) by tandem mass spectrometry, determination of urinary organic acids by gas chromatography/mass spectrometry (GC/MS), and mitochondrial DNA quantification were performed in all groups. When comparisons were made between the two psoriatic groups, no differences were found between: C5DC + C6OH, C16:1, Met/Leu, Met/Phe, C16:1/C16, and C5DC + C6OH/C4DC + C5OH ratios. Nine analytes were different: phenylalanine, Cit/Phe, and Cit/Tyr ratios, C0, C3, C5, C6DC, C16, and C18:1OH. There were no correlations between psoriasis area and severity index (PASI), body mass index (BMI) and duration of disease with ACs. A higher proportion of patients with psoriasis showed increased urine levels of uric acid and hippuric acid (p=0.01). The mtDNA content was significantly higher in cases than in controls, with no differences between IR and non-IR psoriatic patients. Psoriasis patients with and without IR have a different acylcarnitine profile reflecting impaired ß-oxidation. A distinctive profile of acylcarnitines suggests an involvement of mitochondrial function associated with an increase in stearoyl CoA desaturase (SCD) activity in psoriatic patients with and without IR.

Fabrication of hollow fiber membranes with different inner diameters for enhanced uremic toxins removal in hemodialysis: Exploring from high-flux to high molecular weight retention onset classes

Developing a hemodialysis membrane that sufficiently removes both small-sized toxins and the middle molecule is essential. Protein-bound uremic toxins (PBUTs) are involved in an increased risk of cardiovascular events and mortality; however, their removal pathway has not been explored yet. Herein, this work aimed to fabricate novel hemodialysis membranes under different inner diameters (ID) with approaching two classes: high-flux (M#1, M#2) and high molecular weight retention onset (MWRO) (M#3, M#4). The results showed that membrane with smaller ID (M#1: 218 μm) performed a superior removal of small molecules i.e., urea: 266,394 mg/m2 and creatinine: 11,985 mg/m2. Spinning conditions, such as bore and dope solution flowrate, had a significant impact on pore size distribution, porosity, and dimensions, but not entirely on the membrane structure. These factors are crucial to govern the efficiency of uremic toxin clearance and the level of protein loss/leaking. Consequently, a high MWRO of M#4 at 13,998 Da favored enhanced removal of middle molecules, resulting in lysozyme removal of 5120 mg/m2 and a high sieving coefficient of β2-microglobulin (0.91). A minimized loss (2.46 g/session) and minor leaking (0.08 g/session) of protein were attained in M#4 e.g., MWRO class. Notably, we first explored the removal pathway of protein-bound uremic toxins (PBUTs) with i) Free Form-PBUTs removal by diffusion ii) Free Form-PBUTs removal by adsorption iii) Bovine serum albumin (BSA)-PBUTs conjugate adsorption on a membrane, and iv) Leaking of BSA-PBUTs conjugate to the dialysate. Our high-flux and MWRO membranes removed hippuric acid of 2911 mg/m2; 3476 mg/m2, indoxyl sulfate of 1640 mg/m2; 1452 mg/m2, p-cresol of 3,1469 mg/m2; 3702 mg/m2, respectively. Overall, our study proposes a promising membrane for hemodialysis application that exhibited either higher flux or high molecular weight retention onset compared to commercial membranes. Their properties facilitate an increase in the removal of middle molecules but still retain a minimized loss of protein and minor leakage.

Relationship Between the Concentration of Airborne Benzene Pollutant and the Amount of Urinary Metabolites of Trans, Trans-muconic Acid, and Hippuric Acid in Employees Working in Different Plants of Bou Ali Sina Petrochemical Company

Background & Aims: The petrochemical industry as a modern industry, despite the positive outcomes it has brought to mankind, is a source of gaseous and aerosol pollution and industrial effluents on a large scale, which can have direct and indirect destructive effects on the environment and human life. This study investigated the relationship between the amount of airborne benzene with the amount of trans,trans-muconic acid (ttMA) and hippuric acid metabolites in the urine of workers working in petrochemical complexes with different exposure times and methods. Materials and Methods: For this purpose, breathing the air of different petrochemical plants of Bou Ali Sina was sampled by the National Institute for Occupational Safety and Health 1501 method, and the urine of workers (n = 24) was also sampled in these units. In addition, the amount of benzene in the air samples and the amount of urinary metabolites of ttMA and hippuric acid were analyzed in urine samples sent to the laboratory using a high-performance gas chromatography-mass spectrometry device and gas-liquid chromatography. Finally, urinary creatinine was measured by an ultraviolet-visible spectrophotometer. Results: The results showed that the concentration of benzene in the aromatic unit had the highest value, which had a higher level of pollution than both standards. The xylene mixing unit with a concentration of 3.6 µg/m3 , the loading unit with a benzene content of 3.4 µg/m3 , and a tank unit with 2.8 µg/m3 had a lower amount of benzene pollution compared to the Occupational Safety and Health Administration permissible exposure limit-short-term exposure limit (OSHA PEL-STEL) standard but had higher pollution levels in comparison to the OSHA PEL-TWA (time-weighted average) standard. In the sampling unit of the laboratory with a benzene amount of 0.94 µg/m3 and in the technician unit of the laboratory, the amount of pollution was lower than both OSHA PEL-TWA and OSHA PEL-STEL standards. The aromatic unit demonstrated the highest amount of benzene, while the lowest amount was related to the laboratory section. Conclusion: The results of the measurement of urinary benzene metabolites revealed that the concentration of urinary phenol and inhaled benzene in evening shift workers was higher than the corresponding amount in the morning shift workers, which may be due to the high level of pollution evenings compared to the morning. On the other hand, the results represented that the average hippuric acid in the exposed people (n=24) was higher than the control (n=20) so that it was 0.35 in the exposed and 0.26 in the control subjects. In addition, the average muconic acid in the exposed and control subjects decreased to 1.57 and 0.89, respectively. The minimum and maximum amounts of muconic and hippuric acids in the exposed subjects were 0.97 and 2.62, as well as 0.14 and 0.83, respectively. The maximum and minimum concentrations of muconic and hippuric acids were 2.62 and 0.97, as well as 0.83 and 0.14 in exposed subjects, respectively, which was less than muconic acid.

Cerebrovascular Disease, Cardiovascular Disease, and Chronic Kidney Disease: Interplays and Influences.

We reviewed reasons for the high cardiovascular risk (CVD) of patients with chronic kidney disease (CKD), and explored alternatives to treatment of traditional risk factors to reduce CVD in CKD. Besides traditional risk factors, patients with CKD are exposed to uremic toxins of two kinds: systemically derived toxins include asymmetric dimethylarginine (ADMA), total homocysteine (tHcy), thiocyanate, tumor necrosis factor alpha, and interleukin 6. Gut-derived uremic toxins (GDUT), products of the intestinal microbiome, include hippuric acid, indoxyl sulfate, p-cresyl sulfate, p-cresyl glucuronide, phenylacetylglutamine, and trimethylamine N-oxide (TMAO). Cyanocobalamin is toxic in patients with CKD. Approaches to reducing plasma levels of these uremic toxins would include diet to reduce GDUT, kidney transplantation, more intensive dialysis, and vitamin therapy to lower tHcy with methylcobalamin rather than cyanocobalamin. The high CVD risk in CKD requires consideration of therapies beyond treatment of traditional risk factors.

Design, synthesis and anticancer evaluation of 1,2,4-oxadiazole incorporated structurally modified hippuric acid derivatives

A new series of 1,2,4,-oxadiazole incorporated hippuric acid derivatives (11a-j) have been synthesized and characterized by 1HNMR, 13CNMR and mass spectral data. All these derivatives were tested for their anticancer profile against human cancer cell lines such as breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by utilized of MTT assay. All the compounds displayed more potent anticancer activity with IC50 values range from 0.018±0.009 µM to 21.5±7.85µM. Among them, compounds 11b, 11c, 11f, 11g and 11h showed most potent activity. Molecular docking was carried out for synthesized compounds (11a-j) to identify the molecular interactions with protein targets.

Integrated 16S rRNA sequencing and metabolomics analysis to investigate the antidepressant role of Yang-Xin-Jie-Yu decoction on microbe-gut-metabolite in chronic unpredictable mild stress-induced depression rat model.

Objectives: Our goals were to evaluate the antidepressant efficacy of Yang-Xin-Jie-Yu Decoction (YXJYD) in Chronic Unpredictable Mild Stress (CUMS)-induced depression rat model and to investigate the underlying mechanisms. Design: We used CUMS-induced depression rat model to evaluate whether oral administration of YXJYD with different doses (2.1 g/kg, 1.05 g/kg and 0.525 g/kg, respectively) improve the depressive-like symptoms, and then performed UHPLC-Q-TOF-MS to explore the active ingredients of YXJYD. Subsequently, rat’s cecal contents, serum, and urine were collected from the control group, CUMS model group, and YXJYD high-dose (2.1 g/kg) treatment group. The 16S rRNA sequencing was performed on the cecal contents, based on Illumina MiSeq platform, and ANOVA analysis were used to analyze the composition variety and screen differential expression of gut bacteria in the three groups. 1H Nuclear Magnetic Resonance (NMR) analysis was used for analyzing the metabolites obtained from cecal contents, serum, and urine, and KEGG enrichment analysis was used to identify pathways of differential metabolites. An integrated 16S rRNA sequencing and metabolomic data were conducted to characterize the underlying mechanisms of YXJYD Results: The gut microbial communities, and serum, cecal content, urine metabolic compositions were significantly significantly altered in CUMS-induced depressive rats, while YXJYD effectively ameliorated the CUMS-associated gut microbiota dysbiosis, especially of Monoglobus, and alleviated the disturbance of serum, cecal content, urine metabolome and reversed the changes of key depressive and gut microbiota-related metabolites, such as succinic acid, taurine, hippuric acid, melatonin. With an integrated study of the gut microbiota and metabolomes, we identified the pathway of tricarboxylic acid cycle (TCA cycle) and propanoate metabolism as the regulated target of YXJYD on host-microbiome interaction. Conclusion: Our findings further confirmed the imbalance of metabolism and intestinal microbial is closely related to CUMS-induced depression. YXJYD regulates gut microbiome to affect body metabolomes and then produce antidepressant-like effect in CUMS-induced depressive rats while its molecular mechanism possibly be increased Monoglobus abundance in gut microbiota and regulated the TCA cycle pathway and propanoate metabolism in host.

The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial

BackgroundMediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT).MethodsIn the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.ResultsParticipants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: − 2.7%, green-MED: − 3.9%) and waist circumference (MED: − 4.7%, green-MED: − 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: − 4.2%, MED: − 6.0%, green-MED: − 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models).ConclusionsA green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression.Trial registrationClinicalTrials.gov, NCT03020186

Gut microbiota-derived metabolites in inflammatory diseases based on targeted metabolomics.

The gut microbiota plays an important role in inflammatory diseases. Metabolites in the three metabolic pathways of tryptophan (Trp), histidine (His), and phenylalanine (Phe) can affect various inflammatory conditions, such as obesity, diabetes, arthritis, colitis, atherosclerosis, and neuroinflammation. We established an LC–MS/MS method to measure 17 metabolites—Trp, 3-indole-acetic acid (Iaa), 3-indole-lactate (Ila), 3-indole-propionic acid (Ipa), 3-indole formaldehyde (Iald), kynurenine (Kn), kynurenic acid (Kyna), 3-Hydroxyanthranilic acid (3-Haa), His, 3-methylhistidine (3-Mhis), histamine (Hist), imidazole propionic acid (Imp), 4-imidazoacetic acid (Imaa), urocanic acid (Ua), Phe, phenylethylamine (Pea), and hippuric acid (Ha)—in the three metabolic pathways. The method exhibited high sensitivity and good selectivity, linearity, accuracy, precision, stability; and recovery rate; all met the requirements of biological sample analysis. By establishing a rheumatoid arthritis (RA) model of Sprague–Dawley rats and performing 16S rRNA sequencing on their feces, it was found that there was dysbiosis, including changes in phylum level, genus level, and α biodiversity of gut bacteria. The contents of the microbiota metabolites Iaa and Ipa in the model group were significantly decreased, and those of Iald, Kn, Kyna, Ha, and Imp were significantly increased. The common therapeutic drugs Tripterygium glycosides, total glucosides of peony, and their main active ingredients were screened by in vitro incubation with gut bacteria: it was found that Tripterygium glycosides and their active ingredients could lead to a variation in metabolites in the Trp and Phe pathways. Total glucosides and active components of peony could lead to a variation in metabolites in the Phe pathway of the gut microbiota.

Urine NMR Metabolomics for Precision Oncology in Colorectal Cancer.

Metabolomics is a fundamental approach to discovering novel biomarkers and their potential use for precision medicine. When applied for population screening, NMR-based metabolomics can become a powerful clinical tool in precision oncology. Urine tests can be more widely accepted due to their intrinsic non-invasiveness. Our review provides the first exhaustive evaluation of NMR metabolomics for the determination of colorectal cancer (CRC) in urine. A specific search in PubMed, Web of Science, and Scopus was performed, and 10 studies met the required criteria. There were no restrictions on the query for study type, leading to not only colorectal cancer samples versus control comparisons, but also prospective studies of surgical effects. With this review, all compounds in the included studies were merged into a database. In doing so, we identified up to 100 compounds in urine samples, and 11 were found in at least three articles. Results were analyzed in three groups: case (CRC and adenomas)/control, pre-/post-surgery, and combining both groups. When combining the case-control and the pre-/post-surgery groups, up to twelve compounds were found to be relevant. Seven down-regulated metabolites in CRC were identified, creatinine, 4-hydroxybenzoic acid, acetone, carnitine, d-glucose, hippuric acid, l-lysine, l-threonine, and pyruvic acid, and three up-regulated compounds in CRC were identified, acetic acid, phenylacetylglutamine, and urea. The pathways and enrichment analysis returned only two pathways significantly expressed: the pyruvate metabolism and the glycolysis/gluconeogenesis pathway. In both cases, only the pyruvic acid (down-regulated in urine of CRC patients, with cancer cell proliferation effect in the tissue) and acetic acid (up-regulated in urine of CRC patients, with chemoprotective effect) were present.

Assessment of inflammatory cytokines in exhaled breath condensate and exposure to mixtures of organic pollutants in brick workers.

Brick production causes a lot of pollution in the form of dust, fumes, and toxic substances. Therefore, brick workers are highly exposed to pollutants and present a high risk of developing respiratory diseases. The objective of this research was to determine the exposure to polycyclic aromatic hydrocarbons (PAHs) and toluene in urine and evaluate the effects on health using markers of oxidative stress in exhaled breath condensate (EBC) as well as the exposure to pollutants in suspended particles of the studied area. Exposure to PAHs and toluene was evaluated using hydroxylated markers (OH) of PAHs and hippuric acid in urine, respectively. Cytokines like TNF-α, INF-y, IL-2, IL-4, IL-6, IL-8, IL-10 y GMCSF in EBC were also evaluated. PM2.5 particles were measured during an 8-h work shift. The results in brick workers presented a total OH-PAHs concentration of 97.3µg/L and hippuric acid concentration of 0.2g/L. The environmental concentrations of suspended particles were found within a range of 41.67-3541.6μg/m3. The median of cytokines oscillated between 11.8pg/mL to 1041pg/mL. In conclusion, these results are similar to those of occupations in which there is high exposure to pollutants and populations with lung diseases. For that reason, the brick production sector requires prevention and control strategies against the pollutants emitted.

Metabolomics strategy comprehensively unveils the effect of catechins intervention on the biomarkers of exposure to acrylamide and biomarkers of cardiometabolic risk

Polyphenolic antioxidants have been suggested to control the generation of acrylamide during thermal reactions. However, their role in protecting against the toxicity of acrylamide and the mechanism of action regarding profile alteration of biomarkers and metabolome remains unclear. A total of 65 adults were randomized into tea polyphenols (TP) and control groups and served with potato chips, which corresponded to an intake level of 12.6 μg/kg·bw of acrylamide, followed by capsules containing 200 mg, 100 mg or 50 mg TP, or equivalent placebo. Moreover, nontargeted urinary metabolomics analysis in acrylamide exposed rats was conducted using ultra-high performance liquid chromatography linked with a quadrupole-orbitrap high-resolution mass spectrometry. Our results showed that supplementation with catechins promoted the excretion of N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine in both humans and rats. We also found that epigallocatechin gallate (EGCG) or epicatechin (EC) intervention attenuated the ratio of hemoglobin adduct of glycidamide to hemoglobin adduct of acrylamide in rat blood. Metabolomics analysis revealed that EGCG/EC intervention regulated the differential expressed metabolites, including l-glutamic acid, 2-oxoglutarate, citric acid, and cysteinylglycine. Kyoto Encyclopedia of Genes and Genomes pathway analysis further showed acrylamide-induced metabolic disorders were improved after EGCG/EC supplementation by glycolipid metabolism (alanine, aspartate and glutamate metabolism, and d-Glutamine and d-glutamate metabolism) and energy metabolism (tricarboxylic acid cycle). Notably, the supplement use of EGCG prevented the cardiometabolic risk after exposure to acrylamide by mediating the phenylalanine and hippuric acid in phenylalanine metabolism. Here we showed the beneficial effect of catechins as major polyphenolic antioxidant ingredients on the toxicity of acrylamide by the changes in biomarkers from metabolic profile analysis based on human and animal studies. These findings shed light into the catechins as natural polyphenolic antioxidants that could be a therapeutic ingredient for preventing acrylamide-induced cardiometabolic toxicity.

Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.

Hierarchically structural layered double oxides with stretchable nanopores for highly effective removal of protein-bound uremic toxins

The global outbreak and prevalence of coronavirus disease 2019 (COVID-19) has triggered an urgent demand for family hemodialysis equipment. It is particularly vital to design and apply superior adsorbents to adsorb toxins for reducing the usage of dialysate. In this work, hierarchically structural MgAl layered double oxides (LDO) with stretchable nanopores were exploited through a facile one-pot trisodium citrate (TSC) assistant hydrothermal reaction followed by calcination treatment for effectively adsorbing protein-bound uremic toxins such as hippuric acid (HA) or indoxyl sulfate (IS). The optimized MgAl LDO possessed flower-like spherical morphology, ultrahigh specific surface area (187.3 m2/g) and uniquely stretchable nanopores, which were more conducive to incorporating anions due to their unique memory effect endowing them with promising adsorption capacities for HA or IS. And the adsorption data could be better conformed to pseudo-second-order kinetic model and Langmuir isotherm determining that the maximum adsorption capacity of HA and IS was 129.8 mg/g and 63.1 mg/g, respectively. Furthermore, the computation of molecular size paired with the analysis of adsorption mechanism accurately revealed that high-efficiency toxin capture was mainly attributed to electrostatic interaction for internal intercalation and surface adsorption. Therefore, the application of such delicate LDO as new premium adsorbent would facilitate the development and popularization of family hemodialysis equipment.

(-)-Epicatechin and its colonic metabolite hippuric acid protect against dexamethasone-induced atrophy in skeletal muscle cells

Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100μM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25μM HA (11.19±0.39μm) or 25μM EPI (11.01±0.21μm) compared to the vehicle control (VC; 7.61±0.16μm, both P < .001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P=.024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences versus control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/β II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC, and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated versus. CTL cells (all P < .050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health.

Potential Use of Some Indonesian Plants to Inhibits Angiotensin-converting Enzyme In Vitro

BACKGROUND: Some Indonesian plants, such as Vaccinium varingiaefolium Miq., Plectranthus scutellarioides (L.) R.Br., Syzygium myrtifolium Walp., and Eclipta prostrata (L.) L., are rich of flavonoid and anthocyanin. Flavonoid, flavan-3-ol, quercetin, anthocyanin, and tannin compounds can reduce systemic vascular resistance because they cause vasodilation and are thought to be able to influence the function of angiotensin-converting enzyme (ACE) and inhibit ACE activity, which plays an important role in the process of hypertension. AIM: This study aims to determine the potential of some Indonesian plants to inhibit ACE activity. METHODS: Testing of ACE inhibitory activity is carried out by the hippuric acid compounds formed as a result of the reaction between the substrate and the enzyme, then measured spectrophotometrically. The inhibitory and IC50 values of each test sample were compared with the positive control of Captopril. RESULTS: The four plant extracts contained secondary metabolites, such as flavonoids, tannins, saponins, quinones, steroids, triterpenoids, and essential oils. Ethanol extract of V. varingiaefolium Miq., P. scutellarioides (L.) R.Br., S. myrtifolium Walp., and E. prostrata (L.) L. each had an IC50 value of ACE inhibition activity of 131.4 ppm, 206. 7 ppm, 151.2 ppm, and 196.0 ppm. The IC50 value of the Captopril with inhibition of ACE activity is 11.1 ppm. CONCLUSION: This study shows that some Indonesian plants have the activity to inhibit the ACE and potential antihypertensive drug candidates with ACE inhibitory activity.

Quantification of Gut Microbiota Dysbiosis-Related Organic Acids in Human Urine Using LC-MS/MS.

Urine organic acid contains water-soluble metabolites and/or metabolites—derived from sugars, amino acids, lipids, vitamins, and drugs—which can reveal a human’s physiological condition. These urine organic acids—hippuric acid, benzoic acid, phenylacetic acid, phenylpropionic acid, 4-hydroxybenzoic acid, 4-hydroxyphenyl acetic acid, 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenyl propionic acid, and 3-indoleacetic acid—were the eligible candidates for the dysbiosis of gut microbiota. The aim of this proposal was to develop and to validate a liquid chromatography–tandem mass spectrometry (LC-MS/MS) bioanalysis method for the nine organic acids in human urine. Stable-labeled isotope standard (creatinine-d3) and acetonitrile were added to the urine sample. The supernatant was diluted with deionized water and injected into LC-MS/MS. This method was validated with high selectivity for the urine sample, a low limit of quantification (10–40 ng/mL), good linearity (r > 0.995), high accuracy (85.8–109.7%), and high precision (1.4–13.3%). This method simultaneously analyzed creatinine in urine, which calibrates metabolic rate between different individuals. Validation has been completed for this method; as such, it could possibly be applied to the study of gut microbiota clinically.

Anti-adhesion capacities of selected cranberry polyphenols and metabolites against P-type and Type-1 fimbriated uropathogenic E. coli using a fluorometric method

Adhesion of P-type and type-1 fimbriated uropathogenic E. coli (UPEC) to uroepithelial cells initiates urinary tract infections (UTIs). This research aimed to evaluate the capacities of selected cranberry polyphenols and their microbial metabolites to inhibit such adhesion in vitro using a modified fluorometric method. Data showed that the inhibition capacity of myricetin increased with concentration and plateaued at 70%. It had IC50 values of 13.2 μM against P-type E. coli and 5.50 μM against type-1 E. coli. Quercetin showed similar anti-adhesion capacities to myricetin. Procyanidin A2 and B2 had weaker anti-adhesion activities than myricetin and quercetin, with maximal inhibition capacities of 20%–30% against UPEC. Hippuric acid, a major metabolite of cranberry polyphenols in human urine, showed a maximal inhibition of 20% at 558 μM against type-1 E. coli adhesion, whereas no anti-adhesion activity against P-type E. coli was detected. The fractions of cranberry fruit powder enriched with proanthocyanidin polymers showed the highest anti-adhesion activities compared to the fractions enriched with anthocyanins, flavonols, or proanthocyanidin oligomers. Overall, the anti-adhesion activities of cranberry polyphenols and metabolites depend on their structures and the types of fimbriae on E. coli.