JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties.

The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.

Investigation of the Group Purchasing Structure in the Field of Pharmaceuticals and Medical Devices: The Case of Public Pharmacies.

Background: The supply chain of pharmaceuticals and medical devices takes on critical importance regarding group purchasing, given its contribution to a country's healthcare system. One of the primary loops in this chain is the pharmacy as a supplier of goods to consumers and a buyer of goods from distributors. Objectives: Given the importance of proper and productive preparation, this study examined the structure of aggregated procurement of drugs and medical supplies in public pharmacies. Methods: This study used a qualitative method and interviews to collect the necessary data. Fourteen experts and specialists in the public pharmacy field were interviewed and selected using the purposive sampling method. Finally, the textual data were analyzed using efficient thematic analysis. Results: According to experts, the organizational structure for aggregated procurement of medicines and medical supplies in Iran's public pharmacies can take the form of a headquarters structure, a virtual structure, and a semi-centralized virtual structure. The main requirements for these structures are software infrastructure, a productive workforce, and improved storage methods. Conclusions: According to the majority of experts, the most desirable structure for implementing aggregated procurement in hospital pharmacies is the headquarters structure. The aggregated procurement process can reduce pharmacy costs and increase financial reserves and profitability if adequately implemented and equipped with the necessary infrastructure.

CASP5 and CR1 as potential biomarkers for Kawasaki disease: an Integrated Bioinformatics-Experimental Study.

BACKGROUND: Kawasaki disease (KD) is a pediatric inflammatory disorder causes coronary artery complications. The disease overlapping manifestations with a set of symptomatically like diseases such as bacterial and viral infections, juvenile idiopathic arthritis, Henoch-Schönlein purpura, infection of unknown etiology, group-A streptococcal and adenoviral infections, and incomplete KD could lead to misdiagnosis of the disease. METHODS: In the present study, we applied weighted gene co-expression network analysis (WGCNA) to identify network modules of co-expressed genes in GSE73464 and also, limma package was used to identify the differentially expressed genes (DEGs) in KD expression arrays composed of GSE73464, GSE18606, GSE109351, and GSE68004. By merging the results of WGCNA and limma, we detected hub genes. Then, analyzed the peripheral blood mononuclear cells (PBMCs) of 16 patients and 8 control subjects using Real-Time Polymerase Chain Reaction (RT-PCR) to evaluate the previous results. RESULTS: We assessed the diagnostic potency of the screened genes by plotting the area under curve (AUC). We finally identified 2 genes CASP5(Caspase 5) and CR1(Complement C3b/C4b Receptor 1) which were shown to potentially discriminate KD from other similar diseases and also from healthy people. CONCLUSIONS: The results of RT-PCR and AUC confirmed the diagnostic potentials of two suggested biomarkers for KD.

Integrative analysis of DNA methylation and gene expression profiles to identify biomarkers of glioblastoma.

Glioblastoma multiforme (GBM) is the most common, most invasive, and malignant type of primary brain tumor with poor prognosis and poor survival rate. Using GSE22891 the expression and methylation status of same GBM patients was evaluated to identify key epigenetic genes in GBM. Using |log2FC| > 1 and FDR 〈 0.05 as the threshold, DEGs including 4910 downregulated and 2478 upregulated were screened and by |log2FC| 〉 0.2 and p-value < 0.05, 3223 DMCs were detected. By merging the results of DEGs and DMCs, 643 genes were selected for network analysis by WGCNA, and based on expression values three modules and by methylation values, one module was selected. Using STRING and Cytoscape databases, PPI network of genes of all modules were constructed separately. According to the PPI network, core genes were picked out. The expression status of core genes was evaluated using GSE77043, GSE42656, GSE30563, GSE22891, GSE15824, and GSE122498, and 50 genes were validated. The methylation status of 50 genes was explored using GSE50923, GSE22891, and GSE36245, and finally, 12 hub genes including ARHGEF7, RAB11FIP4, PPP1R16B, OLFM1, CLDN10, BCAT1, C1QB, C1QC, IFI16, NUP37, PARP9, and PCLAF were selected. Using GEPIA database, the expression and by cBioportal the survival plot and also scatterplot of methylation versus expression of 12 hub genes were extracted based on TCGA. To determine the diagnostic values of the hub genes, the receiver operating characteristic (ROC) curve and the area under the curve (AUC) were extracted based on GSE22891 and GSE122498. Finally, we evaluated the expression level of the genes in tissue of 83 GBM patients and also non-tumoral adjacent (as control) tissues.

Antioxidant and glycohydrolase inhibitory behavior of curcumin-based compounds: Synthesis and evaluation of anti-diabetic properties in vitro.

Naturally occurring anti-diabetic compound curcumin can prevent diabetes complications due to antioxidant and anti-inflammatory properties as well as the attenuation of postprandial hyperglycemia. In this line, we have synthesized thirteen curcumin based derivatives (L1-L13) by multi-component reaction, characterized by IR, 1HNMR, 13C NMR, MS, elemental analysis and evaluated for possible antioxidant properties and α-glucosidase (α-Glu) and α-amylase (α-Amy) inhibitory potential. The curcumin-based pyrano[2,3-d]pyrimidine derivatives could inhibit α-Glu and α-Amy enzyme activity which showed desirable antioxidant activity. Furthermore, among the series, L5, L12, L9, L10, L8 and L11 were identified as more potent inhibitors of α-Glu enzyme than curcumin and the compounds of L12, L4, L9, L5, L10, L8, L13, and L11 were the stronger inhibitors of the α-Amy enzyme in vitro. Besides, among them, L12 had the lowest IC50 for the inhibition of both enzymes. Since strong inhibitors for pancreatic α-Amy result in the progression of severe gastrointestinal side effects, the inhibitors that show the lower α-Amy/α-Glu inhibitory ratio have attracted much attention in medicinal chemistry. Besides, considering antioxidant characteristics of synthesized compounds, the L7 derivative with the highest antioxidant activity and the lowest "α-Amy/α-Glu inhibitory" ratio could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs.

Curcumin-based Antioxidant and Glycohydrolase Inhibitor Compounds: Synthesis and In Vitro Appraisal of the Dual Activity Against Diabetes.

BACKGROUND: Curcumin, as the substantial constituent of the turmeric plant (Curcuma longa), plays a significant role in the prevention of various diseases, including diabetes. It possesses ideal structure features as an enzyme inhibitor, including a flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors. OBJECTIVE: The present study aimed at synthesizing several novel curcumin derivatives and further evaluation of these compounds for possible antioxidant and anti-diabetic properties along with inhibitory effect against two carbohydrate-hydrolyzing enzymes, α-amylase and α-glucosidase, as these enzymes are therapeutic targets for attenuation of postprandial hyperglycemia. METHODS: Therefore, curcumin-based pyrido[2,3-d]pyrimidine derivatives were synthesized and identified using an instrumental technique like NMR spectroscopy and then screened for antioxidant and enzyme inhibitory potential. Total antioxidant activity, reducing power assay and 1,1-diphenyl-2- picrylhydrazyl (DPPH•) radical scavenging activity were done to appraise the antioxidant potential of these compounds in vitro. RESULTS: Compounds L6-L9 showed higher antioxidant activity while L4, L9, L12 and especially L8 exhibited the best selectivity index (lowest α-amylase/α-glucosidase inhibition ratio). CONCLUSION: These antioxidant inhibitors may be potential anti-diabetic drugs, not only to reduce glycemic index but also to limit the activity of the major reactive oxygen species (ROS) producing pathways.

Exploring Kawasaki disease-specific hub genes revealing a striking similarity of expression profile to bacterial infections using weighted gene co-expression network analysis (WGCNA) and co-expression modules identification tool (CEMiTool): An integrated bioinformatics and experimental study.

Kawasaki disease (KD) has been declared a rare idiopathic condition for a long time. The children age less than five years, as the most susceptible group, are at risk of this disease. Since the cause of the disease is unknown, this study was designed to investigate the cause of KD. We applied metaDE and WGCNA packages in order to perform a meta-analysis and identify network modules of co-expressed genes, respectively, on three expression array datasets and also CEMiTool package to confirm detected modules by WGCNA. Using the Pearson correlation coefficient, the resemblance of KD to other symptomatic-similar diseases, including bacterial infections, viral infections, JIA (juvenile idiopathic arthritis), HSP (Henoch-Schönlein purpura), GAS (group A streptococcal), and HAdV (adenovirus) was accurately estimated. In addition to validation by more three expression array datasets, serum samples of 16 patients and eight control participants have undergone the Real-Time PCR assay so as to evaluate produced bioinformatic results. WGCNA showed 3840 differentially expressed genes (DEGs) in KD in comparison with other diseases accompanying resembling clinical manifestations. Through further bioinformatic analysis and validation, 42 out of DEGs were introduced as hub genes, which the results of Real-Time PCR assay subsequently attested to the majority of them. The DEGs possessed a remarkable commonality with those of bacterial conditions. According to our exhaustive results, the origin of KD has been revealed pertinent to bacterial infections. Another interesting finding in this study is introducing IVIG in combination with particular antibiotics as a novel therapeutic approach, which supported by a score of authentic research studies to overcome KD.

Sunset yellow degradation product, as an efficient water-soluble inducer, accelerates 1N4R Tau amyloid oligomerization: In vitro preliminary evidence against the food colorant safety in terms of "Triggered Amyloid Aggregation".

Today, Alzheimer's disease (AD) as the most prevalent type of dementia turns into one of the most severe health problems. Neurofibrillary tangle (NFT), mostly comprised of fibrils formed by Tau, is a hallmark of a class of neurodegenerative diseases. Tau protein promotes assembly and makes stable microtubules that play a role in the appropriate function of neurons. Polyanionic cofactors such as heparin, and azo dyes, can induce aggregation of tau protein in vitro. Sunset Yellow is a food colorant used widely in food industries. In the current work, we introduced degradation product (DP) of Sunset Yellow as an effective inducer of Tau aggregation. Two Tau aggregation inducers were produced, and then the aggregation kinetics and the structure of 1N4R Tau amyloid fibrils were characterized using ThT fluorescence spectroscopy, X-Ray Diffraction (XRD), circular dichroism (CD) and atomic force microscopy (AFM). Also, the toxic effects of the induced aggregates on RBCs and SH-SY5Y cells were demonstrated by hemolysis and LDH assays, respectively. Both inducers efficiently accelerated the formation of the amyloid fibril. Along with the confirmation of the ß-sheets structure in Tau aggregates by Far-UV CD spectra, X-ray diffractions revealed the typical cross-ß diffraction pattern. The oligomer formation in the presence of DPs was also confirmed by AFM. The possible in vivo effect of artificial azo dyes on Tau aggregation should be considered seriously as a newly opened dimension in food safety and human health.

Physiological changes in the albumin-bound non-esterified free fatty acids critically influence heme/bilirubin binding properties of the protein: A comparative, in vitro, spectroscopic study using the endogenous biomolecules.

Heme and bilirubin (BR), as by-products of red blood cells (and hemoglobin) degradation, show increased plasma concentrations in some diseases. These two toxic hydrophobic molecules are mainly transported in the blood-stream by human serum albumin (HSA) that carries a wide variety of ligands. Under normal physiological conditions, ~3 fatty acid (FA) molecules are bound to each HSA; and its possible effect on BR/heme binding remains to be more clarified. In the present study, to provide deeper insight on this issue, we purified albumin from healthy individuals (as purified non-defatted albumin or PA) with normal plasma levels of FA, then defatted some of the purified protein (as defatted-HSA; or DA). In the next step, using various spectroscopic methods, their interactions with heme and BR were investigated. By 1: 1 binding of the ligands, quenching and thermodynamic analysis of parameters indicated that binding constants (Kb) values of bilirubin and heme for PA and DA are different. It could be perceived that the presence of FAs in high-affinity FA binding sites (FABSs) exerted considerable conformational changes in the structure followed by an improved BR binding while hindered heme interaction. The data was confirmed by determining surface hydrophobicity of the purified albumin (PA) and DA, and then supported by bioinformatics analyses. The physiological and clinical relevance of the observed dynamic interactions is also discussed. This study, also, re-confirmed that the primary BR binding site is subdomain IIA not subdomain IB.

Apoptosis Induced by Prednisolone Occurs without Altering the Promoter Methylation of BAX and BCL-2 Genes in Acute Lymphoblastic Leukemia Cells CCRF-CEM.

OBJECTIVE: one of the main mechanisms in which cancer cells are resistant to chemotherapy drugs and therapeutic strategies is resistance to apoptosis due to these anticancer factors. Regulating the expression of genes through epigenetics, especially regulation through methylation, is one of the key aspects of regulating gene expression and the function of genes, which is also regulated by the pathways regulating the pathway of apoptosis. The epigenetic regulatory phenomenon in cancer cells can undergo a change in regulation and induces resistance to apoptosis against chemotherapy and anticancer factors. The purpose of the present scrutiny was defined to probe the effect of subtoxic prednisolone dose on the level of promoter methylation and gene expression of BAX and BCL2 in the CCRF-CEM cells. METHODS: The treated cells by prednisolone, cultured in RPMI 1640 medium in standard condition. Alteration in promoter DNA methylation was analyzed by use of methylation specific-PCR (MSP) technique after the defined intervened time of Prednisolone treatment with a subtoxic dose. RESULTS: Prednisolone can induce apoptosis via alteration in BAX and BCL2 genes, based on our previous scrutiny. This essay shows no varies in the Pattern of DNA methylation of examined genes; however, prednisolone changes the expression of examined genes. CONCLUSION: Lack of alteration through prednisolone treatment in DNA methylation template of BAX and BCL2 genes make this possible that Prednisolone affects apoptotic gene expression via different pathways, which need more research to be done about it.
.

Pyridine-2,3-dicarboxylate, quinolinic acid, induces 1N4R Tau amyloid aggregation in vitro: Another evidence for the detrimental effect of the inescapable endogenous neurotoxin.

Quinolinic acid (QA) known as a neuro-active metabolite associated with the kynurenine pathway. At high concentrations, QA is often involved in the initiation and development of several human neurologic diseases, like Alzheimer's disease. Because of the QA action as the NMDA receptor, it is considered as a potent excitotoxin in vivo. Since it is probable that different mechanisms are employed by QA, activation of NMDA receptors cannot fully explain the revealed toxicity and it is even believed that there are multiple unknown mechanisms/targets leading to QA cytotoxicity. Herein we report accelerated amyloid oligomerization of 1N4R Tau under the effect of QA, in vitro, then the molecular structure, morphology and toxicity of the protein aggregate were documented by using various theoretical/experimental approaches. The possible mechanism of action of QA-induced Tau oligomerization has also been explored.

The Effects of Aqueous Extract of Eryngium Campestre on Ethylene Glycol-Induced Calcium Oxalate Kidney Stone in Rats.

PURPOSE: This study aimed to evaluate the anti-inflammatory effect of E. campestre using the aqueous extracts, obtained from the aerial parts, on Ethylene Glycol (EG)-induced calcium oxalate kidney stone in rats. MATERIALS AND METHODS: 64 male Wistar rats were randomly divided into 8 groups. Group I was considered as negative control and received normal saline for 30 days, group II as kidney stone control received EG for 30 days, groups III to VI as prophylactic treatment received EG plus 100, 200 or 400 mg/kg extracts for 30 days and groups VI to VIII received EG as therapy from day one and 100, 200 or 400 mg/kg extract from the 15th day. On the 30thday from the start of induction, rats were euthanized. Blood was collected and the kidneys were immediately excised. Slides from each one's kidneys were prepared and stained with Hematoxylin & Eosin method. Also levels of interleukin-1 beta (IL-1?) and interleukin-6 (IL-6) were determined in rat's serum by competitive ELISA kit. RESULTS: E. campestre reduced IL-1? and IL-6 levels, showing a significant reduction for both cytokines in all prophylactic groups, especially at the dose of 400 mg/kg (P-value < .001). Moreover, IL-1? (p = .011) reduced significantly in the therapy groups in 400 mg/kg dose. Crystal count reduction was seen in all prophylactic and therapy groups in comparison with group II. CONCLUSION: These results suggest that the E. campestre extract has potent suppressive effect on pro-inflammatory cytokine production in rat. Also, E. campestre decreases crystal deposition in the kidney of the hyperoxaluric rat.

Inhibitory effects of selected antibiotics on the activities of α-amylase and α-glucosidase: In-vitro, in-vivo and theoretical studies.

Antibiotics are effective drugs that are used to treat infectious diseases either by killing bacteria or slowing down their growth. The well-adapted structural features of antibiotics for the inhibition/activation of enzymes include several available hydrogen bond (H-bond) acceptors and donors, flexible backbone and hydrophobic nature. The substrates of α-amylase and α-glucosidase, known as key absorbing enzymes, have functional groups (OH groups) rembling antibiotics. Given the possibility of developing in diabetics and the significant association between diabetes and infection, the present study was conducted to investigate the influences of tetracycline (TET), kanamycin (KANA), lincomycin (LIN), erythromycin (ERM) and azithromycin (AZM) on α-glucosidase and α-amylase activities with calculating IC50 and Ki values. Also, the efficacy of antibiotics after oral administration was evaluated by analysis of blood glucose concentrations in rats, as well as a molecular docking analysis was explored. α-glucosidase and α-amylase activities were inhibited in a dose dependent fashion by TET with an IC50 of 38.7 ±â€¯1.4 and 47.8 ±â€¯3.2 µM respectively, by KANA with an IC50 of 46.2 ±â€¯1.6 and 65.1 ±â€¯1.6, by LIN with an IC50 of 59.1 ±â€¯2.1 and 51.3 ±â€¯4.1, by ERM with an IC50 of 94.9 ±â€¯4.7 and 65.7 ±â€¯3.8 and by AZM with an IC50 of 69.4 ±â€¯4.4 and 103.6 ±â€¯6.2. Moreover, the Ki values of TET were calculated as 4.4 ±â€¯0.6 and 8.4 ±â€¯0.8 µM for α-glucosidase and α-amylase in a competitive-mode and mixed-mode inhibition. In addition, to communicate with the active site of α-glucosidase and α-amylase respectively, TET presented a binding energy of -9.8 and -8.8 kcal/mol, KANA -7.9 and -7.1, LIN -7.8 and -6.7, ERM -6.8 and -6.4, and AZM -6.4 and -7.5 kcal/mol. In-vivo studies also suggested a decrease in the blood glucose concentration after administering TET compared to the positive controls (P < 0.01). The results obtained from the present research can therefore help the scientific community explore the possible interconnection between the clinical side-effects of antibiotics and their α-glucosidase and α-amylase inhibitory properties, as the target enzymes in hypoglycemia conditions.

ToF-SIMS 3D Analysis of Thin Films Deposited in High Aspect Ratio Structures via Atomic Layer Deposition and Chemical Vapor Deposition.

For the analysis of thin films, with high aspect ratio (HAR) structures, time-of-flight secondary ion mass spectrometry (ToF-SIMS) overcomes several challenges in comparison to other frequently used techniques such as electron microscopy. The research presented herein focuses on two different kinds of HAR structures that represent different semiconductor technologies. In the first study, ToF-SIMS is used to illustrate cobalt seed layer corrosion by the copper electrolyte within the large through-silicon-vias (TSVs) before and after copper electroplating. However, due to the sample's surface topography, ToF-SIMS analysis proved to be difficult due to the geometrical shadowing effects. Henceforth, in the second study, we introduce a new test platform to eliminate the difficulties with the HAR structures, and again, use ToF-SIMS for elemental analysis. We use data image slicing of 3D ToF-SIMS analysis combined with lateral HAR test chips (PillarHall™) to study the uniformity of silicon dopant concentration in atomic layer deposited (ALD) HfO2 thin films.

Dipyridamole inhibits α-amylase/α-glucosidase at sub-micromolar concentrations; in-vitro, in-vivo and theoretical studies.

Dipyridamole (DP) elevates cyclic Adenosine Monophosphate (cAMP) levels in platelets, erythrocytes, and endothelial cells and also blocks adenosine reuptake. It is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease (CAD). The flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors are well suited structural features of DP for inhibition/activation of enzymes. Substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) similar to DP. Since hypoglycemia can occur in diabetes disease and there is a significant link between diabetes and cardiovascular diseases (CVD), thus this study aimed to evaluate the inhibitory properties of DP against α-Amy and α-Glu, as enzyme targets of interest under hypoglycemia condition. DP inhibited the α-Glu and α-Amy activity in a dose dependent manner with IC50 values 19.4 ±â€¯0.3 and 30.1 ±â€¯0.4 µM, respectively. Further, the Ki values of DP for α-Glu and α-Amy were determined as 2.9 ±â€¯0.2 and 3.1 ±â€¯0.4 µM in a competitive-mode and mixed-mode inhibition, respectively. Also, DP had binding energies of -7.3 and -6.5 kcal/mol, to communicate with the active site of α-Glu and α-Amy, respectively. In addition, in-vivo studies revealed that the blood glucose concentration diminished after taking of DP compared to positive control group (p < 0.01). Accordingly, the results of the current work may prompt the scientific community to investigate the possible interconnection between DP clinical (side) effects and its α-Glu and α-Amy inhibitory properties.

Diverse Effects of Different "Protein-Based" Vehicles on the Stability and Bioavailability of Curcumin: Spectroscopic Evaluation of the Antioxidant Activity and Cytotoxicity In Vitro.

BACKGROUND: Curcumin is a natural polyphenolic compound with anti-cancer, antiinflammatory, and anti-oxidation properties. Low water solubility and rapid hydrolytic degradation are two challenges limiting use of curcumin. OBJECTIVE: In this study, the roles of the native/modified forms of Bovine Serum Albumin (BSA), ß-lactoglobulin (ß-lg) and casein, as food-grade biopolymers and also protein chemical modification, in stabilizing and on biological activity of curcumin were surveyed. METHODS: In this article, we used various spectroscopic as well as cell culture-based techniques along with calculation of thermodynamic parameters. RESULTS: Investigation of curcumin stability indicated that curcumin binding to the native BSA and modified ß -lg were stronger than those of the modified BSA and native ß -lg, respectively and hence, the native BSA and modified ß-lg could suppress water-mediated and light-mediated curcumin degradation, significantly. Moreover, in the presence of the native proteins (BSA and casein), curcumin revealed elevated in vitro anti-cancer activity against MCF-7 (human breast carcinoma cell line) and SKNMC (human neuroblastoma cell line). As well, curcumin, in the presence of the unmodified "BSA and ß-lg", was more potent to decrease ROS generation by hydrogen peroxide (H2O2) whereas it led to an inverse outcome in the presence of native casein. Overall, in the presence of the protein-bound curcumin, increased anti-cancer activity and decreased ROS generation by H2O2 in vitro were documented. CONCLUSION: It appears that "water exclusion" is major determinant factor for increased stability/ efficacy of the bound curcumin so that some protein-curcumin systems may provide novel tools to increase both food quality and the bioavailability of curcumin as health promoting agent.

Glomerular Hyperfiltration as Predictor of Cardiometabolic Risk Factors among Children and Adolescents: The Childhood and Adolescence Surveillance and Prevention of Adult-V Study.

BACKGROUND: The prevalence of glomerular hyperfiltration and chronic kidney disease is increasing worldwide in parallel with obesity hypertension epidemic. The effect of increases in glomerular filtrations (GFR) in children with metabolic syndrome has not been studied. The purpose of the present study is to investigate the relationship between GFR and cardiometabolic risk factors in a large sample of pediatric population. METHODS: In this nationwide survey, 3800 participants were selected by cluster random sampling from 30 provinces in Iran. Anthropometric measures, biochemical, and clinical parameters were measured. We also measured estimated GFR (eGFR) using the recently modified Schwartz equations and other known cardiometabolic risk factors such as elevated total cholesterol, high low-density lipoprotein cholesterol (LDL-C), and obesity. RESULTS: The response rate was 91.5% (n = 3843). The mean and standard deviation (SD) (Mean ± SD) of eGFR for girls, boys, and total population were 96.71 ± 19.46, 96.49 ± 21.69, and 96.59 ± 20 ml/min/1.73 m2, respectively. Overall, 38.7% of the participants did not have any cardiometabolic risk factor. In multivariate models, the risk of elevated systolic blood pressure (BP) (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 1.08-2.02), elevated diastolic BP (OR: 1.48; 95% CI: 1.08-2.02), elevated LDL-C (OR: 1.35; 95% CI: 1.07-1.70), and obesity (OR: 1.70; 95%CI: 1.24-2.33) were significantly higher in participants with higher eGFR level than those with the lower level but not with low level of high-density lipoprotein cholesterol (OR: 0.72; 95% CI: 0.60-0.88). CONCLUSIONS: This study demonstrates an association between glomerular hyperfiltration and obesity-related hypertension in a large sample of the Iranian pediatric population, independently of other classical risk factors.

Captopril/enalapril inhibit promiscuous esterase activity of carbonic anhydrase at micromolar concentrations: An in vitro study.

The inhibitory activity of captopril, a thiol-containing competitive inhibitor of the angiotensin-converting enzyme, ACE, against esterase activity of carbonic anhydrase, CA was investigated. This small molecule, as well as enalapril, was selected in order to represents both thiol and carboxylate, as two well-known metal binding functional groups of metalloprotein inhibitors. Since captopril, has also been observed to inhibit other metalloenzymes such as tyrosinase and metallo-beta lactamase through binding to the catalytic metal ions and regarding CA as a zinc-containing metallo-enzyme, in the current study, we set out to determine whether captopril/enalapril inhibit CA esterase activity of the purified human CA II or not? Then, we revealed the inhibitors' potencies (IC50, Ki and Kdiss values) and also mode of inhibition. Our results also showed that enalapril is more potent CA inhibitor than captopril. Since enalapril represents no sulfhydryl moiety, thus carboxylate group may have a determinant role in inhibiting of CA esterase activity, the conclusion confirmed by molecular docking studies. Additionally, since CA inhibitory potencies of captopril/enalapril were much lower than those of classic sulfonamide drugs, the findings of the current study may explain why these drugs exhibit no effective CA inhibition at the concentrations reached in vivo and also may shed light on the way of generating new class of inhibitors that will discriminately inhibit various CA isoforms.

Degradation products of the artificial azo dye, Allura red, inhibit esterase activity of carbonic anhydrase II: A basic in vitro study on the food safety of the colorant in terms of enzyme inhibition.

Allura red is a widely used food colorant, but there is debate on its potential security risk. In the present study, we found that degradation products of the dye were more potent agents with higher carbonic anhydrase inhibitory action than the parent dye. The mechanism by which the compounds inhibit the enzyme activity has been determined as competitive mode. In addition, the enzyme binding properties of the compounds were investigated employing different spectroscopic techniques and molecular docking. The analyses of fluorescence quenching data revealed the existence of the same binding site for the compounds on the enzyme molecule. The thermodynamic parameters of ligand binding were not similar, which indicates that different interactions are responsible in binding of the parent dye and degradation products to the enzyme. It appears that enzyme inhibition should be considered, more seriously, as a new opened dimension in food safety.

Heme-coordinated histidine residues form non-specific functional "ferritin-heme" peroxidase system: Possible and partial mechanistic relevance to oxidative stress-mediated pathology in neurodegenerative diseases.

Ferritin is a giant protein composed of 24 subunits which is able to sequester up to 4500 atoms of iron. We proposed two kinds of heme binding sites in mammalian ferritins and provided direct evidence for peroxidase activity of heme-ferritin, since there is the possibility that "ferritin-heme" systems display unexpected catalytic behavior like heme-containing enzymes. In the current study, peroxidase activity of heme-bound ferritin was studied using TMB(1), l-DOPA, serotonin, and dopamine, in the presence of H2O2, as oxidant substrate. The catalytic oxidation of TMB was consistent with first-order kinetics with respect to ferritin concentration. Perturbation of the binding affinity and catalytic behavior of heme-bound His-modified ferritin were also documented. We also discuss the importance of the peroxidase-/nitrative-mediated oxidation of vital molecules as well as ferritin-induced catalase inhibition using in vitro experimental system. Uncontrollable "heme-ferritin"-based enzyme activity as well as up-regulation of heme and ferritin may inspire that some oxidative stress-mediated cytotoxic effects in AD-affected cells could be correlated to ferritin-heme interaction and/or ferritin-induced catalase inhibition and describe its contribution as an important causative pathogenesis mechanism in some neurodegenerative disorders.