Kidney Tissue Concentrations Research Articles

Abstract P300: Modulation of Osmolyte Levels by ACE Inhibitors and SGLT-2 Inhibitors in Normotensive Rats

Hypertension is associated with disturbances in the water-electrolyte balance, leading to changes in osmotic pressure. Osmolytes, such as taurine among other compounds, play a critical role in maintaining cellular integrity under osmotic stress. This study evaluated the effects of ACE inhibitors (ACE-I) and SGLT-2 inhibitors (SGLT2i) on osmolyte homeostasis. Twelve-week-old male Sprague-Dawley (SD, n = 38) rats were divided into five groups: control (water), low and high doses of canagliflozin, and low and high doses of captopril. Metabolic studies were conducted in metabolic cages. Using liquid chromatography coupled with mass spectrometry (LC-MS), we measured osmolyte concentrations in blood, urine, kidney, liver and heart tissues. The obtained results demonstrated significant increases in liver taurine concentrations (13.34 ± 1.39 vs. 10.49 ± 1.45, p=0.029) and urinary taurine excretion (25.08 ± 2.81 vs. 16.54 ± 3.77, p=0.001) in the high-dose canagliflozin group compared to controls. Both treatments enhanced the total urinary excretion of L-alanine, β-alanine, choline, glycine, taurine, and carnitine. Additionally, canagliflozin increased the excretion of betaine and glycerophosphorylcholine (GPC). A reduction in serum β-alanine was noted in the captopril-treated rats. These findings highlight the novel effects of SGLT-2 inhibitors and ACE-I on osmolyte levels in normotensive rats, suggesting potential mechanisms contributing to their cardioprotective effects. Further research is required to elucidate the clinical significance of osmolyte changes in enhancing the protective effects of these drug classes.

Trace Metal Bioaccumulation in Feral Pigeons (Columba livia f. domestica) and Rooks (Corvus frugilegus) Residing in the Urban Environment of Iasi City, Romania.

Nowadays, trace metal contamination within urban atmospheres is a significant and concerning global issue. In the present study, two synanthropic bird species, namely, the feral pigeon (Columba livia f. domestica) and the rook (Corvus frugilegus), were employed as bioindicators to assess the atmospheric trace metal pollution in Iasi City, Romania. The concentrations of Ni, Pb, Cd, Co, Cr, and Cu were determined through high-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS GF-AAS) of various tissues, including the liver, kidney, lung, heart, muscle, and bone, of feral pigeons and rooks collected in Iasi City. The order of trace metal concentrations in the tissues of feral pigeons and rooks in Iasi City was similar: Cu > Pb > Ni > Cd > Cr > Co. However, trace element values in most tissues were higher in the rook samples than in feral pigeon ones, except for Co, which had elevated levels in feral pigeon renal and cardiac tissues, and Cu, which registered the highest concentrations in feral pigeon liver and kidney tissues. While not statistically significant, Pb concentration values in the PM10 fraction of atmospheric particles positively correlated with Pb concentrations in rook kidney samples (p = 0.05). The concentration levels of Cd, Pb, and Ni in the PM10 fraction of air particles showed a positive correlation with Cd levels in the samples of pigeon heart and rook liver, kidney, and heart, Pb levels in the samples of pigeon kidney, heart, and muscle and rook liver and bone, and Ni levels in the samples of pigeon liver, kidney, and bone and rook liver, muscle, and bone, respectively.

The role of tissue persistent organic pollutants and genetic polymorphisms in patients with benign and malignant kidney tumors

This study aimed to explore whether there is an association between environmental exposure to POPs and kidney tumor induction, and whether blood POP concentrations reflect kidney tissue concentrations. POP derivatives were determined in blood, tumor tissue, tumor surrounding tissue, and perirenal fat tissue samples taken from patients who underwent surgery for renal tumors. A voluntary control group was recruited for blood and urine samples as well. Urinary excretions of o,o′-dityrosine, chlorotyrosine, nitrotyrosine, and 8-OHdG were measured in the same patients. The possible role of genetic polymorphisms in CYP1A1, GST isozymes P, M, and T, and hOGG1 genes on the predisposition to renal cancer was investigated. Some POPs have been found to be associated with kidney cancer, as evidenced by their significantly high ORs. 8-OHdG levels were significantly higher compared to the control group. The GSTT1 null polymorphism can be a risk factor for malignant but not for benign kidney tumors.

Significance of Intestinal Helminth Infection and Animal Sex for Mercury Concentrations in Two Rodent Species.

We compared the effects of animal gender, species, and intestinal helminth burden on mercury concentrations in rodents. Total mercury concentrations were determined in the liver and kidney tissues of 80 small rodents (44 yellow-necked mice, Apodemus flavicollis, and 36 bank voles, Myodes glareolus) captured in the Ore Mountains (northwest Bohemia, Czech Republic). Overall, 25/80 (32%) of animals were infected by intestinal helminths. The differences in mercury concentration between rodents infected and not infected with intestinal helminths were not statistically significant. Statistically significant differences in mercury concentrations were found only between voles and mice (that were not infected with intestinal helminths). This suggests the differences may be associated with host genetics. Apodemus flavicollis body tissues had significantly lower (P=0.01) mean Hg concentrations (0.032 mg/kg) than Myodes glareolus (0.279 mg/kg), provided that animals were not infected by intestinal helminths; if the animals were infected by intestinal helminths, the difference between both groups was insignificant. The effect of gender in this study was significant only for voles (without helminth infection); for mice (either with or without helminth infection) the differences between genders were not significant. Myodes glareolus males had significantly lower (P=0.03) Hg concentrations in liver and kidney tissues (0.050 mg/kg) than Myodes glareolus females (0.122 mg/kg). These results reveal the importance of considering species and gender when evaluating mercury concentrations.

Essential and non-essential elements in the bowhead whale: epidermis-based predictions of blubber, kidney, liver and muscle tissue concentrations

Assessment of element concentrations in wildlife must address both nutritional and toxicological considerations. The liver, epidermis, muscle and kidney of the bowhead whale are rich in some essential and non-essential elements. Blubber tends to have lower concentrations of these elements. Various cetaceans have been evaluated for these elements using a variety of sample sources (live and dead stranded whales, bycaught animals, remote and capture-release biopsy techniques, hunter killed whales etc). One constant shared by these approaches is the sampling of epidermis and adjacent dermis (blubber). In this study, the ability of elemental concentrations in bowhead whale epidermal samples to predict the corresponding elemental concentrations in blubber, kidney, liver and muscle is investigated. Epidermal concentrations had no predictive value for copper (Cu), manganese (Mn), lead (Pb), selenium (Se) or zinc (Zn) in any of the other tissues evaluated, except that the epidermal measurement provided an upper bound for blubber concentration of Cu, Mn, Se and Zn. Epidermal concentrations of the four other elements considered were predictive for some other tissues. Arsenic (As) concentrations could be predicted in kidney, liver and muscle but not blubber, although the preponderance of samples with concentrations below the minimum level reported (MLR, also known as ‘detection limit’) and the small sample sizes that resulted from their omission suggest that these data should be interpreted with caution. Epidermal concentrations of cadmium (Cd) were strongly predictive for blubber and weakly predictive for muscle concentrations. Epidermal concentrations of mercury (Hg) were weakly predictive of blubber, liver and muscle concentrations. Epidermal concentrations of magnesium (Mg) were strongly predictive in blubber, kidney and liver but only weakly predictive in muscle. Thus epidermal biopsy cannot predict elemental concentrations in four key tissues in bowhead whales in most cases. Cobalt (Co) and molybdenum (Mo) were not detected in any epidermal samples. This inability of epidermal element concentrations to reflect concentrations in internal tissues is likely true for other mysticetes and perhaps for cetaceans in general. At a minimum, before using epidermal biopsies to predict internal tissue concentrations of elements, researchers must establish that a sound scientific basis exists for doing so. Such proof must be specific to the elements, species and tissues in question as well as based upon statistically adequate sample sizes.

The Total Mercury Concentration in Organs of Eurasian Magpies (Pica pica) and Common Woodpigeons (Columba palumbus) from the Warsaw Municipal Area.

Mercury is a toxic element widely distributed in the natural environment, affecting animals' health. It is released into the environment from both natural and anthropogenic sources. The present study analyzed the mercury concentrations in liver, kidney, heart and muscle tissue in two species of birds from the Warsaw area, which were used as bioindicators of local environmental pollution with this metal. The mercury content in the examined samples was determined using atomic absorption spectrometry (AAS) utilizing automatic mercury analyzer type AMA 254. The highest mercury content was found in the body of Eurasian magpies, in which it was 0.025; 0.021; 0.006; 0.0037 and 0.029 mg kg-1 of tissue wet weight for kidney, liver, heart, thigh muscles and pectoral muscles, respectively. In the case of common woodpigeons, the content of this metal was significantly lower, amounting to 0.007; 0.005; 0.002; 0.001 and 0.001 mg∙kg-1 wet weight for kidney, liver, heart, thigh muscles and pectoral muscles, respectively. In light of data from the available literature, the values obtained should be considered low, not causing a risk to animal health. The results obtained indicate low environmental exposure to this element.

Effects of intrarenal angiotensin 1-7 infusion on renal haemodynamic and excretory function in anaesthetised two-kidney one-clip and deoxycorticosterone acetate-salt hypertensive rats.

What is the central question of this study? Are renal functional responses to intrarenal angiotensin 1-7 (Ang (1-7)) infusion dependent on the level of the endogenous renin-angiotensin system (RAS) in the two-kidney one-clip (2K1C) and deoxycorticosterone acetate (DOCA)-salt animal models of hypertension? What is the main finding and its importance? The renal actions of Ang (1-7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II-angiotensin II type 1 receptor (AT1 R) axis and those of the Ang (1-7)-Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT1 R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1-7) infusion. This study investigated the action of angiotensin 1-7 (Ang (1-7)) on renal haemodynamic and excretory function in the two-kidney one-clip (2K1C) and deoxycorticosterone acetate (DOCA)-salt rat models of hypertension, in which the endogenous renin-angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1-7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1-7) were determined. Intrarenal infusion of Ang (1-7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (UNa V) and fractional sodium (FENa ) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1-7) concentration. By contrast, Ang (1-7) infusion decreased UV, UNa V, and FENa by 27%, 24% and 21%, respectively in the non-clipped kidney in which tissue Ang (1-7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1-7) infusion in DOCA-salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, UNa V and FENa by ∼30%. Renal Ang (1-7) concentrations were higher and Ang II concentrations were lower in DOCA-salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1-7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II-AT1 receptor axis and Ang (1-7)-Mas receptor axis.

Tamsulosin alters the pharmacokinetics of metformin via inhibition of renal multidrug and toxin extrusion protein 1 and organic cation transporter 2 in rats

Among the endocrine and metabolic disorders, type-2 diabetes mellitus (T2DM) and benign prostatic hyperplasia (BPH) are common progressive diseases related to aging. Metformin and tamsulosin as the first-choice drug for patients with T2DM and BPH, respectively, are often co-administered to male patients with T2DM and BPH. However, whether concomitantly administering metformin and tamsulosin leads to drug-drug interactions (DDIs) remains unclear.This study aimed to evaluate the effect of tamsulosin on the pharmacokinetics of metformin and explore the relevant underlying mechanism. The plasma, urine, and tissue concentrations of metformin were analyzed using HPLC, and metformin cell uptake was analyzed using LC-MS/MS. In addition, western blotting was used to investigate the expression of Oct1, Oct2, and Mate1. As demonstrated by comparison with metformin alone, tamsulosin significantly increased the area under concentration-time curves (AUC0−t), the maximum plasma concentration (Cmax) and the decreased 24 h cumulative urinary excretion of metformin after single or multiple-dose administration in rats, as well as increased the kidney tissue concentration of metformin after multiple-dose. In addition, tamsulosin treatment significantly inhibited the expression of Mate1 and Oct2 in rat kidneys, but Oct1 and Mate1 did not show a significant difference in the liver. Consistently, tamsulosin inhibited OCT2 and MATE1 expressions and decreased metformin uptake in HEK293 cells. Notably, serum LCA level in the co-administration group was increased by 34% and 39% after multiple-dose (7 and 14 consecutive days, respectively) administration compared to the metformin alone group. Altogether, our data suggest that tamsulosin could increase systemic exposure and reduce excretion of metformin via inhibiting Oct2 and Mate1-mediated transport cooperatively.

Pharmacokinetics and tissue distribution characteristics of the novel photosensitizer 32-(4-methoxyphenyl)-152-aspartyl-chlorin e6

二氢卟吩类衍生物32-(4-甲氧基苯基)-152-天冬氨酸-二氢卟吩e6(DYSP-C34)是从程海湖螺旋藻中提取并合成的新型光敏剂。研究DYSP-C34在生物体内的药代动力学及组织分布过程对光动力疗法(PDT)的有效性和安全性至关重要。该文运用高效液相色谱-紫外(HPLC-UV)检测技术,建立了大鼠血浆中DYSP-C34的检测方法。采用沉淀蛋白-液液萃取法处理血浆和组织样品,采用Unitary C18色谱柱(250 mm×4.6 mm, 5 μm)分离,流动相为甲醇-5 mmol/L四丁基磷酸氢铵缓冲盐溶液(70:30, v/v),流速为1.0 mL/min,进样量为20 μL,检测波长为400 nm,柱温为40 ℃。实验结果表明,大鼠血浆药物质量浓度在1~200 μg/mL范围内线性良好,判定系数(r2)为0.9941。在低、中、高(8、40、120 μg/mL)3个添加水平下的提取回收率分别为74.39%、69.71%和65.89%,日内和日间相对标准偏差(RSD)均在5%以内。运用此方法测定静脉注射DYSP-C34(16 mg/kg)后大鼠血浆中以及荷瘤小鼠组织中的药物浓度,采用DAS 2.0计算出药物半衰期t1/2z为6.98 h,药-时曲线下面积AUC(0-∞)为1025.01 h·mg/L,平均驻留时间MRT(0-∞)为9.19 h。DYSP-C34在荷瘤小鼠体内的分布结果显示,DYSP-C34可以在肿瘤组织中蓄积,并具有一定的滞留作用。综上,该文建立了大鼠血浆中DYSP-C34的HPLC-UV测定方法,并进行了方法学验证,此方法简便、快速,结果准确。阐明了DYSP-C34在静脉给药方式下大鼠体内药代动力学和荷瘤小鼠组织中的分布特征,对临床合理用药和药效学研究具有重要意义。

Kidney and Liver Tissue Tacrolimus Concentrations in Adult Transplant Recipients-The Influence of the Whole Blood and Tissue Concentrations on Efficiency of Treatment during Immunosuppressive Therapy.

Tacrolimus (TAC) has a narrow therapeutic index and highly variable pharmacokinetic characteristics. Close monitoring of the TAC concentrations is required in order to avoid the risk of acute rejection or adverse drug reaction. The results in some studies indicate that inter-tissue TAC concentrations can be a better predictor with regards to acute rejection episode than TAC concentration in whole blood. Therefore, the aim of the study was to assess the correlation between dosage, blood, hepatic and kidney tissue concentration of TAC measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) and clinical outcomes in a larger cohort of 100 liver and renal adult transplant recipients. Dried biopsies were weighed, mechanically homogenized and then the samples were treated with a mixture of zinc sulfate—acetonitrile to perform protein precipitation. After centrifugation, the extraction with tert-butyl methyl ether was performed. The analytical range was proven for TAC tissue concentrations of 10–400 pg/mg. The accuracy and precision fell within the acceptance criteria for intraday as well as interday assay. There was no correlation between dosage, blood (C0) and tissue TAC concentrations. TAC concentrations determined in liver and kidney biopsies ranged from 8.5 pg/mg up to 160.0 pg/mg and from 7.1 pg/mg up to 215.7 pg/mg, respectively. To the best of our knowledge, this is the first LC-MS/MS method for kidney and liver tissue TAC monitoring using Tac13C,D2 as the internal standard, which permits measuring tissue TAC concentrations as low as 10 pg/mg.

Comparison of Pharmacokinetics and Tissue Distribution Characteristics of Three Diterpenoid Esters in Crude and Prepared Semen Euphorbiae.

Background Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP) have a long history of medicinal use. SEP is the processed product of SE; both ancient and modern studies have shown that SEP has a lower toxicity compared to SE. To clarify the influence of processing on the pharmacological properties of SE and SEP, a study was carried out to compare the pharmacokinetics and distribution characteristics of three active compounds after oral administration of SE and SEP extracts. Methods A UPLC-MS/MS method was established to simultaneously determine the contents of Euphorbia factors L1, L2, and L3 in rat plasma and mouse tissues after an oral administration of crude and processed SE with approximately the same dosage. Plasma and heart, liver, spleen, lung, kidney, and colon tissue samples were treated with ethyl acetate and separated by gradient elution on a C18 column with a mobile phase of 0.1% formic acid and methanol. Results The established method had good selectivity, linear range, accuracy, precision, stability, matrix effect, and extraction recovery. The area under the concentration time curve, time to maximum concentration, maximum concentration, half-life of elimination, and mean retention time of plasma samples in SEP-treated group decreased, and the clearance in SEP-treated group increased. Moreover, the active component concentrations in colon, liver, and kidney tissues were more followed by those in the heart, lungs, and spleen. Conclusion These results indicate that the processing could influence the pharmacokinetics and tissue distribution of Euphorbia factors L1, L2, and L3 after oral administration of crude and processed SE. The data obtained may lay a foundation for the clinical use of SE and for further study on the processing mechanism of SE.

Identification of biomarkers on kidney failure by Raman spectroscopy

AbstractChronic kidney disease (CKD) is a global health problem. Our study employed Raman spectroscopy for the first time to analyze potential biomarker such as tryptophan (Trp) on kidney failure and show the difference between normal and CKD groups. Adenine model of CKD characterized most of the physiological changes observed in human CKD. For that, 6‐week‐old Wistar male rats were assigned to the two groups: the control group, 0.5% carboxymethyl cellulose (CMC) was administered; the CKD group, adenine was administered to rats at a dose 600 mg/kg for 10 days. The Raman spectra were obtained in the spectral range of 100–2500 cm−1. The excitation source was 532 nm, the laser power was ~40 mW, and the analyzed tissue area was 10.02 × 82.12 μm2. The results showed a significant reduction in the case of Raman peak intensities at 748, 1359, 1554, and 1636 cm−1, which can be assigned as Trp. Moreover, it was shown that tyrosine at 1169 cm−1 and phenylalanine at 1001 cm−1 decreased in the CKD group. Trp and kynurenine (Kyn) levels in kidney tissue and plasma were analyzed by using the high‐performance liquid chromatography (HPLC). The Trp concentrations in plasma and kidney tissue significantly decreased in CKD 7.4 μg/ml and 0.1 μg/mg, respectively. However, Kyn level was not a statistically significant change in kidney tissue. In this work, we showed that Raman spectroscopy usage in CKD model and Raman spectroscopy can be considered a promising technique for semi‐quantitative analysis of potential biomarkers such as phenylalanine, tyrosine, and Trp of renal function because of the little or no need for sample preparation, and it is easily observing several biomarkers at the same time. The utilization of multivariate analysis method, such as partial least square analysis can be considered as a promising tool for the discrimination of control and CKD groups.

Tissue Depletion of Olaquindox and Its Six Metabolites in Pigs and Broilers: Identification of a Suitable Marker Residue.

The depletion profiles of olaquindox and its six major metabolites, including O1 (N1-deoxyolaquindox), O2 (deoxyolaquindox), O3 (2-carboxamide-3-methylquinoxaline-N4-oxide), O4 (2-carboxymethylaminocarbonyl-3-methylquinoxaline-N4-oxide), O5 (2-carboxymethylaminocarbonyl-3-methylquinoxaline), and O6 [3-methyl-quinoxaline-2-carboxylic acid (MQCA)] were studied with a sensitive and accurate HPLC-UV method in pigs and broilers after oral administration of olaquindox at the rate of 50 mg kg−1 feed for 14 consecutive days. Five medicated pigs and six medicated broilers and one control animal for each time point were anesthetized and killed at different time points (6 h and 1, 3, 7, and 14 days for pigs and 6 h and 1, 3, 5, and 7 days for broilers) after ingestion of the medicated feed ceased and samples of muscle, liver, kidney, and fat were collected. The samples were assayed using a liquid chromatographic method. Mean concentrations of O2 (deoxyolaquindox) metabolite residues in all tissues of pigs were higher than other metabolite residues at each time point. MQCA was detected at lower concentrations and eliminated more rapidly than deoxyolaquindox (calculated t1/2 1.78–2.28 days vs. t1/2 2.04–2.46 days). The elimination half-lives of deoxyolaquindox residue in broilers' liver and kidney tissues (t1/2 >4 days) were much longer than those in pigs. Thus, the use of olaquindox in poultry is clearly inappropriate, as significant drug residues will occur without a withdrawal time. The results that deoxyolaquindox occurs at higher concentrations in kidney tissue and is more persistent than other residues in edible tissues of pigs which indicate that deoxyolaquindox is the most relevant marker residue and should be monitored in the routine surveillance of olaquindox-related residues in foods of animal origin.

Evaluation of homing pigeon feather tissue as a biomonitor of environmental metal concentrations in China.

Biomonitoring provides direct evidence of the bioavailability and accumulation of toxic elements in the environment, and homing pigeons have been proposed as a biomonitor of atmospheric pollution. We evaluated metal concentrations in homing pigeon feather tissue as a biomonitoring tool. We measured cadmium, lead, and mercury concentrations in feathers collected from 5-6-yo homing pigeons from Guangzhou, Beijing, and Harbin, China during 2011, and feathers of 1, 5, and 10-yo homing pigeons collected from Guangzhou, Beijing, and Harbin, China during 2015-16. We compared metal concentrations in feathers between sexes and among ages and evaluated spatio-temporal differences. Correlations between feather metal concentrations and previously evaluated kidney and liver metal concentrations are reported. There were no significant differences in feather metal concentrations between male and female pigeons or among 1, 5, and 10-yo pigeons. Cadmium, lead, and mercury concentrations in feathers of 1-yo pigeons were significantly correlated with concentrations in liver and kidney tissues, although the correlations were not consistent. Spatio-temporal differences in feather metal concentrations suggest the usefulness of feathers in identifying areas of concern and remedial effectiveness. Homing pigeon feather metal concentrations appear to be useful as a screening biomonitoring tool.

Protective Role of Chichorium intybus Extract Against Renal Toxicity Induced by Magnetite Silver Nanoparticles in Male Rats

Magnetite silver nanoparticles (Fe3O4/AgNPs) symbolize a new candidate in several industrial and biological products for their activities, simple preparation and low synthesis costs. Many studies recommended the usage of Fe3O4/AgNPs to overcome lacking biocompatibility of AgNPs inside the body. However, Fe3O4/AgNPs also has toxic effects on kidney tissues. In this study, AgNPs was synthesized on the surface of magnetic nanoparticles (Fe3O4) as a core-shell hetero-structure and used to induce renal injury. The microstructure, morphology and magnetic properties of Fe3O4/AgNPs were characterized using different analysis as X-ray diffraction, scanning electron microscopy and vibrating sample magnetometry. This study aimed to evaluate the protective effects of chicory (Chichorium intybus) fruit extract against kidney injury induced by Fe3O4/AgNPs administration in rats. The study was carried out on 40 male adult Sprague Dawley rats (12 weeks old, 140-145 g). Rats were randomly classified into four groups. Group-1 included control rats; group-2 contained the administered chicory extract rats; group-3 was the rats injected withFe3O4/AgNPs; and group-4-in which rats administered with Fe3O4/AgNPs then treated by chicory extract. The obtained results showed that kidney function tests as urea and creatinine increased by about 1.5 folds in rats injected with Fe3O4/AgNPs (G3). Malondialdehyde (MDA) concentrations in kidney tissue duplicated and serum potassium levels increased by about 1.2 folds, while serum sodium and calcium ions slightly decreased in G3. On the other hand, reduced glutathione declined in G3 to nearly one-half normal values in G1. Superoxide dismutase and catalase enzymes decreased to about 0.7 folds in G3. Chicory extract administration in G4 improved all these parameters to nearly their normal values. In conclusion, the obtained results in the current study indicated the protective effects of chicory extract against kidney injury and oxidative stress induced by Fe3O4/AgNPs.

Beneficial effect of black rice ( Oryza sativa L. var. japonica ) extract on amyloid β-induced cognitive dysfunction in a mouse model.

Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disease, resulting in memory loss and cognitive dysfunction. The accumulation of amyloid β (Aβ) has been identified as the most important risk factor for AD. Black rice (BR; Oryza sativa L. var. japonica), which is widely consumed in Asia, is a good source of bioactive compounds including anthocyanins. Therefore, the aim of the present study was to evaluate the protective effect of BR extracts against Aβ25-35-induced memory impairment in an in vivo AD mouse model. After intracerebroventricular injection of Aβ25-35, mice were treated with BR extract supplementation for 14 days. Memory and cognition function were evaluated over this period in both treated and untreated animals using T-maze, novel object recognition and Morris water maze tests. After behavioral tests, malondialdehyde (MDA) and nitric oxide (NO) concentrations in brain, liver and kidney tissues were analyzed. Mice treated with Aβ25-35 had impaired memory and cognitive function; however, mice administered BR extract (100 mg/kg/day) demonstrated an improvement in cognition and memory function compared with the Aβ25-35-injected control group. Furthermore, injection of Aβ25-35 significantly increased MDA and NO generation in the brain, liver and kidney of mice. However, the group administered with BR extract had significantly inhibited lipid peroxidation and NO generation in the brain, liver and kidney. In addition, the protective effect of BR on lipid peroxidation and NO production by Aβ25-35 was stronger in the brain compared with other tissues. Collectively, these findings suggested that BR supplementation may prevent memory and cognition deficits caused by Aβ25-35-induced oxidative stress.

Postmortem Liver and Kidney Tissue Concentrations of Heroin Biomarkers and Their Metabolites in Heroin‐Related Fatalities*†

A method was developed and validated for analyzing 6-monoacetylmorphine, morphine, 6-acetylcodeine, and codeine in routine postmortem liver and kidney specimens using liquid chromatography-tandem mass spectrometry. Samples were prepared with a Stomacher instrument followed by solid-phase extraction. All calibration curves [0.5-1000ng/g] were linear with coefficients of determination greater than 0.99 and limits of quantification of 1.0ng/g. Within-run precision ranged between 2.0% and 8.0%, between-run precision ranged between 1.0% and 9.0%, and accuracy ranged between -5.0% and +3.0%. Matrix effects ranged from -18% to +9%. After matrix effects were excluded, analytical recoveries ranged from 76% to 94%. The distributions of 6-monoacetylmorphine, morphine, 6-acetylcodeine, and codeine were investigated in 31 postmortem cases in which heroin was the primary cause of death. In the current study, the median free morphine ratios were calculated for liver to blood and kidney to blood, which were 2.2 and 4.0, respectively. The current report highlights the importance of testing multiple specimens, including liver and kidney, in heroin-related deaths, especially if no blood samples are available. Furthermore, this work presents new information regarding the distribution of heroin metabolites in liver and kidney.

Vitamin K Tissue Distribution Is Modified by Large-Dose Warfarin and Menaquinone-4 Content of the Diet

Abstract Objectives Investigate the influence of large-dose warfarin (W) on tissue K1 and MK-4 distribution in rats fed a standard K1 diet, or enriched with MK4. Methods Male Wistar rats were fed a regular K1 (750 mcg K1/kg/diet; WK1) or enriched MK-4 (100 mg MK-4/kg/diet; WK1 + MK4) diet for 1 week after which they were administered 14 mg W/kg/day (in drinking water) and subcutaneous K1 (94 mg/kg, 3X/week; to maintain coagulation), for 12 weeks; diets were maintained throughout the experimental period. Respective diet controls (C and C + MK4) received subcutaneous saline and regular water. K1 and M-4 quinone and their epoxide forms (K1O and MK-4O) were assessed in serum, liver, heart, kidney, pancreas, adipose tissue and brain, by HPLC. Group differences were tested by one-way ANOVA, and by t-test for each K vitamer. Results In C group, K1 was the predominant K vitamer in serum, liver and heart, whereas MK-4 was found in relative higher concentrations in kidney, pancreas, brain, and adipose tissue. In MK-4 containing organs, W treatment was associated with significantly lower MK-4 concentration in pancreas, brain, and heart (P < 0.05) despite the local presence of K1, which suggests that W may block the production of MK-4 by UBIAD1. Compared to C group, K1 concentrations were significantly higher in all organs and serum in WK1 and WK1 + MK4 groups as a result of the subcutaneous administration. Interestingly, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), K1 concentrations in naturally K1 rich tissues (i.e., liver, heart and serum) were significantly increased when compared to those from the WK1 group (P < 0.05), suggesting that dietary MK-4 may play a role in modulating the uptake of K1 in these tissues. Except in liver, W administration (WK1 and WK1 + MK4) was associated with higher tissue concentrations of K1 and MK-4 epoxide when compared to C group (P < 0.05). Noteworthy, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), naturally rich MK-4 containing organs (i.e., kidney, pancreas, adipose tissue and brain) presented significantly higher concentration of MK-4 epoxide (relative to K1 epoxide), suggesting a preferential use of MK4 by these organs when available from the diet. Conclusions In conclusion, results from this study point to modulatory roles of W and dietary MK-4 on tissue distribution of K1 and MK-4 in what appears to be a tissue specific manner. Funding Sources CIHR.

Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine

Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only group, berberine significantly decreased the maximum plasma concentration (Cmax), area under the curve from 0 to 4 h (AUC0–4h), and urinary and bile excretion, and increased the kidney tissue concentration of metformin in rats. The non-everted intestinal sac study showed that berberine inhibited the absorption of metformin, and in transfected Madin-Darby canine kidney (MDCK)-rat organic cation transporter 1 (MDCK-rOCT1), MDCK-rat organic cation transporter 2 (MDCK-rOCT2), and MDCK-rat multidrug and toxin extrusion 1 (MDCK-rMATE1) cells, berberine significantly inhibited metformin transport mediated by OCT1, OCT2, and MATE1 in a concentration-dependent manner with half-maximal inhibitory concentration (IC50) values of 18.8, 1.02, and 10.7 μM, respectively. In contrast, co-administration of metformin increased the Cmax and AUC0-4h of berberine with no significant difference in pharmacokinetics parameters between co-administration and berberine-only groups. Furthermore, metformin increased kidney and liver concentrations and reduced the urinary and biliary excretion of berberine. Metformin (≥1 or ≥0.3 mM) decreased berberine transport in MDCK-rOCT1, MDCK-rOCT2, and MDCK-rMATE1 cells. However, metformin did not affect berberine concentration in MDCK-multidrug resistance protein 1 cells. These results suggest that the combination of metformin and berberine induced a pharmacokinetic interaction by cooperatively inhibiting OCT and MATE1-mediated transport.

Cadmium Tissue Concentrations in Kidney, Liver and Muscle in Moose (Alces alces) From First Nations Communities in Northern Alberta

The consumption of traditional foods, including moose, is vitally important to Canada’s indigenous communities for dietary, social, and cultural reasons. Cadmium is a key contaminant of concern in moose as it accumulates primarily the organs, with the kidney accumulating more than the liver. The objectives of this study were to identify relationships between cadmium concentrations in the kidney, liver and muscle tissue of moose, and to estimate benchmark consumption quantities that are associated with minimal health risk for three First Nation communities: the Chipewyan Prairie Dene First Nation, the Swan River First Nation and Cold Lake First Nations. Moose quality studies were conducted with the Chipewyan Prairie Dene First Nation in 2012, the Swan River First Nation in 2014 and the Cold Lake First Nations in 2016, all located in Alberta, Canada. The measured cadmium tissue concentrations from these studies were found to be comparable to those reported in the 2016 Alberta First Nations Food, Nutrition and Environment Study and other North American studies. The results of our study suggest that linear relationships exist between cadmium concentrations in kidney and liver tissue, which can be used as a tool to predict organ concentrations in moose from northern Alberta. First Nations communities can use this information to predict cadmium tissue concentrations in both kidney and liver in the absence of actual, measured cadmium concentrations. Benchmark consumption quantities that are associated with minimal risk were estimated for the different tissue types.