scholarly journals Metabolic Acidosis Alters Expression of Slc22 Transporters in Mouse Kidney

2020 ◽  
Vol 45 (2) ◽  
pp. 263-274
Author(s):  
Janine Gottier Nwafor ◽  
Marta Nowik ◽  
Naohiko Anzai ◽  
Hitoshi Endou ◽  
Carsten A. Wagner
Keyword(s):  
Metabolic Acidosis ◽  
Mrna Level ◽  
The Body ◽  
Large Set ◽  
Protein Abundance ◽  
Waste Products ◽  
Anion Transporters ◽  
Solute Carrier ◽  
The Impact ◽  
Oxonic Acid

Introduction: The kidneys play a central role in eliminating metabolic waste products and drugs through transporter-mediated excretion along the proximal tubule. This task is mostly achieved through a variety of transporters from the solute carrier family 22 (SLC22) family of organic cation and anion transporters. Metabolic acidosis modulates metabolic and renal functions and also affects the clearance of metabolites and drugs from the body. We had previously shown that induction of metabolic acidosis in mice alters a large set of transcripts, among them also many transporters including transporters from the Slc22 family. Objective: Here we further investigated the impact of acidosis on Slc22 family members. Methods: Metabolic acidosis was induced for 2 or 7 days with NH4Cl, some animals also received the uricase inhibitor oxonic acid for comparison. Expression of transporters was studied by qPCR and immunoblotting. Results: NH4Cl induced no significant changes in plasma or urine uric acid levels but caused downregulation of Slc22a1 (Oct1), Slc22a6 (Oat1), Slc22a19 (Oat5), and ­Slc22a12 (Urat1) at mRNA level. In contrast, Slc22a4 mRNA (Octn1) was upregulated. On protein level, NH4Cl increased Octn1 (after 7 days) and Urat1 (after 2 days) abundance and decreased Oat1 (after 2 days) and Urat1 (after 7 days). Oxonic acid had no impact on protein abundance of any of the transporters tested. Conclusion: In summary, metabolic acidosis alters expression of several transporters involved in renal excretion of metabolic waste products and drugs. This may have implications for drug kinetics and clearance of waste metabolites.

scholarly journals The reference liver—CYP450 and UGT enzymes in healthy donor and metastatic livers: the impact of genotype

2021 ◽  
Author(s):  
Mateusz Kurzawski ◽  
Sylwia Szeląg-Pieniek ◽  
Joanna Łapczuk-Romańska ◽  
Maciej Wrzesiński ◽  
Stefan Oswald ◽  
...  
Keyword(s):  
Protein Content ◽  
Mrna Level ◽  
Inverse Correlation ◽  
Control Group ◽  
Drug Metabolizing Enzymes ◽  
Protein Abundance ◽  
Metabolizing Enzymes ◽  
Functional Variants ◽  
Common Genetic Variants ◽  
The Impact

Abstract Background Hepatic enzymes involved in drug metabolism vary markedly in expression, abundance and activity, which affects individual susceptibility to drugs and toxicants. The present study aimed to compare mRNA expression and protein abundance of the most pharmacologically relevant drug-metabolizing enzymes in two main sources of the control liver samples that are used as the reference, i.e. organ donor livers and non-tumorous tissue from metastatic livers. An association analysis of the most common genetic variants with mRNA and protein levels was also performed. Methods The CYP450 and UGT enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 and UGT2B15) were analyzed for mRNA (qPCR) and protein abundance (LC–MS/MS) in healthy donors (n = 11) and metastatic (n = 13) livers. Genotyping was performed by means of TaqMan assays and pyrosequencing. Results Significantly higher protein abundance in the metastatic livers was observed in case of CYP2C9, CYP2D6, and UGT2B7, and for UGT1A3 the difference was only significant at mRNA level. For all the enzymes except CYP2E1 some significant correlation between mRNA and protein content was observed, and for UGT1A1 an inverse correlation with age was noted. CYP2C19, CYP3A5 and CYP2D6 were significantly affected by genotype. Conclusion The selection of a control group for the study on drug-metabolizing enzymes (e.g. in pathological states) may possibly affect its conclusions on differences in mRNA and protein content. Genotyping for common functional variants of CYP450 enzymes should be performed in all studies on drug-metabolizing enzymes.

scholarly journals Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys

2019 ◽  
Vol 20 (21) ◽  
pp. 5303 ◽  
Author(s):  
Stefan Oswald ◽  
Janett Müller ◽  
Ute Neugebauer ◽  
Rita Schröter ◽  
Edwin Herrmann ◽  
...  
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Tubular Secretion ◽  
Transport Processes ◽  
Protein Abundance ◽  
Multidrug Resistance Proteins ◽  
Anion Transporters ◽  
Slc Transporters ◽  
Potential Factors ◽  
The Impact

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs.

The Impact of Shariah Governance and Corporate Governance on the Risk Management Practices: Evidence from Local and Foreign Islamic Banks in Malaysia

2018 ◽  
Vol 15 (2) ◽  
pp. 1-20
Author(s):  
Sabri Embi ◽  
Zurina Shafii
Keyword(s):  
Risk Management ◽  
Corporate Governance ◽  
Management Practices ◽  
Principal Component ◽  
T Test ◽  
The Body ◽  
Primary Data ◽  
Islamic Banks ◽  
Shariah Governance ◽  
The Impact

The purpose of this study is to examine the impact of Shariah governance and corporate governance (CG) on the risk management practices (RMPs) of local Islamic banks and foreign Islamic banks operating in Malaysia. The Shariah governance comprises the Shariah review (SR) and Shariah audit (SA) variables. The study also evaluates the level of RMPs, CG, SR, and SA between these two type of banks. With the aid of SPSS version 20, the items for RMPs, CG, SR, and SA were subjected to principal component analysis (PCA). From the PCA, one component or factor was extracted each for the CG, SR, and RMPs while another two factors were extracted for the SA. Primary data was collected using a self-administered survey questionnaire. The questionnaire covers four aspects ; CG, SR, SA, and RMPs. The data received from the 300 usable questionnaires were subjected to correlation and regression analyses as well as an independent t-test. The result of correlation analysis shows that all the four variables have large positive correlations with each other indicating a strong and significant relationship between them. From the regression analysis undertaken, CG, SR, and SA together explained 52.3 percent of the RMPs and CG emerged as the most influential variable that impacts the RMPs. The independent t-test carried out shows that there were significant differences in the CG and SA between the local and foreign Islamic banks. However, there were no significant differences between the two types of the bank in relation to SR and RMPs. The study has contributed to the body of knowledge and is beneficial to academicians, industry players, regulators, and other stakeholders.

Influence of DAFS-25+polizon composition on blood and functional state of liver of steers at fattening

2020 ◽  
pp. 15-18
Author(s):  
Inna R. Kilmetova ◽  
◽  
Igor A. Rodin ◽  
Nazira I. Khayrullina ◽  
Nikolay G. Fenchenko ◽  
...  
Keyword(s):  
Functional State ◽  
White Blood Cells ◽  
Live Weight ◽  
The Body ◽  
Farm Animals ◽  
Control Group ◽  
Standard Diet ◽  
The Impact ◽  
Experimental Group ◽  
Stimulation Of

Summary. The disbalanced feeding and the uneven distribution of micro- and macroelements in the environment leads to a trace element, in particular hypomelanosis. To accelerate the growth and preservation of young farm animals include in the diet of various biological additives and drugs, which include selenium. For stimulation of weight gain in the livestock industry, as well as for the prevention and treatment of pathological processes in addition to micro - and macrouse amino acids, primarily methionine. The aim of this work was to study the influence of composition of DAFS-25+Polizon on morpho-biochemical parameters of blood and functional state of the liver in fattening bulls of black-motley breed in the conditions of the Republic of Bashkortostan. Experiments using were conducted on bull-calves of black-motley breed of the properties in the properties age from 6 to 15 months. The first experimental group during the experiment was additionally given the composition of DAFS-25+Polizon at a dose of 2 mg/kg, the animals of the control group received a standard diet. To assess the impact of the composition DAFS-25+Polizon on metabolism cattle studied morphological and biochemical indicators of blood and conducted histological examination of the liver. It is established that the use of the composition of DAFS-25+Polizon at a dose of 2 mg/kg increases the number of erythrocytes and hemoglobin in the experimental group and reduces the amount of white blood cells. The serum content of total protein, phosphorus and calcium increases in the group of experimental animals. Microscopic examination of the liver revealed no changes in the structure of the organ and hepatocytes in the experimental group, whereas in the control group hemodynamic disorders and dystrophic changes in liver cells were observed. Thus, the use of the composition DAFS-25+Polizon at a dose of 2 mg/kg of live weight in fattening bulls black-and-white breed contributes to the increase of redox processes in the body, stimulation of metabolism, prevent the development of liver disorders of cellular mechanisms of metabolism, optimizes the structure of the liver, which generally provides higher productivity.

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

Experience in the use of double broncholytic therapy in occupational practice

2019 ◽  
pp. 303-307
Author(s):  
Elena A. Beigel ◽  
Natalya G. Kuptsova ◽  
Elena V. Katamanova ◽  
Oksana V. Ushakova ◽  
Oleg L. Lakhman
Keyword(s):  
Quality Of Life ◽  
Personal Data ◽  
The Body ◽  
Step Test ◽  
Aluminum Production ◽  
Chronic Obstructive ◽  
Body Plethysmography ◽  
Occupational Copd ◽  
The Impact

Introduction. Occupational chronic obstructive pulmonary disease (COPD) is one of the leading nosological forms of occupational respiratory disease. Numerous studies have shown high effectiveness of the combination of indacaterol/glycopyrronium (Ultibro®breezhaler®) on the impact on clinical and functional indicators in the treatment of COPD in General practice.The aim of the investigation the case of occupational COPD with the analysis of the dynamics of functional indicators, tolerance to physical load and evaluation of the quality of life of workers engaged in aluminum production by using combination of indacaterol/glycopyrronium.Materials and methods. The random sampling method included 20 men, workers of aluminum production, with the established diagnosis of professional COPD at the age of 40 to 60 years. The survey was conducted (Borg scale, medical Research Council scale (mMRC) and COPD Assessment Test (CAT). Functional methods of studies were conducted: spirometry, body plethysmography, electrocardiography (ECG) and the six-minute stepper test (6-MST).Results. Against the background of 8 weeks of therapy, the volume of forced exhalation for 1 minute (FEV1) increased by 14.7% and amounted to 67.90% of the due values, the forced vital capacity of the lungs (FVC) increased by 11.3% and amounted to 76.95% of the due. According to the body plethysmography (BPG) is set to decrease in residual lung volume on average by 13.4% and static hyperinflation, confirmed by the decrease in functional residual volume (FRV) of 18.8%. During the study period increased physical activity of patients. The average difference between the distance traveled in the six-minute step test before and after treatment was 58.8 m. The analysis of personal data showed that the quality of life of patients improved, the total score in the questionnaire CAT at the beginning of the study was 16.9 points, and after 8 weeks decreased by 63% and amounted to 10.7 points.Conclusions: The Results indicate a positive effect of combination therapy with indacaterol/glycopyrronium on the course and progression of occupational COPD.

Studying Abroad in Nepal: Assessing Impact

2003 ◽  
Vol 9 (1) ◽  
pp. 175-188 ◽  
Author(s):  
Patricia Farrell ◽  
Murari Suvedi
Keyword(s):  
Personal Development ◽  
Intellectual Development ◽  
Longitudinal Research ◽  
Adult Learning Theory ◽  
Academic Program ◽  
The Body ◽  
Study Abroad Programs ◽  
Studying Abroad ◽  
Perceived Impact ◽  
The Impact

The purpose of this study is to analyze the reported or perceived impact of studying in Nepal on student’s academic program, personal development and intellectual development. The study draws upon adult learning theory to analyze survey instrument data, interviews, and case studies to discern the impact of the program on college students and to contribute to the body of longitudinal research on U.S. study abroad programs.

Adrenergic and Cholinergic Uterine Innervation and the Impact on Reproduction in Aged Women

2020 ◽  
Vol 26 (3) ◽  
pp. 358-362 ◽  
Author(s):  
Ioannis P. Kosmas ◽  
Antonio Malvasi ◽  
Daniele Vergara ◽  
Ospan A. Mynbaev ◽  
Radmila Sparic ◽  
...  
Keyword(s):  
Negative Impact ◽  
Smooth Muscles ◽  
Nerve Fibers ◽  
The Body ◽  
Autonomous Nervous System ◽  
Childbearing Age ◽  
Assisted Reproductive Technique ◽  
Aged Patients ◽  
Post Menopause ◽  
The Impact

: In recent years, the development of Assisted Reproductive Technique, the egg and embryo donation changed substantially the role of the uterus in recent years. It provided a higher chance for a pregnancy even in women over 45 years or post-menopause. In fact, the number of aged patients and in peri/post-menopause in pregnancy is nowadays increasing, but it increases obstetrical and neonatal related problems. The human uterus is richly innervated and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Immunohistochemical study demonstrated the localization and quantitative distribution of neurofibers in the fundus, the body and cervix of young women of childbearing age. : Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality. In such aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing. The Adrenergic and AChE neurofibers decreasing has a dramatical and negative impact on uterine physiology, as the reduction of pregnancy chance and uterine growth, and the increase of abortion risk and prematurity.

scholarly journals Timing of Bisphosphonate Initiation After Fracture: What Does the Data Really Say?

2020 ◽  
Vol 11 ◽  
pp. 215145932098036
Author(s):  
David W. Barton ◽  
C. Taylor Smith ◽  
Amit S. Piple ◽  
Sterling A. Moskal ◽  
Jonathan J. Carmouche
Keyword(s):  
Fracture Healing ◽  
Clinical Studies ◽  
Osteoporosis Treatment ◽  
The Body ◽  
Non Union ◽  
Increased Risk ◽  
Level I ◽  
Timing Of Initiation ◽  
The Impact ◽  
Published Research

Introduction: Osteoporosis is often not clinically recognized until after a fracture occurs. Individuals who have 1 fracture are at increased risk of future fractures. Prompt initiation of osteoporosis treatment following fracture is critical to reducing the rate of future fractures. Antiresorptives are the most widely used class of medications for the prevention and treatment of osteoporosis. Many providers are hesitant to initiate antiresorptives in the acute post-fracture period. Concerns include interference with bone remodeling necessary for successful fracture healing, which would cause increased rates of non-union, malunion, and refracture. While such concerns should not extend to anabolic medications, physicians may also hesitate to initiate anabolic osteoporosis therapies due to high cost and/or lack of familiarity. This article aims to briefly review the available data and present a digestible narrative summary to familiarize practicing orthopaedic surgeons with the essential details of the published research on this topic. Results: The results of 20 clinical studies and key pre-clinical studies related to the effect of anti-resorptive medications for osteoporosis on fracture healing are summarized in the body of this narrative review. Discussion & Conclusions: While few level I studies have examined the impact of timing of initiation of osteoporosis medications in the acute post-fracture period, the few that have been published do not support these concerns. Specifically, data from level I clinical trials indicate that initiating bisphosphonates as early as 2 weeks post-fracture does not increase rates of non-union or malunion. By reviewing the available data, we hope to give clinicians the confidence to initiate osteoporosis treatment promptly post-fracture.

scholarly journals 695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Loise Francisco-Anderson ◽  
Loise Francisco-Anderson ◽  
Mary Abdou ◽  
Michael Goldberg ◽  
Erin Troy ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Extracellular Vesicle ◽  
The Body ◽  
Checkpoint Inhibition ◽  
Small Intestinal ◽  
The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

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