Kidney Enzyme Research Articles

Synergistic effect of arginine and Lactobacillus plantarum against potassium dichromate induced-acute liver and kidney injury in rats: Role of iNOS and TLR4/NF-κB signaling pathways.

Our study was conducted to evaluate the synergistic effect of arginine (ARG) and Lactobacillus plantarum against potassium dichromate (K2Cr2O7) induced-acute hepatic and kidney injury. Fifty male Wistar rats were divided into five groups. The control group received distilled water. The potassium dichromate group (PDC) received a single dose of PDC (20 mg/kg; SC). The arginine group (ARG) and Lactobacillus plantarum group received either daily doses of ARG (100 mg/kg, PO) or L. plantarum (109 CFU/ml, PO) for 14 days. The combination group (ARG+L. plantarum) received daily doses of ARG (100 mg/kg) with L. plantarum (109 CFU/ml), orally for 14 days, before induction of acute liver and kidney injury. Forty eight hours after the last dose of PDC, serum biochemical indices, oxidative stress biomarkers, pro-inflammatory cytokines, histopathological and immunohistochemical analysis were evaluated. Combining ARG with L. plantarum restored the levels of serum hepatic & kidney enzymes, hepatic & renal oxidative stress biomarkers, and TLR 4/ NF-κB signaling pathway. Furthermore, they succeeded in decreasing the expression of iNOS and ameliorate the hepatic and renal markers of apoptosis: Caspase-3, Bax, and Bcl2. This study depicts that combining ARG with L. plantarum exerted a new bacteriotherapy against hepatic and renal injury caused by PDC.

Ethanol Extracts of Eriobotrya japonica (Loquat) Seeds, Leaves, and Fruits Have Anti-obesity and Hypolipidemic Effects in Rats

Background: Obesity is a serious public health problem contributing to development of several diseases, including hyperlipidemia, hyperglycemia, and hypertension. The plant Eriobotrya japonica (loquat) has been used in traditional Chinese medicine to treat many ailments and traditional healers used it to reduce weight. Objectives: To examine the potential anti-obesity and hypolipidemic effects of ethanol extract of loquat in rats. Materials and Methods: Loquat leaves, fruits, or seeds were extracted with ethanol. About 96 Wistar male rats were fed either a normal rat diet (normal control group; group 1) or a high-fat diet (HFD) for 12 weeks (obese; groups 2−12). Obese rats were divided into11 groups as follows: (obese control: group 2) (obese positive control which received the hypolipidemic reference drug atorvastatin: group 3). Groups (4−6), (7−9), and (10−12) were given seed, leaf, or fruit extract, respectively, at 40,100, and 400 mg/kg. Body weight, serum glucose, lipid profile, creatinine, liver enzymes, albumin, and total protein were measured weekly. Results: HFD consumption significantly increased body weight and serum total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), very-low density lipoprotein (VLDL), and glucose and decreased HDL compared to rats fed the normal diet. HFD also increased serum glutamic-oxaloacetic transaminase (GOT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and creatinine but decreased serum albumin and total protein. Administration of E. japonica seed, leaf, or fruit extract significantly decreased body weight, TC, TGs, LDL, VLDL, glucose, liver, and renal enzymes but increased HDL, albumin, and total protein levels. Conclusion: E. japonica seed, leaf, and fruit ethanol extract regulates body weight gain, has hypolipidemic properties, and positively affects liver and kidney enzymes.

The metabolites of de novo NAD+ synthesis are a valuable predictor of acute kidney injury.

Acute kidney injury (AKI) is often iatrogenic and potentially preventable. Reduced renal nicotinamide adenine dinucleotide (NAD+) is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts. The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: the methotrexate (MTX) cohort with high-dose MTX treatment for lymphoma (n=189) and the liver transplantation cohort with orthotopic liver transplantation (n=49). Urinary metabolomics study of NAD+ de novo synthesis was performed by liquid chromatography with mass spectrometry, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI-susceptible conditions. Human proximal tubule was the main structure in the kidney that expressed the necessary enzymes for NAD+ de novo synthesis. In the MTX cohort, the urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in the liver transplantation cohort. The area under the receiver-operating characteristic curve (AUC) of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts, respectively. 3-Hydroxyanthranilic acid dioxygenase (HAAO), the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.

Characterization of CPH:SA microparticle-based delivery of interleukin-1 alpha for cancer immunotherapy.

Interleukin-1 alpha (IL-1α) is a pro-inflammatory cytokine that can activate immune effector cells and trigger anti-tumor immune responses. However, dose-limiting toxicities including cytokine storm and hypotension has limited its use in the clinic as a cancer therapy. We propose that polymeric microparticle (MP)-based delivery of IL-1α will suppress the acute pro-inflammatory side effects by allowing for slow and controlled release of IL-1α systemically, while simultaneously triggering an anti-tumor immune response. Polyanhydride copolymers composed of 1,6-bis-(p-carboxyphenoxy)-hexane:sebacic 20:80 (CPH:SA 20:80) was utilized to fabricate MPs. Recombinant IL-1α (rIL-1α) was encapsulated into CPH:SA 20:80 MPs (IL-1α-MPs) and the MPs were characterized by size, charge, loading efficiency, and in-vitro release and activity of IL-1α. IL-1α-MPs were injected intraperitonially into head and neck squamous cell carcinoma (HNSCC)-bearing C57Bl/6 mice and monitored for changes in weight, tumor growth, circulating cytokines/chemokines, hepatic and kidney enzymes, blood pressure, heart rate, and tumor-infiltrating immune cells. CPH:SA IL-1α-MPs demonstrated sustained release kinetics of IL-1α (100% protein released over 8-10 days) accompanied by minimal weight loss and systemic inflammation compared to rIL-1α-treated mice. Blood pressure measured by radiotelemetry in conscious mice demonstrates that rIL-1α-induced hypotension was prevented in IL-1α-MP-treated mice. Liver and kidney enzymes were within normal range for all control and cytokine-treated mice. Both rIL-1α and IL-1α-MP-treated mice showed similar delays in tumor growth and similar increases in tumor-infiltrating CD3+ T cells, macrophages, and dendritic cells. CPH:SA-based IL-1α-MPs generated a slow and sustained systemic release of IL-1α resulting in reduced weight loss, systemic inflammation, and hypotension accompanied by an adequate anti-tumor immune response in HNSCC-tumor bearing mice. Therefore, MPs based on CPH:SA formulations may be promising as delivery vehicles for IL-1α to achieve safe, effective, and durable antitumor responses for HNSCC patients.

Simultaneous solving high-resolution structures of various enzymes from human kidney microsomes.

The ability to investigate tissues and organs through an integrated systems biology approach has been thought to be unobtainable in the field of structural biology, where the techniques mainly focus on a particular biomacromolecule of interest. Here we report the use of cryo-electron microscopy (cryo-EM) to define the composition of a raw human kidney microsomal lysate. We simultaneously identify and solve cryo-EM structures of four distinct kidney enzymes whose functions have been linked to protein biosynthesis and quality control, biosynthesis of retinoic acid, gluconeogenesis and glycolysis, and the regulation and metabolism of amino acids. Interestingly, all four of these enzymes are directly linked to cellular processes that, when disrupted, can contribute to the onset and progression of diabetes. This work underscores the potential of cryo-EM to facilitate tissue and organ proteomics at the atomic level.

Rheumatoid Arthritis Effects on Kidney and Liver and their Correlations with CDAI

Rheumatoid arthritis (RA) is a disease characterized by chronic autoimmune inflammation of body joints, causing movement disability, loss of functions, joint damage, and many complications. Persistent usage of anti-rheumatic drugs has several side effects, which may cause heart, kidney, or liver diseases. This study aims to assess the influence of RA duration on kidney and liver enzymes and study the correlation between these enzyme levels and RA disease activity (CDAI). This study collected a total of 150 blood samples. 100 samples for RA patients (61 were seropositive, 39 were seronegative), and 50 for healthy Control. throughout the period from November 2021 to February 2022. The blood samples were collected from Baghdad Teaching Hospital / Rheumatology Consulting Clinic. General information had been collected from each subject according to a questionnaire that had been applied for this purpose. The age groups of patients and control were between 22-72 years, and 26-62 years old, respectively. The female participants were more than the male counterparts. The blood samples were taken from patients and control groups to screen liver and kidney functions by an automated biochemical system using the SELECTRA PRO X2 device, in addition to the ESR test. The study showed that the levels of urea, creatinine, GPT, and GOT were either normal or slightly elevated and they are non-significantly associated with RA disease activity, the little effect of RA on kidney and liver may be related to the low doses of methotrexate and corticosteroid therapy which used mostly for these patients and didn’t reach to toxicity.

Asian Pigeonwing Plants (Clitoria ternatea) Synergized Mesenchymal Stem Cells by Modulating the Inflammatory Response in Rats with Cisplatin-Induced Acute Kidney Injury.

Acute kidney injury is a heterogeneous set of disorders distinguished by a sudden decrease in the glomerular filtration rate, which is evidenced by an increase in the serum creatinine concentration or oliguria and categorized by stage and cause. It is an ever-growing health problem worldwide, with no reliable treatment. In the present study, we evaluated the role of Clitoria ternatea combined with mesenchymal stem cells in treating cisplatin-induced acute kidney injury in rats. Animals were challenged with cisplatin, followed by 400 mg/kg of Asian pigeonwing extract and/or mesenchymal stem cells (106 cells/150 g body weight). Kidney functions and enzymes were recorded, and histopathological sectioning was also performed. The expression profile of IL-1β, IL-6, and caspase-3 was assessed using the quantitative polymerase chain reaction. The obtained data indicated that mesenchymal stem cells combined with the botanical extract modulated the creatinine uric acid and urea levels. Cisplatin increased the level of malondialdehyde and decreased the levels of both superoxide dismutase and glutathione; however, the dual treatment was capable of restoring the normal levels. Furthermore, all treatments modulated the IL-6, IL-1β, and caspase-3 gene expression profiles. The obtained data shed some light on adjuvant therapy using C. ternatea and mesenchymal stem cells in treating acute kidney injury; however, further investigations are required to understand these agents' synergistic mechanisms fully. The total RNA was extracted from the control, the positive control, and all of the therapeutically treated animals. The expression profiles of the IL-6, IL-1β, and caspase-3 genes were evaluated using the real-time polymerase chain reaction. Cisplatin treatment caused a significant upregulation in IL-6. All treatments could mitigate the IL-6-upregulating effect of cisplatin, with the mesenchymal stem cell treatment being the most effective. The same profile was observed in the IL-1β and caspase-3 genes, except that the dual treatment (mesenchymal stem cells and the botanical extract) was the most effective in ameliorating the adverse effect of cisplatin; it downregulated caspase-3 expression better than the positive control.

GC-MS Analysis of the Phytochemical Constituents, Safety Assessment, Wound Healing and Anti-Inflammatory Activities of Cucurbita pepo Leaf Extract in Rats

In traditional medicine, Cucurbita pepo L. is used for the treatment of rheumatism, diabetes, inflammations, and wound injuries. This study was conducted to evaluate the phytochemical constituents, safety profile, wound healing, and anti-inflammatory activities of Cucurbita pepo leaf extract in rats. The phytochemical analysis of C. pepo extract was carried out using gas chromatography-mass spectrometry (GC-MS). In acute toxicity tests, the rats orally received a single dose of 5 g/kg extract of C. pepo. In a subacute toxicity study, the rats received 200, 400, and 800 mg/kg of the C. pepo extract via daily gavage for 14 days. Bioactive compounds 1-octen-3-ol, nonanal, trans-β-ionone, phytol, trans-farnesol, and squalene were identified. There were no toxic effects detected in any of the evaluated parameters, namely liver, kidney, haematological, lipid, and antioxidant enzymes. In wound healing, C. pepo extract showed greater % wound contraction and tensile strength, as well as reduced wound healing time (12 days) and epithelialization when compared to the control (normal saline) and povidone-iodine treated groups. Rats treated with C. pepo extract elicit anti-inflammatory activity. The findings of this study revealed that the C. pepo extract has wound healing and anti-inflammatory properties with a wide margin of safety.

Lactobacillus-fermented yogurt exerts hypoglycemic, hypocholesterolemic, and anti-inflammatory activities in STZ-induced diabetic Wistar rats

Hyperglycemia is a symptom of type 2 diabetes mellitus, a chronic metabolic disease characterized by elevated blood glucose concentrations. Antidiabetic drugs are common treatments for this metabolic disorder; however, they may have unpleasant side effects. This study hypothesized that probiotic fermented products could preserve nutritional value, maintain metabolic homeostasis, and attenuate the inflammatory response associated with diabetes while reducing side effects. Lactobacillus plantarum KU985438 and Lactobacillus rhamnosus KU985439 showed the lowest alfa-amylase enzyme (α-amylase) activity among 8 lactobacilli tested. These 2 strains were used to develop functional fermented milk products, and their antidiabetic efficacy was tested in induced diabetic Wistar rats. The treatment of diabetic rats with L. plantarum KU985438 or L. rhamnosus KU985439 fermented yogurt resulted in a considerable reduction in blood glucose concentrations (136.79% and 145.17%, respectively) and α-amylase concentrations (56.84% and 56.84%, respectively) compared with conventional treatments. Diabetes relief began after 4 days of yogurt consumption compared with drug-based treatment. Significant improvements in both liver and kidney enzyme concentrations were also observed, in addition to a significant increase in high-density lipoprotein cholesterol concentrations and improved lipid profiles. Inhibition in nuclear factor κB and an increase in Bcl-2 concentrations were also detected. Histopathological examination of both hepatic and pancreatic cells revealed the positive effects of the studied treatment compared with standard treatment. Therefore, the selected Lactobacilli, which has hypoglycemic potential, could be used to produce functional nutraceutical antidiabetic supplements.

Sexual Dimorphism in the Expression of Cytochrome P450 Enzymes in Rat Heart, Liver, Kidney, Lung, Brain, and Small Intestine.

Cytochrome P450 (P450) enzymes are monooxygenases that are expressed hepatically and extrahepatically and play an essential role in xenobiotic metabolism. Substantial scientific evidence indicates sex-specific differences between males and females in disease patterns and drug responses, which could be attributed, even partly, to differences in the expression and/or activity levels of P450 enzymes in different organs. In this study, we compared the mRNA and protein expression of P450 enzymes in different organs of male and female Sprague-Dawley rats by real-time polymerase chain reaction and western blot techniques. We found significant sex- and organ-specific differences in several enzymes. Hepatic Cyp2c11, Cyp2c13, and Cyp4a2 showed male-specific expression, whereas Cyp2c12 showed female-specific expression. Cyp2e1 and Cyp4f enzymes demonstrated higher expression in the female heart and kidneys compared with males; however, they showed no significant sexual dimorphism in the liver. Male rats showed higher hepatic and renal Cyp1b1 levels. All assessed enzymes were found in the liver, but some were not expressed in other organs. At the protein expression level, CYP1A2, CYP3A, and CYP4A1 demonstrated higher expression levels in the females in several organs, including the liver. Elucidating sex-specific differences in P450 enzyme levels could help better understand differences in disease pathogeneses and drug responses between males and females and thus improve treatment strategies. SIGNIFICANCE STATEMENT: This study characterized the differences in the mRNA and protein expression levels of different cytochrome P450 (P450) enzymes between male and female rats in the heart, liver, lung, kidney, brain, and small intestine. It demonstrated unique sex-specific differences in the different organs. This study is considered a big step towards elucidating sex-specific differences in P450 enzyme levels, which is largely important for achieving a better understanding of the differences between males and females in the disease's processes and treatment outcomes.

Oral Administration of Copper Chloride Damages DNA, Lowers Antioxidant Defense, Alters Metabolic Status, and Inhibits Membrane Bound Enzymes in Rat Kidney.

Copper (Cu) is a heavy metal that is widely used in industries and is also an essential micronutrient for living beings. However, excess Cu is toxic and human exposure to high levels of this metal results in numerous adverse health effects. We have investigated the effect of oral administration of copper chloride (CuCl2), a Cu(II) compound, on various parameters of oxidative stress, cellular metabolism, and DNA integrity in the rat kidney. This was done to delineate the molecular mechanism of Cu(II) toxicity. Adult male rats were randomly divided into five groups. Animals in four CuCl2-treated groups were separately administered single acute oral dose of CuCl2 at 5, 15, 30, and 40mg/kg body weight. Animals in the fifth group were not given CuCl2 and served as the control. All rats were sacrificed 24h after the dose of CuCl2 and their kidneys removed. CuCl2 administration led to significant alterations in enzymatic and non-enzymatic parameters of oxidative stress. It changed the activities of metabolic and membrane bound enzymes and also decreased the activities of brush border membrane enzymes. CuCl2 treatment dose-dependently enhanced DNA damage and DNA-protein crosslinking in renal cells, when compared to the control group. The administration of CuCl2 also resulted in marked morphological changes in the kidney, with more prominent alterations at higher doses of CuCl2. These results clearly show that CuCl2 impairs the antioxidant defense system resulting in oxidative damage to the kidney.

Moringa oliefera Leaves Powder Controlling Blood Glucose Level in Diabetes Mellitus Patients , No Side Effect in Kidney and Liver Enzymes

Moringa oleifera grown and used in many countries around the world is a multi-purpose tree with medicinal and nutritional values. This study evaluates the effect of taking moringa oleifera leaves powder on blood sugar levels in humans, and study side effect on kidney (urea, creatinine) and liver enzyme (AST, ALT) after taken leaves powder for a month. The study targeted patients who their blood glucose not lowering by drugs. Blood glucose, urea, creatinine, AST and ALT for all diabetic patients was determined before and after taking 0.5g leaves powder. Results showed blood sugar levels decreased statistically significant (p<0.001) for all diabetic patients, and no statistically significant difference in the mean values of urea, creatinine, (AST) and (ALT) before and after taking leaves powder (p˃0.001). This study concluded that leaves powder have a significant impact on anti-diabetic property for the selected patients, so it's promising in the prevention for risk of diabetes mellitus.

The potential effect of the Rumex vesicarius water seeds extract treatment on mice before and during pregnancy on the serum enzymes and the histology of kidney and liver

Abstract Rumex vesicarius (R. vesicarius or RV) is an annual plant having rounded leaves, with flowers containing seeds. RV protects liver, resists cancer, and removes free radicals in cells. The aim of this study was to illustrate the effect of the R. vesicarius water seeds extract (RVWSE) treatment on mice before and during pregnancy, and its action on the liver and kidney histology and enzymes, aspartate aminotransferase and alanine aminotransferase, the blood urea nitrogen, the creatinine, and the uric acid. The seeds of R. vesicarius were collected, extracted, and its component analyzed via Gas chromatography mass spectrometry. Mice treated with 10 mg kg−1 RVWSE via feeding tube for 1 week before mating, or during pregnancy. The number of offspring or litter size was recorded and the blood sample was collected at the end of the experiment to test the kidney and liver enzymes, and their histology. Results showed that RVWSE contains different phytochemicals consisting of some hexane and chloroform compounds. The fertility rate of 1st treated pre-pregnancy group is 30% and the 2nd group is 35%. The offspring rate of 1st treated group showed higher new born rate (8 new born/female) than 2nd treated group (5.4 new born/female). The blood enzyme levels of the kidney and liver showed some variation between the two groups and their histology illustrates some non-significant variation between the treated and control groups of mice. The implications of the results of this study illustrate the safe use of the RVWSE, its effectiveness in improving mice fertility, and positive impact on biomarker of serum enzymes of liver and kidney with their histopathology.

Utilizing lemon peel extract and its nano-emulsion to control aflatoxin toxicity in rats

The lemon peel is a flavonoid-hefty source and also has bioactive constituents, such as polyphenols. This research was performed to assess the potential of lemon peel essential oil and its nano-emulsion as a fruit waste in protecting against aflatoxin B1-induced toxicity in experimental animals. Thirty-six male Sprague-Dawley rats were administered a daily dosage of aflatoxin (80 μg/kg b.w) treated with lemon peel essential oil and its nano-emulsion (100 mg/kg). All nutritional parameters, biochemical parameters, and histopathological examinations were evaluated. The results revealed severe toxicity and carcinogenicity of AFB1 established by elevation of TNF-α and IL-6 and pathogenic elevation in kidney and liver enzymes manifested by significant elevation of creatinine, urea, uric acid, AST, ALT, and ALP to 0.98, 79.4, 3.2, 57.6, 38, and 98.14, respectively. All these biochemical changes were confirmed by histopathological examination. All these harmful changes were amended by the use of lemon peel essential oil and its nano-emulsion, which led to the conclusion that lemon peel essential oil and its nano-emulsion as a fruit waste could be a promising source for the immune-enhancing drug that could protect against aflatoxin ingestion.

Effect of Methanolic Extract of Carica papaya Seed on Renal Function and Antioxidant Activities Following Ibuprofen-induced Toxicity on Male Wistar Rats

In this study, the effect of methanolic seed extract of Carica papaya (MSECP) was investigated to ascertain its effect on the renal function and antioxidants activities following ibuprofen induced renal toxicity. Phytochemical screening of crude extract revealed the presence of alkaloids, flavonoids, glycosides, saponins and tannins while anthraquinone and phlobatannins were found to be absent. Thirty (30) healthy male Wistar rats were divided into 5 groups. Group A (received feed and water only); Group B received 80mg/kg of ibuprofen only; Group C received 80mg/kg of ibuprofen + 150mg/kg of MSECP; Group D received 80mg/kg of ibuprofen + 300mg/kg of MSECP; Group E (received 80mg/kg of ibuprofen and treated with 600mg/kg of (MSECP). The administration of the extract lasted for 21 days within hours of 7-8 am via oral gavage. After 21 days the animals were anesthetized with 25% Urethane and blood was collected using a heparinized capillary tube and transferred into a plain container and centrifuged. The serum retrieved was used to assay serum antioxidants Superoxide dismutase (SOD), Catalase activity (CAT), Glutathione (GSH), Glutathione peroxidase (GPX), Total Antioxidant capacity (TAC) and kidney enzymes (urea and creatinine). MSECP significantly reduced the plasma concentration of urea and creatinine (p>0.05) when compared to group A. The antioxidant enzymes reduced significantly (p>0.05) in groups that was administered with MSECP when compared to the group A and B. MSECP was discovered to have some therapeutic effect on renal function probably as a result of some of the antioxidants and phytonutrients present in Carica papaya which have the capability of increasing glomerular filtration of toxic substances from the kidney and hence recommend that Carica papaya seed could be included in our daily diet.

Experimental therapy of chronic kidney ischemia using drug basic fibroblast growth factor

Abstract. The aim of the work was to experimentally study the effect of the created injectable drug basic fibroblast growth factor (bFGF) with the controlled release on morphological changes and indicators of renospecific enzymes in the ischemic kidney (experiment on rabbits).
 Methods. Studies on the release dynamics of the created bFGF drug were performed in vitro and the study of the induction of bFGF angiogenesis in the model of the chick chorioallantoic membrane of the chicken was performed. The experimental model was performed in 25 rabbits: in 10 rabbits we studied the effect of 1-8 months of "pure ischemia" of the kidney without injection of the drug (control); in 12 rabbits 1 month after the creation of the model of ischemia in the renal parenchyma was injected the prolonged-acting drug bFGF, deposited on our polymeric carrier at a dose of 5 μg (experiment). The reference group consisted of 3 intact rabbits. Histological examinations of renal tissue and morphometric examinations with the determination of vascular coefficient (VC) and interstitial coefficient (IC) were performed. Enzymological indicators of enzyme activity in the homogenate of the renal parenchyma were determined by biochemical methods; statistical analysis was performed.
 Results. Using chick chorioallantoic membrane as a model it was preliminarily demonstrated that developed injectable prolonged-acting drug bFGF deposited on a polymeric carrier based on cross-linked modified heparin, effectively enhances neoangiogenesis.
 The results of morphological and morphometric studies with the determination of vascular and interstitial coefficients showed, that the injection of the prolonged-acting drug bFGF in all cases was accompanied by an increased blood supply in the kidneys and neoangiogenesis, which reduced the effects of ischemia.
 Injection of bFGF at a dose of 5 μg in the model of chronic segmental renal ischemia for 3-4 months completely prevented the development of initial sclerotic and atrophic changes, that developed in the kidney during this period under the influence of chronic ischemia without bFGF. Injection of prolonged-acting bFGF at a dose of 5 μg in the model of chronic segmental renal ischemia for 5-8 months prevented expressed sclerotic and atrophic changes, that developed under the influence of chronic ischemia during this period without the use of bFGF.
 As a result of biochemical studies, the activation and normalization of indicators of renospecific tubular enzymes in the ischemic kidney under the action of the created experimental drug bFGF were determined.
 Conclusions. Therapy of ischemic changes in the kidney with the developed injectable long-acting drug bFGF at a dose of 5 µg in the experimental model of chronic ischemia protects the organ from hypoxic damage, has a positive effect on the structural and functional state and metabolism of the kidney, and prevents the development of nephrosclerosis.

Therapeutic potential of royal jelly to control Toxoplasma gondii infection in mice.

At present, there are several synthetic medications for toxoplasmosis therapy; however, these agents cannot be permanently applied because of adverse side effects or therapeutic failures and drug resistance in parasites. The present experimental investigation was aimed to study the effects of royal jelly (RJ) obtained from Apis mellifera in comparison with atovaquone against Toxoplasma gondii infection in mice. After treatment of infected mice with RJ at the doses of 200, 400, and 600 mg/kg for 14 consecutive days, we evaluated the therapeutic activity of RJ by measuring the mean number and the mean size of T. gondii tissue cysts, oxidant-antioxidant enzymes, pro-inflammatory cytokines, the mRNA expression levels of bradyzoite surface antigen 1 (BAG1), as well as the toxic effect on liver and kidney function. Treatment of the infected mice with RJ significantly (p < 0.001) decreased the mean number and the mean diameter of T. gondii tissue cysts and downregulated BAG1 in a dose-dependent response. After treatment of infected mice with RJ, the level of oxidative stress markers was significantly diminished, but a significant increase (p < 0.05) in the level of antioxidant markers such as glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzymes was observed. Treatment of the infected mice with RJ significantly enhanced the level of pro-inflammatory cytokines IFN-γ and IL-1β, whereas it caused no substantial change in the serum levels of liver and kidney enzymes. The findings of this in vivo study revealed the favorable therapeutic effect of RJ on latent T. gondii infection in mice. It was found that RJ considerably inhibited the infection by decreasing the number and size of tissue cysts, reducing oxidative stress, and boosting the level of pro-inflammatory cytokines, but had no significant toxic impact on the function of vital organs such as liver and kidney. However, additional surveys are required to confirm these findings and clarify the exact mechanisms and their efficiency in clinical subjects.

Effects of Elephantopus scaber extract on growth, proximate composition, immunity, intestinal microbiota and resistance of the GIFT strain of Nile tilapia Oreochromis niloticus to Streptococcus agalactiae

This study aimed to investigate the effects of Elephantopus scaber extract on the GIFT (genetic improvement of farmed tilapia) strain of Nile tilapia Oreochromis niloticus. A total of 800 tilapia with an initial body weight of 1.34 ± 0.09 g each were randomly divided into five groups. The tilapia in the control group (E0 group) were fed on a basal diet only. Meanwhile, tilapia in the four experimental groups were fed on a basal diet supplemented with 1 g/kg (E1 group), 3 g/kg (E2 group), 5 g/kg (E3 group), and 7 g/kg (E4 group) of E. scaber extract for 10 weeks. Results showed that the survival rate was higher in the experimental groups than in the control group. Compared with the control group, some growth parameters (FW, WGR, SGR, VSI, and HSI) were significantly improved in the E1 group and E2 group. The crude lipid content in the dorsal muscle and liver was lower in the E1 group than in the control group. After E. scaber extract supplementation, activities of immunity-related enzymes (ACP, AKP, T-AOC, SOD, CAT, GSH-Px and LZM) in plasma, liver, spleen and head kidney, and expressions of immunity-related genes (IL-1β, IFN-γ, TNF-α, and CCL-3) in liver, spleen and head kidney showed various degrees of improvement, while MDA content and Hsp70 expression level were decreased. The survival rate of tilapia increased in all the supplementation groups after Streptococcus agalactiae treatment. E. scaber extract addition changed the species composition, abundance, and diversity of intestinal microbiota in tilapia. These results demonstrate that E. scaber extract supplementation in diet can improve the growth, immunity, and disease resistance of GIFT against S. agalactiae. E. scaber extract supplementation can also change intestinal microbiota and reduce crude lipid content in dorsal muscle and liver. The above indicators show that the optimal dose of E. scaber extract for GIFT is 1 g/kg.

Examining Physiologically Based Pharmacokinetic Model Assumptions for Cross-Tissue Similarity of Activity per Unit of Enzyme: The Case Example of Uridine 5′-Diphosphate Glucuronosyltransferase

The default assumption during in vitro in vivo extrapolation (IVIVE) to predict metabolic clearance in physiologically-based pharmacokinetics (PBPK) is that protein expression and activity have the same relationship in various tissues. This assumption is examined for uridine 5'-diphosphate glucuronosyltransferases (UGTs), a case example where expression and, hence, metabolic activity are distributed across various tissues. Our literature analysis presents overwhelming evidence of a greater UGT activity per unit of enzyme (higher kcat) in kidney and intestinal tissues relative to liver (greater than 200-fold for UGT2B7). This analysis is based on application of abundance values reported using similar proteomic techniques and within the same laboratory. Our findings call into question the practice of assuming similar kcat during IVIVE estimations as part of PBPK, and call for a systematic assessment of the kcat of various enzymes across different organs. The analysis focused on compiling data for probe substrates that were common for two or more of the studied tissues, to allow for reliable comparison of cross-tissue enzyme kinetics; this meant that UGT enzymes included in the study were limited to UGT1A1, 1A3, 1A6, 1A9 and 2B7. Significantly, UGT1A9 (n=24) and the liver (n=27) were each found to account for around half of the total dataset; these were found to correlate, with hepatic UGT1A9 data found in 15 of the studies, highlighting the need for more research into extrahepatic tissues and other UGT isoforms. Significance Statement During PBPK modelling (in vitro in vivo extrapolation) of drug clearance, the default assumption is that the activity per unit of enzyme (kcat) is the same in all tissues. The analysis provides preliminary evidence that this may not be the case, and that renal and intestinal tissues may have almost 250-fold greater UGT activity per unit of enzyme than liver tissues.

The Modulation of Arachidonic Acid Metabolism and Blood Pressure-Lowering Effect of Honokiol in Spontaneously Hypertensive Rats.

Background: Cardiovascular diseases have consistently been the leading cause of death in the United States over the last two decades, with 30% of the adult American population having hypertension. The metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the antihypertensive effect of honokiol (HON), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Methods: Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered HON intraperitoneally at concentrations of 5, 20, and 50 mg/kg. Blood pressure was monitored at seven-day intervals. After a total of 3 weeks of treatment, the rats were euthanized and the kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Results: Rats treated with HON did not experience the rise in blood pressure observed in the untreated SHR. High-dose HON significantly reduced blood pressure and inhibited the activity and protein expression of the CYP4A enzyme in the rat kidney. The activity of the sEH enzyme in renal cytosol was significantly inhibited by medium and high doses of HON. Conclusion: Our data demonstrate the antihypertensive effect of HON and provide a novel mechanism for its underlying cardioprotective properties.