Metabolism and Pharmacokinetics of San-Huang-Xie-Xin-Tang, a Polyphenol-Rich Chinese Medicine Formula, in Rats and Ex-Vivo Antioxidant Activity

San-Huang-Xie-Xin-Tang (SHXXT), a widely used Chinese herbal formula, consists of rhizomes of Rheum officinale, roots of Scutellaria baicalensis and rhizomes of Coptis chinesis. This study investigated the metabolism and pharmacokinetics of polyphenols in SHXXT, including baicalin, baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol. The quantitation methods of SHXXT decoction and rat serum using high performance liquid chromatography were developed and validated in this study. After oral administration of SHXXT decoction to rats, the parent forms of various constituents and their conjugated metabolites in serum were determined before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that only free form of rhein can be quantitated, whereas the parent forms of coptisine, palmatine, berberine, baicalein, wogonin, emodin, aloe-emodin and chrysophanol were not detected in serum. The glucuronides of baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol were the predominant forms in bloodstream. In order to evaluate the in vivo antioxidant activity of SHXXT, the serum metabolite of SHXXT was prepared, characterized and followed by evaluation of the effect on AAPH-induced hemolysis. The results indicated that metabolites of SHXXT exhibited significant free radical scavenging activity. We suggest that biologists redirect their focus to the bioactivity of the conjugated metabolites of these polyphenols

Metabolism and Pharmacokinetics of San-Huang-Xie-Xin-Tang, a Polyphenol-Rich Chinese Medicine Formula, in Rats and Ex-Vivo Antioxidant Activity

San-Huang-Xie-Xin-Tang (SHXXT), a widely used Chinese herbal formula, consists of rhizomes of Rheum officinale, roots of Scutellaria baicalensis and rhizomes of Coptis chinesis. This study investigated the metabolism and pharmacokinetics of polyphenols in SHXXT, including baicalin, baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol. The quantitation methods of SHXXT decoction and rat serum using high performance liquid chromatography were developed and validated in this study. After oral administration of SHXXT decoction to rats, the parent forms of various constituents and their conjugated metabolites in serum were determined before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that only free form of rhein can be quantitated, whereas the parent forms of coptisine, palmatine, berberine, baicalein, wogonin, emodin, aloe-emodin and chrysophanol were not detected in serum. The glucuronides of baicalein, wogonin, emodin, aloe-emodin, rhein and chrysophanol were the predominant forms in bloodstream. In order to evaluate the in vivo antioxidant activity of SHXXT, the serum metabolite of SHXXT was prepared, characterized and followed by evaluation of the effect on AAPH-induced hemolysis. The results indicated that metabolites of SHXXT exhibited significant free radical scavenging activity. We suggest that biologists redirect their focus to the bioactivity of the conjugated metabolites of these polyphenols

Green tea inhibited the elimination of nephro-cardiovascular toxins and deteriorated the renal function in rats with renal failure

Chronic kidney disease (CKD) is a major health problem worldwide. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are highly protein-bound nephro-cardiovascular toxins, which are not efficiently removed through hemodialysis. The renal excretions of IS and PCS were mediated by organic anion transporters (OATs) such as OAT1 and OAT3. Green tea (GT) is a popular beverage containing plenty of catechins. Previous pharmacokinetic studies of teas have shown that the major molecules present in the bloodstream are the glucuronides/sulfates of tea catechins, which are putative substrates of OATs. Here we demonstrated that GT ingestion significantly elevated the systemic exposures of endogenous IS and PCS in rats with chronic renal failure (CRF). More importantly, GT also significantly increased the levels of serum creatinine (Cr) and blood urea nitrogen (BUN) in CRF rats. Mechanism studies indicated that the serum metabolites of GT (GTM) inhibited the uptake transporting functions of OAT1 and OAT3. In conclusion, GT inhibited the elimination of nephro-cardiovascular toxins such as IS and PCS, and deteriorated the renal function in CRF rats

Different Influences on Tacrolimus Pharmacokinetics by Coadministrations of Zhi Ke and Zhi Shi in Rats

Tacrolimus, an immunosuppressant with narrow therapeutic window, has been used widely in transplant patients. Grapefruit juice and pomelo have been reported to increase the blood levels of tacrolimus. Zhi Ke and Zhi Shi, the ripe peels and unripe fruits of Citrus aurantium which is chemotaxonomically related to grapefruit and pomelo, are in wide use in clinical Chinese medicine. To investigate the possible interaction of these two Citrus herbs with tacrolimus, male Sprague-Dawley rats were orally given tacrolimus (1.5 mg/kg) with and without Zhi Ke and Zhi Shi decoctions in a cross-over design. Blood samples were withdrawn via cardiopuncture at specific time and quantitated by a microparticle enzyme immunoassay. In addition, to explore the mechanism of interaction, LS 180 cell line was used for the transport study of rhodamine 123, a typical substrate of P-glycoprotein (P-gp). The results showed that Zhi Shi significantly decreased the Cmax and AUC0−t of tacrolimus by 72.4% and 72.0%, respectively, whereas Zhi Ke did not affect tacrolimus pharmacokinetics. LS 180 cell line study indicated that Zhi Shi increased the efflux activity of P-gp, enabling us to explain the decreased oral bioavailability of tacrolimus caused by Zhi Shi. Hence, we suggest that Zhi Shi be contraindicated for transplant patients treated with tacrolimus to reduce the risk of allograft rejection

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Cranberry Ingestion Modulated Drug Transporters and Metabolizing Enzymes: Gefitinib Used as a Probe Substrate in Rats

Cranberry, a polyphenol-rich functional food, is commonly used for the prophylaxis of urinary tract infections. Gefitinib, an anticancer agent clinically prescribed to treat non-small-cell lung cancer, is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and metabolized mainly by cytochrome P450 (CYP) 3A4 and CYP2D6. This study used gefitinib as a probe substrate to investigate the modulation of cranberry on P-gp, BCRP, CYP3A4 and CYP2D6. Rats were administered gefitinib with and without 5.0 g/kg of cranberry as juice (CJ). The concentration of gefitinib in serum was determined by LC-MS/MS. The results showed that CJ significantly increased the Cmax and AUC0-t of gefitinib by 28% and 55%, respectively. Mechanism studies indicated that CJ activated P-gp, and cranberry metabolites (CM) inhibited CYP2D6. Moreover, the protein level of P-gp in rat enterocytes was decreased, whereas that in hepatocytes was increased. In addition, the protein levels of BCRP, CYP3A4 and CYP2D6 in enterocytes and hepatocytes were decreased. In conclusion, CJ ingestion affected the activities and protein levels of P-gp, BCRP, CYP3A4 and CYP2D6