Experimental study and modeling of extreme ultraviolet 4000 lines/mm diffraction gratings coated with periodic and aperiodic Al/Mo/SiC multilayers.

Multilayer coated diffraction gratings are crucial components for extreme ultraviolet (EUV) applications such as spectroscopy or spectro-imaging. However, for high groove density, the smoothening of the grating surface profile with multilayer deposition remains a limitation that requires further investigation. In this paper, we report on the design, characterization, and modeling of 4000 lines/mm diffraction gratings coated with periodic and aperiodic Al/Mo/SiC multilayers for EUV radiation. Two types of gratings with different groove depths are compared. Multilayer coatings were designed using a genetic algorithm to maximize the first-order diffraction efficiency in the 17-21 and 19-23 nm wavelength ranges at normal incidence. Periodic and aperiodic multilayers with different numbers of layers were deposited by magnetron sputtering on the two types of fused silica gratings, and the grating groove profile evolution was measured by atomic force microscopy and cross-section transmission electron microscopy. The first-order diffraction efficiency was measured in the EUV at 5° incidence using monochromatic synchrotron radiation and modeled using the rigorous coupled-wave analysis method. The simulation models refined by using the Debye-Waller factor to account for the multilayer interfacial roughness show good agreement with experimental data. The results reported in this study will allow for designing efficient EUV multilayer gratings for high-resolution spectro-imaging instruments.

Mass Spectrometry Applications to Study Human Microbiome.

Microbiotas are an adaptable component of ecosystems, including human ecology. Microorganisms influence the chemistry of their specialized niche, such as the human gut, as well as the chemistry of distant surroundings, such as other areas of the body. Metabolomics based on mass spectrometry (MS) is one of the primary methods for detecting and identifying small compounds generated by the human microbiota, as well as understanding the functional significance of these microbial metabolites. This book chapter gives basic knowledge on the kinds of untargeted mass spectrometry as well as the data types that may be generated in the context of microbiome study. While data analysis remains a barrier, the emphasis is on data analysis methodologies and integrative analysis, particularly the integration of microbiome sequencing data. Mass spectrometry (MS)-based techniques have resurrected culture methods for studying the human gut microbiota, filling in the gaps left by high-throughput sequencing methods in terms of culturing minor populations.

Applications of Proteomics in Probiotics Having Anticancer and Chemopreventive Properties.

Proteomics has grown in importance in molecular sciences because it gives vital information on protein identification, expression levels, and alteration. Cancer is one of the world's major causes of death and is the major focus of much research. Cancer risk is determined by hereditary variables as well as the body's immunological condition. Probiotics have increasing medical importance due to their therapeutic influence on the human body in the prevention and treatment of numerous chronic illnesses, including cancer, with no adverse effects. Several anticancer, anti-inflammatory, and chemopreventive probiotics are studied using different proteomic approaches like two-dimensional gel electrophoresis, liquid chromatography-mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry. To gain relevant information about probiotic characteristics, data from the proteomic analysis are evaluated and processed using bioinformatics pipelines. Proteomic studies showed the significance of different proteomic approaches in characterization, comparing strains, and determination of oxidative stress of different probiotics. Moreover, proteomic approaches identified different proteins that are involved in glucose metabolism and the formation of cell walls or cell membranes, and the differences in the expression of critical enzymes in the HIF-1 signaling pathway, starch, and sucrose metabolism, and other critical metabolic pathways.

Deep Learning Model for Efficient Protein-Ligand Docking with Implicit Side-Chain Flexibility.

Protein-ligand docking is an essential tool in structure-based drug design with applications ranging from virtual high-throughput screening to pose prediction for lead optimization. Most docking programs for pose prediction are optimized for redocking to an existing cocrystallized protein structure, ignoring protein flexibility. In real-world drug design applications, however, protein flexibility is an essential feature of the ligand-binding process. Flexible protein-ligand docking still remains a significant challenge to computational drug design. To target this challenge, we present a deep learning (DL) model for flexible protein-ligand docking based on the prediction of an intermolecular Euclidean distance matrix (EDM), making the typical use of iterative search algorithms obsolete. The model was trained on a large-scale data set of protein-ligand complexes and evaluated on independent test sets. Our model generates high quality poses for a diverse set of protein and ligand structures and outperforms comparable docking methods.

Point-of-care diagnostics for rapid determination of prostate cancer biomarker sarcosine: application of disposable potentiometric sensor based on oxide-conductive polymer nanocomposite.

One of the most important reasons for an increased mortality rate of cancer is late diagnosis. Point-of-care (POC) diagnostic sensors can provide rapid and cost-effective diagnosis and monitoring of cancer biomarkers. Portable, disposable, and sensitive sarcosine solid-contact ion-selective potentiometric sensors (SC-ISEs) were fabricated as POC analyzers for the rapid determination of the prostate cancer biomarker sarcosine. Tungsten trioxide nanoparticles (WO3 NPs), polyaniline nanoparticles (PANI NPs), and PANI-WO3 nanocomposite were used as ion-to-electron transducers on screen-printed sensors. WO3 NPs and PANI-WO3 nanocomposite have not been investigated before as ion-to-electron transducer layers in potentiometric SC sensors. The designated sensors were characterized using SEM, XRD, FTIR, UV-VIS spectroscopy, and EIS. The inclusion of WO3 and PANI in SC sensors enhanced the transduction at the interface between the screen-printed SC and the ion-selective membrane, offering lower potential drift, a longer lifetime, shorter response time, and better sensitivity. The proposed sarcosine sensors exhibited Nernstian slopes over linear response ranges 10-3-10-7 M, 10-3-10-8 M, 10-5-10-9 M, and 10-7-10-12 M for control, WO3 NPs, PANI NPs, and PANI-WO3 nanocomposite-based sensors, respectively. From a comparative point of view between the four sensors, PANI-WO3 nanocomposite inclusion offered the lowest potential drift (0.5 mV h-1), the longest lifetime (4 months), and the best LOD (9.95 × 10-13 M). The proposed sensors were successfully applied to determine sarcosine as a potential prostate cancer biomarker in urine without prior sample treatment steps. The WHO ASSURED criteria for point-of-care diagnostics are met by the proposed sensors.

Hematology profile, digestive enzymes, thyroid hormones, productivity, and nitrogen balance of growing male rabbits supplemented with exogenous dietary lysozyme.

In a simple randomized design trial, 420 growing male V-Line rabbits were randomly distributed into four groups to investigate the impact of exogenous dietary lysozyme on some physiological and nutritional parameters of male growing rabbits supplemented with exogenous dietary lysozyme. The witness group received a basal diet without exogenous dietary lysozyme (LYZ0), while the exogenous dietary lysozyme groups received 50, 100 and 150 mg/kg of basal diet (Groups; LYZ50, LYZ100 and LYZ150), respectively. The results showed significantly increased in blood cell count, hemoglobin concentration, total white blood cell, lipase, protease, amylase, total protein, triiodothyronine and thyroxine levels, while thyroid stimulating hormone levels significantly lessened in rabbits received LYZ. The LYZ- rabbit diets improved total digestible nutrient, digestible crude protein, and digestible energy values, with the LYZ100 group outperforming the others. LYZ-treated rabbits had significantly higher nitrogen intake, digestible nitrogen, and nitrogen balance than the witness group. The lysozyme in a rabbit's diet is taking on a new role as a digestive enzyme, enhancement thyroid hormones, as well as improvement hematology, daily protein efficiency ratio, daily performance index, hot carcass, total edible parts, nutritional value, and nitrogen balance, with decreasing the daily caloric conversion ratio and total non-edible parts.

True aneurysm of the dorsalis pedis artery.

OBJECTIVES: Aneurysm of the pedal arteries is uncommon. I present a case of non-traumatic fusiform true aneurysm of the dorsalis pedis artery in an otherwise well 45-year-old man. Color flow duplex imaging revealed aneurysmal dilation, involving all layers of the artery wall, measuring 16.5 * 10 mm with irregular intraluminal thrombus across a 6.33-mm segment. Due to concerns over embolization, our patient underwent successful ligation of the dorsalis pedis artery. He had an uneventful post-operative recovery. METHODS: Case report. RESULTS: No postoperative complication or signs of ischemia. CONCLUSIONS: Treatment of asymptomatic dorsalis pedis artery aneurysm may be of value to prevent risk of thrombo-embolic complications, foot ischemia, or rupture without warning signs. Patency of the pedal arch is important to avoid foot ischemia in case of dorsalis pedis artery ligation.

Dietary-Induced Bacterial Metabolites Reduce Inflammation and Inflammation-Associated Cancer via Vitamin D Pathway.

Environmental factors, including westernised diets and alterations to the gut microbiota, are considered risk factors for inflammatory bowel diseases (IBD). The mechanisms underpinning diet-microbiota-host interactions are poorly understood in IBD. We present evidence that feeding a lard-based high-fat (HF) diet can protect mice from developing DSS-induced acute and chronic colitis and colitis-associated cancer (CAC) by significantly reducing tumour burden/incidence, immune cell infiltration, cytokine profile, and cell proliferation. We show that HF protection was associated with increased gut microbial diversity and a significant reduction in Proteobacteria and an increase in Firmicutes and Clostridium cluster XIVa abundance. Microbial functionality was modulated in terms of signalling fatty acids and bile acids (BA). Faecal secondary BAs were significantly induced to include moieties that can activate the vitamin D receptor (VDR), a nuclear receptor richly represented in the intestine and colon. Indeed, colonic VDR downstream target genes were upregulated in HF-fed mice and in combinatorial lipid-BAs-treated intestinal HT29 epithelial cells. Collectively, our data indicate that HF diet protects against colitis and CAC risk through gut microbiota and BA metabolites modulating vitamin D targeting pathways. Our data highlights the complex relationship between dietary fat-induced alterations of microbiota-host interactions in IBD/CAC pathophysiology.

Combined anterior and posterior ring fixation versus posterior ring fixation alone in the management of unstable Tile B and C pelvic ring injuries: A randomized controlled trial.

PURPOSE: Combined anterior and posterior ring (APR) fixation is classically performed in Tile B2 and C1 injuries to achieve superior biomechanical stability. However, the posterior ring (PR) is the main weight bearing portion that is responsible for weight transmission from the upper parts of the body to the lower limbs through the sacrum and the linea terminalis. It is hypothesized that isolated PR fixation can achieve comparable radiological and clinical outcomes to APR fixation. Therefore, we conducted this study to compare the two fixation principles in managing Tile B2 and C1 injuries. METHODS: Our study included 20 patients with Tile B2 injuries and 20 patients with Tile C1 injuries. This study was a randomized control single-blinded study via computerized random numbers with a 1:1 allocation by using random block method. The study was performed at a level one trauma center. A total of 40 patients with Tile B2 and C1 injuries underwent combined APR or isolated PR fixation (Group A and B, respectively). Matta & Tornetta radiological principles and Majeed pelvic scoring system were used for the assessment of primary outcomes and postoperative complications. Secondary outcomes included operative time, amount of blood loss, intraoperative assessment of reduction, need of another operation, length of hospital stay, ability to weight bear postoperatively and pain control metrics. We used student t-test to compare the difference in means between two groups, and Chi-square test to compare proportions between two qualitative parameters. We set the confidence interval to 95% and the margin of error accepted to 5%. So, p ≤ 0.05 was considered statistically significant. RESULTS: The mean follow-up duration was 18 months. The operative time (mean difference 0.575 h) and the intraoperative blood loss (mean difference 97.5 mL) were lower in Group B. Also, despite the higher frequency of rami displacement before union in the same group, there were no significant differences in terms of radiological outcome (excellent outcome with OR = 2.357), clinical outcome (excellent outcome with OR = 2.852) and postoperative complications assessment (OR = 1.556) at last follow-up. CONCLUSION: The authors concluded that isolated PR fixation could favorably manage Tile B2 and C1 pelvic ring injuries with Nakatani zone II pubic rami fractures and intact inguinal ligament. Its final radiological and clinical outcomes and postoperative complications were comparable to combined APR fixation, but with less morbidity (shorter operation time, lower amount of blood, and no records of postoperative wound infection).

Relation Between Baseline CXCR1 Expression And Neoadjuvant Chemotherapy Response In Breast Cancer Patients.

Objectives: To examine the C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues prior to neo-adjuvant chemotherapy, and its relationship to neo-adjuvant chemotherapy effectiveness and other prognostic variables. Method: The prospective study was conducted at Kafrelsheikh University Hospital, Egypt, from November 2018 to March 2021, and comprised patients with recent histopathologically proven breast cancer cases eligible for chemotherapy. Paraffin blocks of tumourspecimens were stained by immunohistochemicalstain using concentrating rabbit anti-human C-X-C Motif Chemokine Receptor 1 polyclonal antibody kits. C-X-C Motif Chemokine Receptor 1 expression was classified into low and high categories. Patients were followed for 2 years for treatment response, disease recurrence and mortality. Data was analysed using SPSS 25. RESULTS: Of the 100 females with mean age 50.2±12.1 years, 52(52%) had their left side affected, while 48(48%) had their rightside affected. There were 52(52%) cases with mean age 49.2±12.9 years having high C-X-C Motif Chemokine Receptor 1 expresssion, while 48(48%) with mean age 51.4±11.2 years had low expression. There was a significant association between high expression and advanced tumour grade, advanced tumourstage, higher frequency of triple negative breast cancer and higher frequency of Ki-67-positive cancers (p<0.05). Patients with high C-X-C Motif Chemokine Receptor 1 expression had significantly lower frequency of complete pathological response when compared with patients with low expression (p<0.001). Patients with high expression had higher frequency of recurrence, shorter disease-free survival, higher mortality and shorter overall survival, but the difference was not significant (p>0.05). Multivariate logistic regression analysis identified triple negative hormonal status (p=0.031) and high baseline C-X-C Motif Chemokine Receptor 1 expression (p<0.001) as significant predictors of complete pathological response. CONCLUSIONS: There was found to be a link between baseline C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues and pathological response to neoadjuvant therapy in breast cancer patients.

Clinical Significance Of Baseline And Post-Treatment CXCR1 Expression In Women With Breast Cancer Having Received Neoadjuvant Chemo Therapy.

Objectives: To examine the chemokine receptor type 1 expression in breast cancer tissues before and after neoadjuvant chemotherapy, and its relationship with pathological response to neoadjuvant chemotherapy and other clinical variables. Method: The prospective study was conducted at Kafrelsheikh University Hospital, Egypt, from November 2018 to March 2021, and comprised female patients with new histopathologically proven breast cancer eligible for chemotherapy. Paraffin blocks of tumourspecimens were stained immunohistochemically using concentrated rabbit anti-human chemokine receptor type 1 polyclonal antibody kits. The patients were followed up for treatment response, disease recurrence and mortality. Data was analysed using SPSS 25. RESULTS: Of the 100 patients with mean age 50.2±12.1 years, 40(40%) in group A with mean age 55.1±9.3 showed marked response and 60(60%) in group B with mean age 47.0±12.7 yearsshowed mild/moderate response (p<0.001). Group A patients had significantly lower baseline and post-treatment chemokine receptor type 1 expression compared to group B patients (p<0.05). The change in chemokine receptor type 1 expression was not significantly different (p>0.05). Patients with tumour grade 3 had significantly higher baseline chemokine receptor type 1 expression compared to patients with tumour grade 2. Tumourstage and post-treatment chemokine receptor type 1 expression were also significantly interlinked (p<0.05). Multivariate regression analysisidentified patients'age, baseline chemokine receptor type 1 and post-treatment chemokine receptor type 1 expressions as predictors of treatment response. CONCLUSIONS: There was found to be an association between baseline and post-treatment chemokine receptor type 1 expression in breast cancer tissues and pathological response to neoadjuvant chemo therapy in such patients.

Al/Mo/SiC multilayer diffraction gratings with broadband efficiency in the extreme ultraviolet.

Al/Mo/SiC periodic and aperiodic multilayers were optimized and deposited on high groove density gratings to achieve broadband efficiency in the extreme ultraviolet (EUV). Grating efficiencies were measured by monochromatic synchrotron radiation under 5° and 45° incident angles in the wavelength ranges 17-25 nm and 22-31 nm, respectively. We study the influence of the number of deposited periods on the initial trapezoidal profile and the EUV diffraction efficiency. We propose models of periodic and aperiodic coatings based on a combination of characterizations and compare rigorous coupled-wave analysis (RCWA) simulations with experimental data. We demonstrate the possibility to select the optimal balance between peak efficiency and bandwidth by adjusting the number of periods in the case of periodic multilayer grating. We also report unprecedented broadband diffraction efficiency with an Al/Mo/SiC aperiodic multilayer grating.

Accurate Sampling of Macromolecular Conformations Using Adaptive Deep Learning and Coarse-Grained Representation.

Conformational sampling of protein structures is essential for understanding biochemical functions and for predicting thermodynamic properties such as free energies. Where previous approaches rely on sequential sampling procedures, recent developments in generative deep neural networks rendered possible the parallel, statistically independent sampling of molecular configurations. To be able to accurately generate samples of large molecular systems from a high-dimensional multimodal equilibrium distribution function, we developed a hierarchical approach based on expressive normalizing flows with rational quadratic neural splines and coarse-grained representation. Furthermore, system specific priors and adaptive and property-based controlled learning was designed to diminish the likelihood for the generation of high-energy structures during sampling. Finally, backmapping from a coarse-grained to fully atomistic representation is performed through an equivariant transformer model. We demonstrate the applicability of the method on the one-shot configurational sampling of a protein system with more than a hundred amino acids. The results show enhanced expressivity that diminish the invertibility constraints inherent in the normalizing flow framework. Moreover, the capacity of the hierarchical normalizing flow model was tested on a challenging case study of the folding/unfolding dynamics of the peptide chignolin.

Acute and chronic metabolic effects of carvedilol in high-fructose, high-fat diet-fed mice: implication of ß-arrestin2 pathway.

We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD) - fed mice and the implication of the ß-arrestin2 pathway. The acute effect of carvedilol (10 mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in ß-arrestin2 and its downstream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (AKT) activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased ß-arrestin2, PIP2, and AKT activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of ß-arrestin2 pathway.

Comparison of Long Term Outcomes After Endovascular Treatment Versus Bypass Surgery in Chronic Limb Threatening Ischaemia Patients with Long Femoropopliteal Lesions.

OBJECTIVE: There are currently two treatments available for patients with chronic limb threatening ischaemia (CLTI): open surgical bypass (OSB) and percutaneous transluminal angioplasty with/without stenting (PTA/S). The aim of this study was to compare short and long term outcomes between PTA/S and OSB in CLTI patients with long (GLASS grade III and IV) femoropopliteal disease. METHODS: This was a two centre retrospective study including all consecutive patients with CLTI undergoing first time lower extremity intervention at two distinct vascular surgical centres. Between 1 January 2012 and 1 January 2018, 1 545 CLTI consecutive limbs were treated for femoropopliteal GLASS grade III and IV lesions at two vascular surgical centres. Using covariables from baseline and angiographic characteristics, a propensity score was calculated for each limb. Thus, comparable patient cohorts (235 in PTA/S and 235 in OSB group) were identified for further analysis. The primary outcomes were freedom from re-intervention in the treated extremity and major amputation. Secondary outcomes were all hospital complications among the two patient groups. RESULTS: Total overall complication rates were significantly higher in the OSB group (20.42% vs. 5.96%, p < .001), especially wound infection/seroma rate that required prolonged hospitalisation and further treatment (7.65% vs. 0%, p < .001). After the median follow up of 61 months, re-intervention rates were significantly higher in the PTA/S group (log rank test, 44.68% vs. 29.79%, p = .002), but there was no significant difference in terms of major amputation rates between the two group of patients (log rank test, PTA/S 27.23% vs. OSB 22.13%, p = .17). CONCLUSION: Bypass surgery seems to be superior to PTA/S for GLASS grade III and IV femoropopliteal lesions in patients with CLTI in terms of long term re-intervention rates, but with considerably higher rates of post-operative complications. A larger cohort of patients in currently ongoing randomised trials, as well as prospective cohort studies are necessary to confirm these findings.

Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer.

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC50 = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC50 = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition.

Pioglitazone Enhances ß-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues.

INTRODUCTION: Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on ß-arrestin2 signaling in classical insulin target tissues. METHODS: Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. RESULTS: The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the ß-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased ß-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. CONCLUSION: To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases ß-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

The concurrent exposure to aluminium and fructose induces liver injury in rats: Protection by monoammonium glycyrrhizinate.

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it unavoidable. It is implicated in the aetiology of different neurodegenerative diseases and can induce liver injury. In addition, insulin resistance (IR) plays an essential role in the pathogenesis and the progression of liver disorders. The increased consumption of fructose contained in soft drinks and western pattern diet results in IR that along with the wide distribution of aluminium make the concurrent exposure conceivable and increase the risk of liver injury. Therefore, the present study explores the hepatotoxic effects of aluminium and fructose administered concurrently and evaluates the possible protection by monoammonium glycyrrhizinate (MAG). Liver injury was induced by the administration of aluminium chloride (34 mg/kg/d) plus 10% (w/v) fructose in drinking water. Male rats were treated with either MAG (40 mg/kg/d) or silymarin (SIL, 100 mg/kg/d). The concurrent administration of aluminium and fructose (FRUAL) induced liver injury manifested as a significant elevation of serum liver enzymes activities, bilirubin level, and prothrombin time, as well as reduction of albumin level. On the other hand, the administration of MAG improved the FRUAL-induced aberrations of liver function tests and hepatic cytoarchitecture. We assume that the MAG-induced suppression of oxidative stress, toll-like receptor 4 pathway activation, inflammation, and apoptosis might play a crucial role in the hepatoprotective effect of MAG in this model. Intriguingly, the hepatoprotective effect MAG against FRUAL-induced liver injury surpasses that of the gold standard SIL, suggesting MAG as a better alternative to SIL.

Point-of-care diagnostics for drugs of abuse in biological fluids: application of a microfabricated disposable copper potentiometric sensor.

The major objective of this work was to develop a portable, disposable, cost-effective, and reliable POC solid-state electrochemical sensor based on potentiometric transduction to detect benzodiazepine abuse, mainly diazepam (DZP), in biological fluids. To achieve that, microfabricated Cu electrodes on a printed circuit board modified with the conducting polymer poly(3-octylthiophene) (POT) have been employed as a substrate. This polymer was introduced to enhance the stability of the potential drift (0.9 mV/h) and improve the limit of detection (0.126 nmol mL-1). Nernstian potentiometric response was achieved for DZP over the concentration range 1.0 × 10-2 to 5.0 × 10-7 mol L-1 with a slope of 55.0 ± 0.4 mV/decade and E0 ~ 478.9 ± 0.9. Intrinsic merits of the proposed sensor include rapid response time (11 ± 2 s) and long life time (3 months). In order to enhance the selectivity of the potentiometric sensor towards the target drug and minimize any false positive results, calix[4]arene (CX4) was impregnated as an ionophore within the PVC plastic ion-sensing membrane. The performance of the POC sensors was assessed using electrochemical methods of analysis and electrochemical impedance spectroscopy as a surface characterization tool. The studied sensors were applied to the potentiometric determination of DZP in different biological fluids (plasma, urine, saliva, and human milk) in the presence of its metabolite with an average recovery of 100.9 ± 1.3%, 99.4 ± 1.0%, 101.8 ± 1.2%, and 99.0 ± 2.0%, respectively. Graphical abstract.

Carvedilol protects against hepatic ischemia/reperfusion injury in high-fructose/high-fat diet-fed mice: Role of G protein-coupled receptor kinase 2 and 5.

Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16 weeks; then mice were subjected to 30 min of ischemia followed by 1 h of reperfusion at the end of feeding period. Carvedilol (20 mg/kg, i.p.) was administered 30 min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10 mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25 mg/kg, i.p.) were administered 30 min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.