Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota

At present, clinical interventions for chronic kidney disease are very limited, and most patients rely on dialysis to sustain their lives for a long time. However, studies on the gut-kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease. This study showed that berberine, a natural drug with low oral availability, significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins, including p-cresol. Furthermore, berberine reduced the content of p-cresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine-p-cresol pathway of the intestinal flora. Meanwhile, berberine increased the butyric acid producing bacteria and the butyric acid content in feces, while decreased the renal toxic trimethylamine N-oxide. These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut-kidney axis.

Strategy to delay the progression of chronic kidney disease by targeting gut microbiota and uremic toxins metabolism pathway / 药学学报

Chronic kidney disease (CKD) is a serious chronic disease with high incidence, poor prognosis, and a variety of complications. Indoxyl-sulfate (IS) and p-cresol sulfate (PCS) are two typical gut-derived uremic toxins, which are produced by the co-metabolism of intestinal microbes and the host. With the progression of CKD, gut-derived uremic toxins such as IS and PCS accumulate in patients with CKD and thereafter accelerate the progression of CKD. Gut microbiota is closely related with CKD, and targeting gut microbiota to regulate gut-derived uremic toxins synthesis and metabolic pathways may be a promising strategy to delay the progression of CKD. In this paper, the relationship between gut microbiota, gut-derived uremic toxins, and CKD was analyzed, and the strategy to delay the progression of CKD by targeting gut microbiota and uremic toxins metabolism pathway was proposed.

Clinical challenges with excipients in insulin formulations and role of concentrated insulin

Most of the insulin formulations in clinical use contain phenol, meta-cresol or both as excipients. These excipients in insulin preparations provide stability and have antimicrobial properties. However, they are reported to be associated with undesirable side-effects especially localised allergic reactions. Amount of excipients injected per unit dose of insulin is a major determining factor in causation of these reactions. This review discusses the excipients in different insulin formulations available in India with potential of precipitating undesirable effects and the use of concentrated insulins to reduce these complications. To avoid the detrimental effects associated with excipients, removal of preservatives or use of insulin preparations devoid of excipients can be an option. Besides these approaches, one approach that can be considered is the use of concentrated insulin to reduce the volume of insulin dose and thereby the excipients. Concentrated insulins address the high insulin requirements of the growing population of patients with type 2 diabetes who require higher insulin doses. Concentrated insulins help in reduction of dose volume as well as amount of excipients injected per unit dose of insulin. U200 (concentrated r-DNA Human Insulin Premix 30/70-200 IU/ml) can be advantageous with better absorption from smaller quantity injected, lesser variability in absorption, lesser pain and discomfort due to smaller quantity, lesser chances of hypoglycaemia all of which can lead to better patient compliance. Thus, concentrated insulin U200 can be one of the alternatives to prevent/reduce clinical complications with excipients in insulins.

Key microbial populations involved in anaerobic degradation of phenol and p-cresol using different inocula

Background: Anaerobic digestion is an alternative bioprocess used to treat effluents containing toxic compounds such as phenol and p-cresol. Selection of an adequate sludge as inoculum containing an adapted microbial consortium is a relevant factor to improve the removal of these pollutants. The objective of this study is to identify the key microorganisms involved in the anaerobic digestion of phenol and p-cresol and elucidate the relevance of the bamA gene abundance (a marker gene for aromatic degraders) in the process, in order to establish new strategies for inocula selection and improve the system's performance. Results: Successive batch anaerobic digestion of phenol and p-cresol was performed using granular or suspended sludge. Granular sludge in comparison to suspended sludge showed higher degradation rates both for phenol (11.3 ± 0.7 vs 8.1 ± 1.1 mg l-1 d-1) and p-cresol (7.8 ± 0.4 vs 3.7 ± 1.0 mg l-1 d-1). After three and four re-feedings of phenol and p-cresol, respectively, the microbial structure from both sludges was clearly different from the original sludges. Anaerobic digestion of phenol and p-cresol generated an abundance increase in Syntrophorhabdus genus and bamA gene, together with hydrogenotrophic and aceticlastic archaea. Analysis of results indicates that differences in methanogenic pathways and levels of Syntrophorhabdus and bamA gene in the inocula, could be the causes of dissimilar degradation rates between each sludge. Conclusions: Syntrophorhabdus and bamA gene play relevant roles in anaerobic degradation of phenolics. Estimation of these components could serve as a fast screening tool to find the most acclimatized sludge to efficiently degrade mono-aromatic compounds.

Niveles urinarios de ácido trans, trans mucónico y orto cresol en una población infanto-juvenil residente en Ciudad Autónoma de Buenos Aires y Conurbano Bonaerense / Urinary levels of trans, trans muconic and ortho cresol in an infant-juvenile population resident in the Autonomous City of Buenos Aires and the Conurbano of Buenos Aires

Introducción: la exposición crónica al benceno y tolueno produce alteraciones sobre la médula ósea y el sistema nervioso central, entre otros. En orina, el ácido trans, trans mucónico (t, t-MA) es uno de los biomarcadores de exposición al benceno y el o-cresol (oCre) al tolueno. Objetivo: analizar los resultados de los niveles de t, t-MA y oCre urinarios en una población infanto-juvenil residente en Ciudad Autónoma de Buenos Aires y Conurbano Bonaerense potencialmente expuesta a benceno y tolueno ambiental. Materiales y métodos: se realizó un estudio retrospectivo de los resultados de t, t-MA y oCre urinarios. Las muestras de orina ingresaron al laboratorio con solicitud de t, t-MA (n=1519) y oCre (n=1447) durante el período 2011-2017 (rango etario entre 0 a 19 años). El t, t-MA se cuantificó por UFLC con detector de arreglo de diodos y el oCre por CG con detector de ionización por llama. Resultados: la edad promedio de los pacientes fue de 4,8 años y la mediana 4,6 años.Las concentraciones de t, t-MA urinario fueron: menor de 50 μg/l (44,8%); entre 50-500 μg/l (52,1%) y mayores de 500 μg/l (3,1%). Expresadas por gramo de creatinina: entre 15-163 μg/g creatinina (60,4%) y mayores de 163 μg/g creatinina (39,6%). El límite de cuantificación de t, t-MA fue de 50 μg/l. Las concentraciones de oCre urinario fueron: menor de 0,20 mg/l (97,7%) y entre 0,20-0,50 mg/l (2,3%) y mayor de 0,50 mg/l (0%). Expresadas por gramo de creatinina: menor de 0,30 mg/g creatinina en el 0,8% y mayores de 0,30 mg/g creatinina en el 1,5%. El límite de cuantificación de oCre fue de 0,20 mg/l. Conclusiones: los resultados del trabajo podrían indicar una contaminación ambiental persistente, en especial en el Conurbano Bonaerense, donde debería continuarse el monitoreo de algunas zonas. Pero, por otro lado, es de vital importancia tener en cuenta los factores de confusión, tales como la dieta, la exposición al humo de tabaco ambiental (fumador pasivo) y la tasa de excreción renal que llevarían a una sobre-estimación de los resultados y a una incorrecta toma de decisiones.

Introduction: Chronic exposure to benzene and toluene produces alterations in the bone marrow and the central nervous system, among other effects. In urine, trans, trans muconic acid (t, t-MA) is one of the biomarkers of exposure to benzene and o-cresol (oCre), to toluene. Objective: To analyze the results of urinary t, t-MA and oCre levels in an infant-juvenile population resident in the Autonomous City of Buenos Aires and the Conurbano Bonaerense, potentially exposed to environmental benzene and toluene. Materials and methods: A retrospective study of urinary t, t-MA and oCre results was performed. The urine samples entered the laboratory with the request of t, t-MA (n = 1519) and oCre (n = 1447) during the period 2011- 2017. The age range of the population was between 0 and 19 years. The t, t-MA was quantified by UFLC with diode array detector and the oCre by GC with flame ionization detector. Results: The average age of the patients was 4.8 years and the median age was 4.6 years. The urinary concentrations of t, t-MA were: below 50 μg/l (44.8%); between 50-500 μg/l (52.1%) and above 500 μg/l (3.1%). Expressed per gram of creatinine: between 15-163 μg/g creatinine (60.4%) and greater 163 μg/g creatinine (39.6%). The limit of quantification of t, t-MA was 50 μg/l. The urinary oCre concentrations were: less than 0.20 mg/l (97.7%) and between 0.20-0.50 mg/l (2.3%). Expressed per gram of creatinine: less than 0.30 mg/g creatinine in 0.8% and greater than 0.30 mg/g creatinine in 1.5%. The limit of quantification of oCre was 0.20mg/l. Conclusions: The results of the study could indicate persistent environmental contamination, especially in the Conurbano Bonaerense, where monitoring of some areas should be continued. However, it is of vital importance to take into account the confounding factors, such as diet, exposure to environmental tobacco smoke (passive smoking) and the rate of renal excretion, which would lead to an over-estimation of the results and to incorrect decision-making.

Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting mTOR-Dependent Autophagy

p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro-senescence changes caused by p-cresol, such as the increase in total 5′-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role.

A Spectrophotometric System for High Precision Measurement of pH of Seawater / 分析化学

Spectrophotometric seawater pH measurement system is an urgent need of device due to its quick speed and high precision. Based on spectrophotometric method and flow injection analysis technique, an automated system for pH measurement of seawater was developed by integrating pump and valve flow path, LED light source, flow cell and spectrophotometer. This measurement system effectively avoided bubbles. The indicator of concentration gradient in the seawater sample was used to correct for the pH perturbation caused by the indicator, thus the operation of system was simple and convenient. with this system, only 1. 5 min was needed for a sample measurement with a precision of 0. 0013 pH units and an offset of 0. 0059 pH units. This system could be used for the rapid determination of pH of seawater collected by laboratory or research ship with high precision pH values.

An in vitro study of effects of the uremic toxin p-cresol on release of inflammatory cytokines from monocytes / 解放军医学杂志

Objective To evaluate the effect of uremic toxin p-cresol on the release of inflammatory cytokines from monocytes and explore its potential mechanism. Methods CCK-8 was employed to evaluate the proliferation status of monocytes cell-line THP-1 after being exposed to 20, 40, 80, 160mg/L of p-cresol for 6, 12 or 24h, while 40mg/L and 80mg/L were assigned as low-dose group and high-dose group. RNA and protein were extracted. RT-PCR and Western blotting were employed to evaluate the mRNA and protein expression of proinflammatory cytokine TNF-α, anti-inflammatory cytokine IL-10, as well as Toll-like receptor-4 (TLR-4) of THP-1 cell exposed to p-cresol for 24h. Results P-cresol depressed the proliferation ability of THP-1 in a dose-and time-dependent manner (P<0.05). RT-PCR and Western blotting showed that both TNF-α and TLR-4 were over-expressed in THP-1 cell exposed to p-cresol, while the expression of IL-10 was reduced (P<0.05). Conclusion P-cresol may inhibit both the proliferation of THP-1 cell and the release of IL-10. By up-regulating the expression of TLR-4, p-cresol may stimulate the release of TNF-α, resulting in microinflammation.

Effects of D-cresol on the proliferation and cell cycle of human umbilical vein endothelial cells / 中华肾脏病杂志

Objective To investigate the effects of p-cresol on human umbilical vein endothelial cells.Methods The effects of p-cresol on endothelial cell growth,cell cycle,cell morphological change and p21 protein were detected by the CCK-8 assay,flow cytometry assay,inverted microscope and Western blotting.Results P-cresol could inhibit the growth of human umbilical vein endothelial cells in dose-and time-dependent manners (all P ＜ 0.05).The human umbilical vein endothelial cells treated with p-cresol became elongated processes,cloudy cytoplasm,and irregular shapes.The p-cresol stopped human umbilical vein endothelial cells at cell cycle G1 and had no effect on cell apoptosis.The p-cresol could increase protein expression of p21 in a dose dependent manner (P ＜ 0.05).Conclusion P-cresol can increase protein expression of p21,induce cell cycle arrest at G1 stage and inhibit the proliferation of human umbilical vein endothelial cells.

Biodegradation kinetics of o-cresol by Pseudomonas putida DSM 548 (pJP4) and o-cresol removal in a batch-recirculation bioreactor system

The biodegradation kinetics of o-cresol was examined by acclimatized P. putida DSM 548 (pJP4) in batch experiments at varying initial o-cresol concentrations (from 50 to 500 mg/L). The kinetic parameters of o-cresol aerobic biodegradation were estimated by using the Haldane substrate inhibition equation. The biodegradation kinetics of o-cresol was investigated. In batch culture reactors, the Maximum specific growth rate (μmax), Monod constant (Ks) and the inhibition constant (Ki) were established as 0.519 h-1, 223.84 mg/L and 130.883 mg/L, respectively. o-cresol biodegradation in a batch-recirculation bioreactor system by immobilized P. putida was also studied. The recycled packed bed reactor system, which was composed of Ca-alginate beads and pumice on which cells immobilized, has been performed to determine possible stability for further developments.

Development and validation of RP-HPLC and RP-UPLC methods for quantification of parathyroid hormones (1-34) in medicinal product formulated with meta-cresol / 药物分析学报

Rapid and sensitive reversed phase high performance liquid chromatography (RP-HPLC) and ultra performance liquid chromatography (RP-UPLC) method with UV detection has been developed and validated for of parathyroid hormone (PTH)in presence of meta-cresol as a stabilizer in a pharmaceutical formulation.Chromatography was performed with phase containing 0.1％ Trifluoroacetic acid (TFA) in MilliQ water and 0.1％ TFA in acetonitrile with gradient and flow rate at 0.3 mL/min for HPLC and 0.4 mL/min for UPLC.Quantification was accomplished with internal reference standard (qualified against innovator product and National for for Biological Standards and Control (NIBSC) standard).The methods were validated for linearity (correlation coefficient=0.99),range,accuracy,precision and robustness.Robustness was confirmed by considering three factors; mobile phase composition,column temperature and flow rate/age of mobile phase.Intermediate precision was confirmed on different equipments,different columns and on different days.The relative standard deviation (RSD) (＜2％ for RP-HPLC and ＜1％ for UPLC n=30) indicated a good precision.Retention time was found about 17min and 2min by HPLC and UPLC methods,respectively.Both methods are simple,highly sensitive,precise and accurate and have the potential of being useful for routine quality control.

What is the optimum concentration of m-cresol in antivenoms?

Antivenoms against snake and scorpion envenomations are usually equine in nature and composed mostly of F(ab')2; additionally, phenol and m-cresol are mainly employed for their preservation. Although there is no study on this subject, m-cresol is utilized by most manufacturers in a concentration that ranges from 0.15 to 0.35 g percent. Decreasing the concentration of m-cresol to its minimal effective level may protect victims from its toxic effects and keep the antivenom stable during its shelf life without forming any aggregates. In the present work, different concentrations of m-cresol, ranging from 0.1 to 0.35 g percent, were used with some selected batches of snake and scorpion antivenoms. A low concentration of 0.15 g percent showed an acceptable preserving result that complies perfectly with antimicrobial specifications stated by the British Pharmacopoeia. Tested antivenoms (in 12 batches), when kept in a cold room for 39 months (more than their shelf life), retained their physical, chemical and microbiological activities according to the specifications of pharmacopeias. The present data demonstrated that reduction of m-cresol concentration to 0.15 g percent in case of equine F(ab')2 antivenoms will improve safety of such preparations and preserve their stability during their shelf life.(AU)

A Case of Acute Renal Failure Caused by Cresol Ingestion / 대한신장학회잡지

Cresol, a commonly used disinfectant, is an extremly toxic material and can cause systemic effects such as respiratory, neurological, gastrointestinal, hepatic and renal damage. Cresol intoxication can be caused by inhalation, cutaneous adsorption or oral ingestion. Cresol denatures and precipitates cellular proteins, thus exer ts their toxic effects directly on all cells. There is only one case of cresol intoxication in Korea, but a case of chemical burn. We report a case of acute renal failure caused by cresol ingestion. A 39-year-old male attempted suicide by ingesting 200 mL of 50% cresol solution. Acute renal failure developed, but he recovered by only supportive care. It was reported that the lethal dose of saponated cresol solution is approximately 60-120 mL and the lethal blood level is 71-190 microgram/mL. The amount of cresol ingested by the patient far exceeded the reported lethal dose. This is the first case of acute renal failure caused by cresol ingestion successfully treated with only supportive care in Korea.

A Study on Urinary Excretion of o-Cresol and Hippuric Acid of Workers Daily Exposed to Toluene on Each Day of the Week / 항공우주의학회지

BACKGROUND: The purpose of this study is to find out the relationship between the airborne toluene concentrations and the daily urinary metabolites such as hippuric acid and o-cresol for a sequential 5 days and to provide the appropriate sampling time for a special physical examination in the workers exposed to toluene. METHODS: The volunteers of 36 workers in the shoe making company were selected to measure the concentrations of airborne toluene exposure and to sample the daily urines in pre and end-shift for sequential 5 days form Monday to Friday and to get self-administered questionnaire including the items such as job records, disease records, smoking, alcohol drinking, eating some foods containing benzoic acid before work. RESULTS: The geometric means of toluene concentrations showed 46.40 ppm as the lowest value on Monday and 62.31 ppm as the highest one on Thursday. But there is no significant difference between both of those. The concentrations of hippuric acid and o-cresol in urine sampled on end-shift were higher than that of the others and showed statistically significant differences on each day. The metabolites of toluene were not related with taking alcohol and some foods containing benzoic acid as a result of logistic regression. CONCLUSION: From the above results, it is suggested that the hippuric acid and o-cresol in urine be very useful for biological monitoring in the workers exposed to toluene. Moreover, the daily hippuric acid and o-cresol concentrations in urine are also important for toluene exposure assessment and the further study has to be conducted to find out the tendency of biological exposure indices for continuous toluene exposure.

Cresol Chemical Burn / 대한피부과학회지

Generally chemical burns are managed with immediate water irrigation. Cresol is one of the few chemicals that cannot be safely washed off with water. If cresol chemical burn is washed off with small amount of water, the involved area may extend. Thus cresol chemical burn must be managed with caution if a generous supply of water is not available. We report a case of cresol chemical burn with a review of literatures.

A Study on the Correlation of Ambient Toluene and Xylene with Biological Monitoring Index / 대한산업의학회지

In order to study the correlation of ambient toluene and xylene exposure with their biological monitoring indices, we measured the concentration of toluene and xylene in the workplace. We also measured their biological monitoring indices of workers from August to November in 1994. The exposed group consisted of 103 male workers and the non-exposed group consisted of 34 male workers. The ambient concentration of toluene was 44.7 +/-55.4 ppm and that of xylene was 2.35+/-2.15 ppm. The urinary concentration of hippuric acid in exposed group was 1.72+/-1.53 g/g creatinine and that of non-exposed group was 0.34+/-0.28 g/g creatinine. The difference was statistically significant between two groups (p0.05). When compensated with urinary creatinine, the correlation coefficient of ambient toluene with urinary hippuric acid and ocresol were 0.63(p=0.0001) and 0.65(p=0.0001), respectively. When compensated with urinary specific gravity, the correlation coefficient of ambient toluene with hippuric acid and ocresol were 0.525 (p=0.0001) and 0.547 (p=0. 0001), respectively. The compensation method using urinary creatinine provided a higher correlation coefficient. We could not find any statistically significant differences between the duration of work and other variables (urinary hippuric acid, o-cresol and methylhippuric acid). In order to monitor biological indices of toluene-exposed workers, we suggest the measurement of urinary hippuric acid rather than o-cresol. As the compensation method, we suggest to use urinary creatinine rather than urinary specific gravity.

Study on the removal of cresol for the agricultural waste water treatment / 日本農村医学会雑誌

Concerning the agricultural waste water treatment, adsorption removal of cresol which is one of disinfectants by commercial activated carbon was investigated.<BR>It was not found the significant correlation between amount of cresol adsorbed and physical properties of eight kinds of activated carbon. The intraparticle diffusivity of cresol onto the pores of activated carbon was significantly related to the mesopore volume.<BR>In the treatment of agricultural waste water, it is concluded that the activated carbon which is rich in mesopore volume is suitable for the adsorption removal of cresol from the standpoint of adsorption rate.