Therapeutic effect of N, N-Diphenyl-1,4-phenylenediamine and adipose-derived stem cells coadministration on diabetic cardiomyopathy in type 1 diabetes mellitus-rat model.

Type 1 diabetes stem-cell-based treatment approach is among the leading therapeutic strategies for treating cardiac damage owing to the stem cells' regeneration capabilities. Mesenchymal stem cells derived from adipose tissue (AD-MSCs) have shown great potential in treating diabetic cardiomyopathy (DCM). Herein, we explored the antioxidant-supporting role of N, N'-diphenyl-1,4-phenylenediamine (DPPD) in enhancing the MSCs' therapeutic role in alleviating DCM complications in heart tissues of type 1 diabetic rats. Six male albinos Wistar rat groups have been designed into the control group, DPPD (250 mg/kg, i.p.) group, diabetic-untreated group, and three diabetic rat groups treated with either AD-MSCs (1 × 106 cell/rat, i.v.) or DPPD or both. Interestingly, all three treated diabetic groups exhibited a significant decrease in serum glucose, HbA1c, heart dysfunction markers (lactate dehydrogenase and CK-MP) levels, and lipid profile fractions (except for HDL-C), as well as some cardiac oxidative stress (OS) levels (MDA, AGEs, XO, and ROS). On the contrary, serum insulin, C-peptide, and various cardiac antioxidant levels (GSH, GST, CAT, SOD, TAC, and HO-1), beside viable cardiac cells (G0/G1%), were markedly elevated compared with the diabetic untreated group. In support of these findings, the histological assay reflected a marked enhancement in the cardiac tissues of all diabetic-treated groups, with obvious excellency of the AD-MSCs + DPPD diabetic-treated group. Such results strongly suggested the great therapeutic potentiality of either DPPD or AD-MSCs single injection in enhancing the cardiac function of diabetic rats, with a great noted enhancement superiority of DPPD and AD-MSCs coadministration.

Plant mediated biosynthesis of Mn3O4 nanostructures and their biomedical applications.

Nanomaterials have drawn significant attention for their biomedical and pharmaceutical applications. In the present study, manganese tetra oxide (Mn3O4) nanoparticles were prepared greenly, and their physicochemical properties were studied. Taxus baccata acetone extract was used as a safely novel precursor for reducing and stabilizing nanoparticles. The synthesized nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), Brunauer-Emmett-Teller (BET), and Barrett-Joyner-Halenda (BJH) and X-ray diffraction (XRD). The cytotoxicity of Mn3O4 (hausmannite) nanostructures was evaluated against murine macrophage cell line J774-A1 and U87 glioblastoma cancer cells for approximately 72 h. Spherical Mn3O4 nanoparticles with tetragonal spinel structures demonstrated minimal toxicity against normal body cells with CC50 around 876.38 µg mL-1. Moreover, Mn3O4 nanoparticles as well as the combination of antimoniate meglumine and Mn3O4 nanoparticles exhibited maximum mortality in Leishmania major. The synthesized nanominerals displayed a significant inhibitory effect against glioblastoma cancer cells at 100 µg mL-1. The selective cytotoxicity of Mn3O4 nanoparticles indicates that these biogenic agents can be employed simultaneously for diagnostic and therapeutic applications in medical applications.

Corrigendum: The association between FokI vitamin D receptor polymorphisms with metabolic syndrome among pregnant Arab women.

[This corrects the article DOI: 10.3389/fendo.2022.844472.].

Genetic Variants of HNF4A, WFS1, DUSP9, FTO, and ZFAND6 Genes Are Associated with Prediabetes Susceptibility and Inflammatory Markers in the Saudi Arabian Population.

Prediabetes is a reversible, intermediate stage of type 2 diabetes mellitus (T2DM). Lifestyle changes that include healthy diet and exercise can substantially reduce progression to T2DM. The present study explored the association of 37 T2DM- and obesity-linked single nucleotide polymorphisms (SNPs) with prediabetes risk in a homogenous Saudi Arabian population. A total of 1129 Saudi adults [332 with prediabetes (29%) and 797 normoglycemic controls] were randomly selected and genotyped using the KASPar SNP genotyping method. Anthropometric and various serological parameters were measured following standard procedures. Heterozygous GA of HNF4A-rs4812829 (0.64; 95% CI 0.47-0.86; p < 0.01), heterozygous TC of WFS1-rs1801214 (0.60; 95% confidence interval (CI) 0.44-0.80; p < 0.01), heterozygous GA of DUSP9-rs5945326 (0.60; 95% CI 0.39-0.92; p = 0.01), heterozygous GA of ZFAND6-rs11634397 (0.75; 95% CI 0.56-1.01; p = 0.05), and homozygous AA of FTO-rs11642841 (1.50; 95% CI 0.8-1.45; p = 0.03) were significantly associated with prediabetes, independent of age and body mass index (BMI). Additionally, C-reactive protein (CRP) levels in rs11634397 (AA) with a median of 5389.0 (2767.4-7412.8) were significantly higher than in the heterozygous GA genotype with a median of 1736.3 (1024.4-4452.0) (p < 0.01). In conclusion, only five of the 37 genetic variants previously linked to T2DM and obesity in the Saudi Arabian population [HNF4A-rs4812829, WFS1-rs1801214, DUSP9-rs5945326, ZFAND6-rs11634397, FTO-rs11642841] were associated with prediabetes susceptibility. Prospective studies are needed to confirm the potential clinical value of the studied genetic variants of interest.

Structural basis of paralog-specific KDM2A/B nucleosome recognition.

The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2-nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation.

Probing the interaction of zinc oxide nanorods with human serum albumin: A spectroscopic approach.

Bio-functionalized metal oxide nanoparticles (NPs) have been taken great importance in biomedical fields. The use of nanoparticles as delivery agents of therapeutic molecules led the researchers to emphasize the potential impact of these NPs on bio-macromolecules as protein-nanoparticle complexes, which also extended their importance as vehicles in targeted drug delivery systems due to increased ease of administration, firmness, reduced toxic side effects, and half-life of drugs. Since human serum albumin is the blood protein responsible for transporting materials in the blood system, the interaction of these particles with HSA is essential to be understood before considering the nanoparticles for any individual biomedical application. In the present study, we synthesized zinc-oxide nanorods (ZONRs) using a microwave-assisted synthesis technique, and characterized them by XRD, FTIR, Raman, SEM-EDX, UV-Vis spectroscopy, and photoluminescence (PL) spectroscopy methods. The interaction studies were carried out using fluorescence spectroscopy, and the change in secondary structure was analyzed using CD spectroscopy. The results of MTT cell viability assay demonstrated that the ZONRs has potential cytotoxic properties.

New Insights into Listeria monocytogenes Antimicrobial Resistance, Virulence Attributes and Their Prospective Correlation.

Listeriosis is one of the most common foodborne diseases caused by Listeria monocytogenes (L. monocytogenes). A poor prognosis has been recorded for the invasive listeriosis, especially neurolisteriosis. In several countries throughout the world, foodborne infections with L. monocytogenes exceeded the legal safety limits in animal sourced foods. Therefore, we decided to investigate the variability, virulence and antimicrobial resistance profiles of this pathogen. Both phenotypic and genotypic methods were used for identifying L. monocytogenes isolates and confirming their virulence profiles. The antimicrobial resistances and their correlation analysis with the existence of virulence genes were detected. Additionally, sequencing and phylogenetic analysis based on L. monocytogenes inlA and inlB genes were undertaken. The prevalence rate (11.9%) and the resistance profiles of L. monocytogenes were shocking. The multi-drug resistance (MDR) phenotypes were common among our isolates (64.9%). Fortunately, the resistance phenotypes were always associated with low virulence arrays and the MDR strains possessed low virulence fitness. Herein, the high genotypic and phenotypic diversity of L. monocytogenes isolates and their weak clonality and adaptability highlighted the difficulty in controlling and managing this pathogen. Therefore, it is important to add more restriction guidelines from national authorities on the consumption of ready to eat foods.

Time Resolved-Fluorescence Resonance Energy Transfer platform for quantitative nucleosome binding and footprinting.

Quantitative analysis of chromatin protein-nucleosome interactions is essential to understand regulation of genome-templated processes. However, current methods to measure nucleosome interactions are limited by low throughput, low signal-to-noise, and/or the requirement for specialized instrumentation. Here, we report a Lanthanide Chelate Excite Time-Resolved Fluorescence Resonance Energy Transfer (LANCE TR-FRET) assay to efficiently quantify chromatin protein-nucleosome interactions. The system makes use of commercially available reagents, offers robust signal-to-noise with minimal sample requirements, uses a conventional fluorescence microplate reader, and can be adapted for high-throughput workflows. We determined the nucleosome-binding affinities of several chromatin proteins and complexes, which are consistent with measurements obtained through orthogonal biophysical methods. We also developed a TR-FRET competition assay for high-resolution footprinting of chromatin protein-nucleosome interactions. Finally, we set up a TR-FRET competition assay using the LANA peptide to quantitate nucleosome acidic patch binding. We applied this assay to establish a proof-of-principle for regulation of nucleosome acidic patch binding by methylation of chromatin protein arginine anchors. Overall, our TR-FRET assays allow facile, high-throughput quantification of chromatin interactions and are poised to complement mechanistic chromatin biochemistry, structural biology, and drug discovery programs.

Multivalent DNA and nucleosome acidic patch interactions specify VRK1 mitotic localization and activity.

A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase that phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.

The Association Between FokI Vitamin D Receptor Polymorphisms With Metabolic Syndrome Among Pregnant Arab Women.

Metabolic syndrome (MetS) is a serious health condition that is becoming extremely threatening in Saudi Arabia. The link between vitamin D receptor (VDR) gene polymorphisms and maternal MetS has been observed in several ethnic groups, but is yet to be clarified in the Arabian population. This study aims to investigate the relationship between the FokI VDR genotype and the risk of MetS and its components in pregnant Saudi women. A cross-sectional study was conducted using 368 pregnant Saudi women on first trimester screened for MetS (44 with MetS and 324 without MetS). Measurements included anthropometrics, glycemic and lipid profile and 25(OH)D. TaqMan genotyping assay was used to determine Fokl VDR genotype of participants. Vitamin D deficiency (25(OH)D <50nmol/l) was seen in 85% of the participants. An estimated 12% of participants had MetS. In the MetS group, the FokI VDR genotyping frequencies for FF, Ff, and ff genotypes were 50%, 36.4% and 13.6%, respectively. In controls, the frequencies were 62.7%, 31.4% and 5.9%, respectively. No significant association between the individual MetS components and FokI VDR genotypes were observed. Nevertheless, carriers of the ff allele had a significant risk for full maternal MetS [Odds Ratio 4.2 (95% Confidence Interval 1.4-12.2; adjusted p=0.009). The study suggests that the ff FokI VDR genotype is a genetic marker of maternal MetS in pregnant Arabian women. Prospective studies that include neonatal outcomes may confirm present findings.

Is a single dose of preoperative antibiotic therapy effective for patients treated with megaendoprosthesis after metastatic bone tumour resection?

Purpose The timing and number of doses of antibiotics required for megaendoprosthetic replacement (MPR) in metastatic bone disease (MBD) is a matter of debate. The aim of our study is to present the results of a prospective cohort of MPR for MBD receiving a single dose of antibiotic at induction of anaesthesia. METHODS: All patients who underwent primary MPR in MBD were included in this prospective study. All penicillin-sensitive patients received one dose of cefuroxime 1.5gm intravenous at induction. In penicillin-allergic patients, teicoplanin 1.2gm and ciprofloxacin 500 mg intravenous was administered. The patients were followed up in the wound clinic and the specialist MBD clinic at 2 weeks, 3 months, 6 months and then annually. Data collected included demographics, primary tumours, surgical procedures, complications and duration of follow-up. All calculations were performed using SPSS® 25(IBM, USA). A p value ≤ 0.05 was considered to be significant. RESULTS: There were 51 patients with a mean age of 65.4 years. Procedures included proximal femoral replacement (35), distal femoral replacement (7), proximal humeral replacement (4), distal humeral replacement (3) and total femoral replacement (2). Thirty-seven patients received cefuroxime, and fourteen patients received teicoplanin and ciprofloxacin at induction of anaesthesia. The deep infection rate was 1.9%. Thirty-seven patients died with a median survival of 10 months (1 to 51 months). Mean follow-up was 18.9 months (1 to 70 months). CONCLUSION: Single dose of preoperative antibiotics at anaesthetic induction seems to be safe and effective for preoperative prophylaxis in orthopaedic oncology.

Quantum dynamics of Mn2+ in dimethylammonium magnesium formate.

Dimethylammonium magnesium formate, [(CH3)2NH2][Mg(HCOO)3] or DMAMgF, is a model used to study high temperature hybrid perovskite-like dielectrics. This compound displays an order-disorder phase transition at about 260 K. Using multifrequency electron spin resonance in continuous wave and pulsed modes, we herein present the quantum dynamics of the Mn2+ ion probe in DMAMgF. In the high temperature paraelectric phase, we observe a large distribution of the zero field splitting that is attributed to the high local disorder and further supported by density functional theory computations. In the low temperature ferroelastic phase, a single structure phase is detected and shown to contain two magnetic structures. The complex electron paramagnetic resonance signals were identified by means of the Rabi oscillation method combined with the crystal field kernel density estimation.

Awareness of Parents About the Emergency Management of Avulsed Tooth in Eastern Province and Riyadh.

Objective: To assess the level of parents knowledge about the emergency management of tooth avulsion in Eastern Province and Riyadh. Methods: A cross-sectional study was carried out by means of a questionnaire-based internet survey in which 1201 parents from Eastern Province and Riyadh participated. The questionnaire contained 10 closed-ended questions and was used to assess the knowledge of parents about the emergency management of avulsed teeth in Eastern Province and Riyadh. Chi-square test was used for data analysis. Results: In response to closed-ended questions, the statistically significant result was obtained for the history of child dental trauma in which 35% (P=0.04) of parents reported history of dental trauma in their children. These parents were belong to Eastern province (51%) and Riyadh (49%). Furthermore, only 31.3% of the parents were aware of possible storage media for transportation of avulsed tooth while 68.7% (49.5% in Eastern Province and 50.5% in Riyadh) were unaware (P=0.02) of it. Conclusion: That the majority of the parents were unaware of emergency management for tooth avulsion in two densely populated regions of Saudi Arabia. Education of parents should be initiated at a national level.

Hydrogen evolution reaction from bare and surface-functionalized few-layered MoS2 nanosheets in acidic and alkaline electrolytes.

Hydrogen is considered as an ideal and sustainable energy carrier because of its high energy density and carbon-free combustion. Electrochemical water splitting is the only solution for uninterrupted, scalable, and sustainable production of hydrogen without carbon emission. However, a large-scale hydrogen production through electrochemical water splitting depends on the availability of earth-abundant electrocatalysts and a suitable electrolyte medium. In this article, we demonstrate that hydrogen evolution reaction (HER) performance of electrocatalytic materials can be controlled by their surface functionalization and selection of a suitable electrolyte solution. Here, we report syntheses of few-layered MoS2 nanosheets, NiO nanoparticles (NPs), and multiwalled carbon nanotubes (MWCNTs) using scalable production methods from earth-abundant materials. Magnetic measurements of as-produced electrocatalyst materials demonstrate that MoS2 nanoflakes are diamagnetic, whereas surface-functionalized MoS2 and its composite with carbon nanotubes have strong ferromagnetism. The HER performance of the few-layered pristine MoS2 nanoflakes, MoS2/NiO NPs, and MoS2/NiO NPs/MWCNT nanocomposite electrocatalysts are studied in acidic and alkaline media. For bare MoS2, the values of overpotential (η10) in alkaline and acidic media are 0.45 and 0.54 V, respectively. Similarly, the values of current density at 0.5 V overpotential are 27 and 6.2 mA/cm2 in alkaline and acidic media, respectively. The surface functionalization acts adversely in the both alkaline and acidic media. MoS2 nanosheets functionalized with NiO NPs also demonstrated excellent performance for oxygen evolution reaction with anodic current of ~60 mA/cm2 and Tafel slope of 78 mVdec-1 in alkaline medium.

Analysis of organophosphate-Zn metalloporphyrin interactions via UV-vis spectroscopy and molecular modeling.

UV-vis absorption spectra of zinc tetraphenylporphine (ZnTPP) on interaction with six organophosphorus (OP) compounds in cyclohexane were compared using ab initio methods and the molecular and solvation ligand descriptors π(*), Vx, and σ. OPs with polarizable hydrocarbon substituents in the homologous series tri-ethyl, -pentyl, -octyl, and -phenyl phosphates and the toxicologically relevant methyl paraoxon (1a-e) each gave a red shift in the Soret band (λsor) of ZnTPP in the range of 8-10 nm. Sensitivity as ΔAsor-b/Δug OP for the spectral band of the ligand bound ZnTPP (λsor-b) decreased with increasing extent of alkyl and aromatic substitution. Calculated and combined energies for OP and ZnTPP examined as a function of distance (Å) between ligand and porphyrin center suggest increased steric crowding with increasing Vx, and aromatic content of the OP. Spectrally fitted K1:1 and ΔAsor-b/ug OP each vary exponentially with Vx/σ. Lack of a red shift in λsor-b where ZnTPP was titrated with the toxic diethyl chlorophosphate (1g) is consistent with a model in which the magnitude of ΔEsor is proportional to the donor capacity of the phosphoryl-O ligand.

Central hemodynamics in prehypertension: effect of the ß-adrenergic antagonist nebivolol.

The aim of the current study was to characterize the effects of the novel ß-adrenergic antagonist nebivolol on central aortic blood pressures, arterial properties, and nitroxidergic activity in individuals with prehypertension. Prehypertension is emerging as a major risk factor for several adverse cardiovascular consequences. Increased pulse wave velocity, aortic augmentation index, and aortic blood pressures have been linked with augmented risk of cardiovascular disease and mortality. While the effects of antihypertensive drugs on these parameters in hypertensive patients have been studied, there are limited data so far in prehypertension. Fifty individuals with prehypertension were randomized to either nebivolol (5 mg per day) or placebo in a double-blind clinical trial. Patients underwent measurement of pulse wave velocity as well as aortic blood pressure and aortic augmentation index via pulse wave analysis at baseline and 8 weeks. Patients also had blood and urine biochemistries done at each visit. Nebivolol achieved significant reductions in central aortic systolic (P=.011), diastolic (P=.009), and mean arterial blood pressure (P=.002). Pulse wave velocity trended toward improvement but did not achieve significance (P=.088). Nitric oxide production, measured as urinary nitrite/nitrite excretion, also rose substantially in the nebivolol group (by approximately 60%, P=.030). Central blood pressures can be effectively lowered by ß-blockade while patients are still in the prehypertension phase, and the effects may be coupled to improve nitric oxide release by the drug.

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

BACKGROUND: Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits. METHODS: We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort. RESULTS: Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h(2) = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h(2) = 66.5±5.0%, p = 3.2E-16) and dopamine (h(2) = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = -0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = -0.223±0.101, p = 2.3E-02). Since dopamine ß-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p = 0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003). CONCLUSIONS: The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.

Spin dynamics of the S = 5/2 2D triangular antiferromagnet Ba3NbFe3Si2O14.

We report pulse-field magnetization, ac susceptibility, and 100 GHz electron spin resonance (ESR) measurements on the S = 5/2 two-dimensional triangular compound Ba3NbFe3Si2O14 with the Néel temperature T(N) = 26 K. The magnetization curve shows an almost linear increase up to 60 T with no indication of a one-third magnetization plateau. An unusually large frequency dependence of the ac susceptibility in the temperature range of T = 20-100 K reveals a spin-glass behavior or superparamagnetism, signaling the presence of frustration-related slow magnetic fluctuations. The temperature dependence of the ESR linewidth exhibits two distinct critical regimes; (i) ΔH(pp)(T) is proportional to (T-T(N))(-p) with the exponent p = 0.2(1)-0.2(3) for temperatures above 27 K, and (ii) ΔH(pp)(T) is proportional to (T-T*)(-p) with T* = 12 K and p = 0.8(1)-0.8(4) for temperatures between 12 and 27 K. This is interpreted as indicating a dimensional crossover of magnetic interactions and the persistence of short-range correlations with a helically ordered state.