The impact of intradialytic cycling on the removal of protein-bound uraemic toxins: A randomised cross-over study.

The evidence on impact of intradialytic exercise on the removal of urea, is conflictive. Impact of exercise on kinetics of serum levels of protein-bound uraemic toxins, known to exert toxicity and to have kinetics dissimilar of those of urea, has so far not been explored. Furthermore, if any effect, the most optimal intensity, time point and/or required duration of intradialytic exercise to maximise removal remain obscure. We therefore studied the impact of different intradialytic cycling schedules on the removal of protein-bound uraemic toxins during haemodialysis (HD).This randomised cross-over study included seven stable patients who were dialysed with an FX800 dialyser during three consecutive midweek HD sessions of 240 min: (A) without cycling; (B) cycling for 60 min between 60th and 120th minutes of dialysis; and (C) cycling for 60 min between 150th and 210th minutes, with the same cycling load as in session B. Blood and dialysate flows were respectively 300 and 500 mL/min. Blood was sampled from the blood inlet at different time points, and dialysate was partially collected (300 mL/h). Small water soluble solutes and protein-bound toxins were quantified and intradialytic reduction ratios (RR) and overall removal were calculated per solute.Total solute removal and reduction ratios were not different between the three test sessions, except for the reduction ratios RR60-120 and RR150-210 for potassium.In conclusion, we add evidence to the existing literature that, regardless of the timing within the dialysis session, intradialytic exercise has no impact on small solute clearance, and demonstrated also a lack of impact for protein-bound solutes.

Artificial liver support systems.

Artificial liver systems are used to bridge between transplantation or to allow a patient's liver to recover. They are used in patients with acute liver failure (ALF) and acute-on-chronic liver failure. There are five artificial systems currently in use: molecular adsorbent recirculating system (MARS), single-pass albumin dialysis (SPAD), Prometheus, selective plasma filtration therapy, and hemodiafiltration. The aim is to compare existing data on the efficiency of these devices. A literature search was conducted using online libraries. Inclusion criteria included randomized control trials or comparative human studies published after the year 2000. A systematic review was conducted for the five individual devices with a more detailed comparison of the biochemistry for the SPAD and MARS systems. Eighty-nine patients were involved in the review comparing SPAD and MARS. Results showed that there was an average reduction in bilirubin (-53 µmol/L in MARS and -50 µmol/L in SPAD), creatinine (-19.5 µmol/L in MARS and -7.5 µmol/L in SPAD), urea (-0.9 mmol/L in MARS and -0.75 mmol/L in SPAD), and gamma-glutamyl transferase (-0.215 µmol/L·s in MARS and -0.295 µmol/L·s in SPAD) in both SPAD and MARS. However, there was no significant difference between the changes in the two systems. This review demonstrated that both MARS and SPAD aid recovery of ALF. There is no difference between the efficiency of MARS and SPAD. Because of the limited data, there is a need for more randomized control trials. Evaluating cost and patient preference would aid in differentiating the systems.

Cytokine Blood Filtration Responses in COVID-19.

The real issue with the COVID-19 pandemic is that a rapidly increasing number of patients with life-threatening complications are admitted in hospitals and are not well-administered. Although a limited number of patients use the intensive care unit (ICU), they consume medical resources, safety equipment, and enormous equipment with little possibility of rapid recovery and ICU discharge. This work reviews effective methods of using filtration devices in treatment to reduce the level of various inflammatory mediators and discharge patients from the ICU faster. Extracorporeal technologies have been reviewed as a medical approach to absorb cytokines. Although these devices do not kill or remove the virus, they are a promising solution for treating patients and their faster removal from the ICU, thus relieving the bottleneck.

Impact of anion exchange adsorbents on regional citrate anticoagulation.

INTRODUCTION: Heparin and citrate are commonly used anticoagulants in membrane/adsorption based extracorporeal liver support systems. However, anion exchange resins employed for the removal of negatively charged target molecules including bilirubin may also deplete these anticoagulants due to their negative charge. The aim of this study was to evaluate the adsorption of citrate by anion exchange resins and the impact on extracorporeal Ca2+ concentrations. METHODS: Liver support treatments were simulated in vitro. Citrate and Ca2+ concentrations were measured pre and post albumin filter as well as pre and post adsorbents. In addition, batch experiments were performed to quantify citrate adsorption. RESULTS: Pre albumin filter target Ca2+ concentrations were reached well with only minor deviations. Citrate was adsorbed by anion exchange resins, resulting in a higher Ca2+ concentration downstream of the adsorbent cartridges during the first hour of treatment. CONCLUSIONS: The anion exchange resin depletes citrate, leading to an increased Ca2+ concentration in the extracorporeal circuit, which may cause an increased risk of clotting during the first hour of treatment. An increase of citrate infusion during the first hour of treatment should therefore be considered to compensate for the adsorption of citrate.

The preparation and validation of chitosan tablets that rapidly disperse and disintegrate as an oral adsorbent in the treatment of lifestyle-related diseases.

A carrier and an oral absorbent for the treatment of chronic diseases in the form of a tablet was prepared from granulated chitosan (G-CS) particles. The resulting tablet was highly dispersible and disintegrated rapidly (< 30 s) in aqueous media. The non-granulated chitosan (N-CS) powder partially crystallized (2θ = 12-15° and 20°) during wet granulation to give G-CS crystalline particles. The rate of penetration of water into G-CS aggregates was markedly faster than that for N-CS aggregates, as evidenced by the ease of disintegration of the tablets. The rapid disintegration and dispersion of the tablets in vivo was confirmed by MRI measurements after the oral administration of the both tablets to rats. Some ureic toxins were adsorbed more strongly to G-CS tablets than on N-CS tablets. The results suggest that G-CS tablets have great potential for use as a fast disintegrating carrier and as an oral adsorbent in lifestyle-related diseases.

Application of the Molecular Adsorbent Recirculating System in Type 1 Hepatorenal Syndrome in the Course of Alcohol-Related Acute on Chronic Liver Failure.

BACKGROUND This study aimed to evaluate the Molecular Adsorbent Recirculating System (MARS) effectiveness in patients with alcohol-related acute-on-chronic liver failure (AoCLF) complicated with type 1 hepatorenal syndrome (HRS). So far, MARS efficacy and safety has been demonstrated in various acute liver failure scenarios. MATERIAL AND METHODS Data from 41 MARS procedures (10 patients with type 1 HRS, in the course of alcohol-related AoCLF were considered for this study. Biochemical tests of blood serum were performed before and after each procedure. The condition of patients was determined before and after the treatment with the use of the model for end-stage liver disease - sodium (MELD-Na) and the stage of encephalopathy severity based on the West Haven criteria. RESULTS During the observation period (20.5±13.9 days), 5 patients died, and the remaining 5 surviving patients were discharged from the hospital. In the group of 10, the 14-day survival, starting from the first MARS treatment, was 90%. The MARS procedure was associated with a 19% reduction in bilirubin (27.5±6.1 versus 22.3±4.0 mg/dL, P<0.001), 37% reduction in ammonia (44.1±22.5 versus 27.6±20.9 P<0.001), 27% reduction in creatinine (1.5±1.0 versus 1.1±0.6 mg/dL, P<0.001) and 14% reduction urea (83.8±36.1 versus 72.1±33.3, P<0.001) in blood serum samples, with stable hemodynamic parameters. In the group of patients discharged from the clinic (n=5), the MARS treatments resulted in an improvement in hepatic encephalopathy (West Haven; P=0.043), as well as a reduction in the MELD-Na score (P=0.015). CONCLUSIONS MARS is a hemodynamically safe method for supporting the function of the liver and the kidneys. Application of the MARS reduces the symptoms of encephalopathy in patients with alcohol-related type 1 HRS.

The Combined Use of Tocilizumab and Hemoadsorption in a Patient with SARS-COV-2-19-Associated Pneumonia: A Case Report.

The SARS-COV-2-19-associated respiratory involvement is caused by the massive release of inflammatory cytokines ultimately leading to interstitial pneumonia and acute respiratory distress syndrome (ARDS). In the absence of an effective antiviral treatment, a reasonable causal approach could be constituted by the neutralization of these substances. The authors describe the clinical course of a patient with SARS-COV-2-19 interstitial pneumonia treated with the combination of an anti-interleukin 6 (IL-6) agent (tocilizumab) and hemoadsorption (HA). This combination was used to abate the surge of inflammatory mediators leading to the lung damage. Blood levels of IL-6 and C-reactive protein (CRP) were measured before the initiation of the treatment and in the following 3 days. At the end of the treatment, the values of IL-6 and CRP decreased from 1,040 to 415 pg/mL and from 229 to 59 mg/L, respectively. The gas exchanges and the chest imaging rapidly improved, and the patient was extubated 10 days later. The combination of tocilizumab and HA could be valuable in the treatment of SARS-COV-2-19-associated pneumonia and ARDS that are caused by the release of inflammatory mediators.

Sorption Mechanism and Optimization Study for the Bioremediation of Pb(II) and Cd(II) Contamination by Two Novel Isolated Strains Q3 and Q5 of Bacillus sp.

The use of bacterial strains as agents in bioremediation processes could reduce the harmfulness of potential toxic elements (PTEs) from water and soil with low or even no impact on the natural ecosystems. In this study, two new metal resistant-bacterial strains (Q3 and Q5) of Bacillus sp. were isolated from a sulfurous spring and their potential (as pure cultures or mixed) to remove Pb(II) and Cd(II) from an aqueous matrix was evaluated and optimized using response surface methodology (RSM). The optimal conditions for Cd(II) removal from all tested strains combinations were observed at an initial pH 5, a temperature of 38 °C, and an initial Cd(II) concentration of 50 mg L-1, while the performance of bacterial strains on Pb(II) removal was strongly correlated to initial pH and temperature conditions. Moreover, the efficiency of bacterial strains in removing both PTEs, Pb(II) and Cd(II), from an aqueous matrix was considerably higher when they were used as a mixed culture rather than pure. According to field emission SEM (FESEM) and EDS analysis, the two bacterial strains showed different mechanisms in removing Cd(II): Bacillus sp. Q5 bio-accumulated Cd(II) in its periplasmic space, whereas Bacillus sp. Q3 bio-accumulated Cd(II) on its cell surface. On the other hand, Pb(II) is removed by chemical precipitation (lead sulfide) induced by both Bacillus sp. Q3 and Q5. This study discloses new aspects of Pb(II) and Cd(II) bioremediation mechanisms in Bacillus species that can be extremely useful for designing and operating novel PTEs bioremediation processes.

A case of complete atrioventricular block in secondary hemophagocytic syndrome/hemophagocytic lymphohistiocytosis recovered by plasma exchange and cytokine absorbing therapy with AN69ST continuous hemodiafiltration.

We report a case of incipient systemic lupus erythematosus (SLE) that rapidly progressed to complete atrioventricular block (cAVB). A 20-year-old man was admitted with facial erythema, painless oral aphtha, polyarthritis, and myalgia of each extremity. On admission, he developed first-degree atrioventricular block, pericarditis, pleuritis, renal failure, hemophagocytic lymphohistiocytosis, neurophychiatric SLE (left cerebellar infarction), and Staphylococcus aureus bacteremia. He was subsequently diagnosed with SLE based on several positive findings on immunological tests (including positive for antinuclear antibody). Despite immediate glucocorticoid pulse therapy and plasma exchange (PE) along with antibiotic, he developed cAVB that required temporary pacing on day 2. Because it was thought that hypercytokinemia exacerbated pericarditis, which progressed to myocarditis and cAVB, we decided to PE and cytokine-adsorbing therapy with AN69ST-continuous hemodiafiltration (CHDF). Other than renal failure, his organ dysfunctions improved with the multidisciplinary therapy. CAVB improved and temporary pacing was no longer required on day 11. Even a first-degree atrioventricular block can rapidly progress to cAVB; therefore, strict attention to electrocardiogram is necessary in severe SLE cases. When presenting with organ dysfunctions caused by hypercytokinemia such as severe SLE cases or SLE with severe infection cases, use of the combination of PE and AN69ST-CHDF might be beneficial.

Immobilization of horseradish peroxidase onto Purolite® A109 and its anthraquinone dye biodegradation and detoxification potential.

Horseradish peroxidase (HRP) is a highly specific enzyme with great potential for use in the decolorization of synthetic dyes. A comprehensive study of HRP immobilization using various techniques such as adsorption and covalent immobilization on the novel carrier Purolite® A109 with a special focus on enzymatic decolorization and toxicity of artificially colored wastewater. The immobilized preparations with an activity of 156.21 ± 1.41 U g-1 and 85.71 ± 1.62 U g-1 after the HRP adsorption and covalent immobilization, respectively, were obtained. Stability and reusability of the immobilized preparations were also evaluated. A noteworthy decolorization level (~90%) with immobilized HRP was achieved. Phytotoxicity testing using Mung bean seeds and acute toxicity assay with Artemia salina has confirmed the applicability of the obtained immobilized preparation in industrial wastewater plants for the treatment of colored wastewater.

Randomised, double-blind, placebo controlled multi-centre study to assess the efficacy, tolerability and safety of Enterosgel® in the treatment of irritable bowel syndrome with diarrhoea (IBS-D) in adults.

BACKGROUND: Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a common and chronic condition that can significantly impair quality of life. The emergence of new drugs for IBS-D has been slow and there is a need for new treatments, including drug-free treatments, which are easy to use and suitable for different patient groups. Currently available drug-free treatments include Enterosgel®, an intestinal adsorbent approved for use in IBS-D and acute diarrhoea and available over-the-counter in the UK and 30 countries worldwide. The aim of this randomised, double-blind, placebo-controlled, multi-centre study is to test the efficacy and safety of Enterosgel® compared to placebo in symptomatic treatment in IBS-D. METHODS/DESIGN: We will recruit 430 participants with IBS-D from approximately 30 primary and secondary care sites in England. Participants meeting the required abdominal pain and stool consistency criteria over a 2-week screening period will be randomly allocated to receive blinded treatment (Enterosgel® or placebo) for 8 weeks. This will be followed by an 8-week open-label treatment phase with Enterosgel®. Participants will be allowed to adjust their daily dosage during both phases based on their symptoms. Participants will then return to standard care and those who responded to treatment will receive a follow-up call 8 weeks later. Co-medication with loperamide will be permitted and use recorded. The primary outcome measure is the percentage of participants defined as responders for abdominal pain and stool consistency during at least 4 weeks in the 8-week blinded phase. Secondary outcome measures include stool frequency, stool consistency, abdominal pain, bloating, urgency, adequate relief, questionnaire scores and rescue medication use. Exploratory outcomes will be assessed in subsets of participants including qualitative and quantitative data on faecal microorganisms and biomarkers and gut-related measurements from magnetic resonance imaging data. DISCUSSION: This is the first large scale randomised controlled trial investigating Enterosgel® in IBS-D. A study design with blinded phase followed by an open-label phase was chosen to encourage participation and study completion. Demonstrating that Enterosgel® is effective and safe in IBS-D could encourage adoption by patients and healthcare professionals and foster future clinical trials assessing its use in related conditions. TRIAL REGISTRATION: ISRCTN17149988. Prospectively registered on 14 November 2017.

Clinical Effect of the Acrylonitrile-Co-Methallyl Sulfonate Surface-Treated Membrane as a Cytokine Adsorption Therapy for Sepsis due to Acute Panperitonitis: A Retrospective Cohort Study.

INTRODUCTION: Sepsis is a systemic inflammatory response syndrome caused by infectious diseases, with cytokines possibly having an important role in the disease mechanism. Acrylonitrile-co-methallyl sulfonate surface-treated (AN69ST) membrane is expected to improve the outcomes of patients with sepsis through cytokine adsorption. OBJECTIVE: This study aimed to investigate the clinical effect of the AN69ST membrane in comparison to standard continuous renal replacement therapy (CRRT) membranes for panperitonitis due to lower gastrointestinal perforation. METHODS: Using the Diagnosis Procedure Combination database, we identified adult patients with sepsis due to panperitonitis receiving any CRRT. Propensity score matching was used to compare patients who received CRRT with the AN69ST membrane (AN69ST group) and those who received CRRT with other membranes (non-AN69ST group). The primary outcome measure was in-hospital mortality. RESULTS: A total of 528 and 1,445 patients were included in the AN69ST group and in the non-AN69ST group, respectively. Propensity score matching resulted in 521 pairs. There was no significant difference in in-hospital mortality (32.1 vs. 35.5%; p = 0.265) and 30-day mortality (41.3 vs. 42.8%, p = 0.074) between the AN69ST group and the non-AN69ST group. CONCLUSION: There is no significant difference in-hospital mortality between CRRT with the AN69ST membrane and CRRT with standard CRRT membranes for panperitonitis due to lower gastrointestinal perforation. These results indicate that the AN69ST membrane is not superior to the standard CRRT membrane.

Hepatic Encephalopathy Challenges, Burden, and Diagnostic and Therapeutic Approach.

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with cirrhosis. The impact of HE on the health care system is similarly profound. The number of hospital admissions for HE has increased in the last 10-year period. HE is a huge burden to the patients, care givers, and the health care system. HE represents a "revolving door" with readmission, severely affects care givers, and has effects on cognition that can persists after liver transplant. This article reviews the current literature to discuss the challenges and diagnostic and therapeutic approaches to HE.

Severe quetiapine voluntary overdose successfully treated with a new hemoperfusion sorbent.

Quetiapine overdose, although rare, is mainly linked with tachycardia, QTc-interval prolongation, somnolence, coma, hyperglycemia, and eventually hepatotoxicity and myocarditis. Extracorporeal techniques for quetiapine removal might be helpful, but only a few cases are reported in the literature. We here describe the case of a 27-year-old healthy woman, admitted to our Intensive Care Unit after voluntary quetiapine intake and successfully treated with CytoSorb hemoperfusion in combination with continuous renal replacement therapy (CRRT), in order to accelerate quetiapine elimination. This is the first published experience about the potential application of hemoadsorption therapies, as CytoSorb sorbent, in large overdoses of quetiapine and this approach might be feasible to rapidly remove the substance from blood, stabilizing the patient condition.

Detoxification of Heterocyclic Aromatic Amines by Probiotic to Inhibit Medical Hazards.

Cancer is the second leading factor of human death in the world. Long-term consumption of cooked red meat brings about various types of cancers like colorectal cancer due to the formation of Heterocyclic Aromatic Amines (HAAs) during the heating process of meat. There are various solutions for the reduction of these toxicants. The aim of this article is to describe probiotic as one of the possible strategies for bioremoval of these carcinogenic and mutagenic substances and change food to functional one as well. The mechanism of biodetoxification is binding by probiotics, which depends on some variables including the probiotic characteristics, kind and content of the mutagens, as well as some properties of media. In this article, after introducing detoxification ability of probiotics and listing of all reported probiotics in this field, the influencing variables are surveyed and finally, opportunities and problems of HAA bioremoval by probiotics are described.

AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs.

PURPOSE: Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective. METHOD: To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6 weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14 days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group). RESULTS: In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-ß1 expression and increases in AKT phosphorylation. CONCLUSIONS: IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.

Clindamycin clearance during Cytosorb® hemoadsorption: A case report and pharmacokinetic study.

Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infections are rare but associated with very high mortality rates. We report the case of a 14-year-old patient with Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infection and Influenza B pneumonia requiring veno-arterial extra-corporeal membrane oxygenator for refractory shock. In the absence of response to conventional therapy, we have inserted a Cytosorb® cartridge within the extra-corporeal membrane oxygenator circuit. A spectacular decrease in vasopressor requirements followed. Since clindamycin, a key component of Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus treatment, might be removed by Cytosorb® hemoadsorption, we have performed serial plasma concentrations measurements of the drug. Based on these measurements, we were able to develop a pharmacokinetic model incorporating variable plasma clearance. Patient's exposure was estimated before, during and after Cytosorb® hemoadsorption. According to this model, Cytosorb® hemoadsorption did not seem to result in significant clindamycin removal. Cytosorb® hemoadsorption during Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infection appears safe and feasible and no adaptation of clindamycin dosage seems necessary.

Hemoadsorption in isolated conjugated hyperbilirubinemia after extracorporeal membrane oxygenation support. Cholestasis of sepsis: A case report and review of the literature on differential causes of jaundice in ICU patient.

Hyperbilirubinemia occurs in up to 40% of critically ill. In ICU, hyperbilirubinemia is an independent factor that influences patients' morbidity and mortality. Jaundice can reflect the course of disease or be caused by treatment (e.g. extracorporeal membrane oxygenation (ECMO)), thus can be difficult to differentiate. Sepsis was also associated with development of jaundice secondary to intrahepatic cholestasis. Prolonged cholestasis should be addressed to avoid liver damage. The patient with diagnosis of septic shock and severe acute respiratory distress syndrome was retrieved to our hospital for ECMO. Three days after initiation of ECMO, the patient developed jaundice, with increase of bilirubin, Gamma-glutamyltransferase and Alkaline phosphatase, without elevation of alanine aminotransferase and INR. Although ECMO was stopped, bilirubin serum levels were increasing, reaching the peak of 18.41 mg/dL of total and 15.67 mg/dL of direct bilirubin. Abdominal computed tomography showed homogeneous liver and non-dilated bile ducts. Viral hepatitis was excluded. CIOMS/RUCAM score was 0. Sepsis-related cholestasis was diagnosed. Despite cessation of sedation, the patient remained unconscious. Hemoadsorption therapy was initiated due to prolonged high levels of conjugated bilirubin. After 48 h of CytoSorb treatment, total bilirubin level was decreased to 2.4 mg/dL, the patient regained spontaneous eyes opening and could be transferred to regional hospital. Hyperbilirubinemia did not return in 3 months. Sepsis-related cholestasis is a diagnosis of exclusion that should be considered in case of jaundice in critically ill patients. In our patient, CytoSorb was a useful therapeutic option in prolonged cholestasis. Adsorption therapy was able to facilitate long-term regain of balance between inflammatory process, cytokine production and bilirubin turnover in the liver.

Removal of Bilirubin with a New Adsorbent System: In Vitro Kinetics.

BACKGROUND/AIMS: Many potentially toxic molecules accumulate in the blood during hepatic dysfunction. In clinical practice, it is very difficult to remove bilirubin, the most widely studied toxin, and particularly the unconjugated form, strongly albumin-bound. The aim of this in vitro study was to assess irreversible bilirubin adsorption as a protein-bound compound marker, using Cytosorb® (Cytosorbents Corp.), a new hemoadsorption device designed to remove cytokines. METHODS: We performed 4 in vitro experiments, dynamic and static, with different albumin-bilirubin solutions. RESULTS: All experiments showed the resin's ability to break the albumin-bilirubin complex (Experiment 1, 2), leading to efficient bilirubin removal for 24 h (Removal Rate: 90% Experiment 3) with minimal albumin loss. No sign of bilirubin release from the charged resin was detected (Experiment 4). CONCLUSION: Cytosorb® seems a promising artificial liver support, thanks to its ability to adsorb bilirubin and its proven ability to modulate the cytokines involved in hepatic dysfunction.

Microbiota facilitates the formation of the aminated metabolite of green tea polyphenol (-)-epigallocatechin-3-gallate which trap deleterious reactive endogenous metabolites.

The in vivo mechanism of tea polyphenol-mediated prevention of many chronic diseases is still largely unknown. Studies have shown that accumulation of toxic reactive cellular metabolites, such as ammonia and reactive carbonyl species (RCS), is one of the causing factors to the development of many chronic diseases. In this study, we investigated the in vivo interaction between (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in tea leaves, and ammonia and RCS. We found that EGCG could be oxidized to EGCG quinone in mice, and then rapidly react with ammonia to generate the aminated EGCG metabolite, 4'-NH2-EGCG. Both EGCG and its aminated metabolite could further scavenge RCS, such as methylglyoxal (MGO), malondialdehyde (MDA), and trans-4-hydroxy-2-nonenal (4-HNE), to produce the RCS conjugates of EGCG and the aminated EGCG. Both the aminated and the RCS conjugated metabolites of EGCG were detected in human after drinking four cups of green tea per day. By comparing the levels of the aminated and the RCS conjugated metabolites in EGCG exposed germ-free (GF) mice and specific-pathogen-free (SPF) mice, we demonstrated that gut microbiota facilitate the formation of the aminated metabolite of EGCG, the RCS conjugates of EGCG, and the RCS conjugates of the aminated EGCG. By comparing the trapping capacities of EGCG and its aminated metabolite under aerobic and anaerobic conditions, we found that oxygen is not essential for the trapping of reactive species by EGCG and 4'-NH2-EGCG suggesting that EGCG and its aminated metabolite could scavenge RCS in the GI track and in the circulation system. Altogether, this study provides in vivo evidences that EGCG has the capacity to scavenge toxic reactive metabolic wastes. This finding opens a new window to understand the underlying mechanisms by which drinking tea could prevent the development of chronic diseases.