Chemical synthesis, in vitro testing and in silico Nampt-based molecular docking of novel aniline aromatic ring-substituted 2-Aminothiazole analogues.

The heterocyclic 2-Aminothiazoles scaffolds are used in a wide range of therapeutic applications against various diseases for its antioxidant, anti-inflammatory, antimicrobial and anticancer actions. In the present study, we synthesized novel aniline aromatic ring-substituted 2-Aminothiazole derivatives. Molecular docking was performed using Glide module of the Schrödinger Suite to fit compounds JG-49, JG-62, and KBA-18 against the Nicotinamide phosphoribosyl transferase (Nampt) enzyme, an intracellular regulator of Nicotinamide adenine dinucleotide (NAD) redox cofactor involved in energy metabolism and epigenetics and are implicated in aging and metabolic diseases.

P7C3 ameliorates barium chloride-induced skeletal muscle injury activating transcriptomic and epigenetic modulation of myogenic regulatory factors.

Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury.

Effect of Detector Orientation and Influence of Jaw Position in the Determination of Small-field Output Factor with Various Detectors for High-energy Photon Beams.

Background: Accurate dose measurements are difficult in small fields due to charge particle disequilibrium, partial source occlusion, steep dose gradient, and the finite size of the detector.

Aim: The study aims to determine the output factor using various detectors oriented in parallel and perpendicular orientations for three different tertiary collimating systems using 15 MV photon beams. In addition, this study analyzes how the output factor could be affected by different configurations of X and Y jaws above the tertiary collimators.

Evaluation of improvements in plan quality with Photon Optimizer v16.1 for single brain lesion SRS treatment.

Background: The purpose of this study is to compare the performance of the Photon Optimizer (PO) version 16.1 algorithm with its earlier version PO v13.6 and with Progressive Resolution Optimizer (PRO) version 13.

Development and testing of nanoparticles delivery for P7C3 small molecule using injury models.

The use of nanoparticles (NPs) has emerged as a potential tool for safe and effective drug delivery. In the present study, we developed small molecule P7C3-based NPs and tested its efficacy and toxicity along with the tissue specific aptamer-modified P7C3 NPs. The P7C3 NPs were prepared using poly (D, L-lactic-co-glycolic acid) carboxylic acid (PLGA-COOH) polymer, were conjugated with skeletal muscle-specific RNA aptamer (A01B P7C3 NPs) and characterized for its cytotoxicity, cellular uptake, and wound healing in vitro.

Genetic deletion of Kvβ2 (AKR6) causes loss of muscle function and increased inflammation in mice.

The voltage-gated potassium channels (Kv) are complex ion channels with distinct roles in neurotransmission, electrical conductivity of the heart, and smooth and striated muscle functions. Previously, we demonstrated that deletion of Kvβ2 in mice results in decreased Pax7 protein levels, hindlimb muscles and body weights, and fiber type switching. In the present study, we tested the hypothesis that Kvβ2 regulates skeletal muscle function in mice.

Cardioprotective Effects of 1-(3,6-Dibromo-carbazol-9-yl)-3-Phenylamino-Propan-2-Ol in Diabetic Hearts via Nicotinamide Phosphoribosyltransferase Activation.

Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD salvage pathway and is dysregulated in diabetes. Nampt activation results in rescued NADH/NAD ratios and provides pharmacological changes necessary for diabetic cardioprotection.

NAD centric mechanisms and molecular determinants of skeletal muscle disease and aging.

The nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD is considered as an anti-oxidant and anti-aging molecule.

Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators.

Background: Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6-dibromo-α-[(phenylamino)methyl]-9H-carbazol-9-ethanol) ameliorates diabetes and muscle function.

Methods: We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice.

Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes.

Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the cardiac function, biochemical changes, and molecular responses.

PPARs and Microbiota in Skeletal Muscle Health and Wasting.

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often accompanied by chronic low-grade inflammation associated to inter- and intra-muscular fat deposition.

Measurements and Monte Carlo calculation of radial dose and anisotropy functions of BEBIG Co high-dose-rate brachytherapy source in a bounded water phantom.

Purpose: The study compared the experimentally measured radial dose function, g(), and anisotropy function, (,θ), of a BEBIG Co (Co0.A86) high-dose-rate (HDR) source in an in-house designed water phantom with egs_brachy Monte Carlo (MC) calculated values. MC results available in the literature were only for unbounded phantoms, and there are no currently published data in the literature for experimental data compared to MC calculations for a bounded phantom.

Experimental Determination of Radial Dose Function and Anisotropy Function of GammaMed Plus Ir High-Dose-Rate Brachytherapy Source in a Bounded Water Phantom and its Comparison with egs_brachy Monte Carlo Simulation.

Objective: The aim of the present study is to experimentally measure the radial dose function g(r) and anisotropy function F(r,θ) of GammaMed Plus Ir high-dose-rate source in a bounded water phantom using thermoluminescent dosimeter (TLD) and film dosimetry and compare the obtained results with egs_brachy Monte Carlo (MC)-calculated values for the same geometry.

Materials And Methods: The recently developed egs_brachy is a fast Electron Gamma Shower National Research Council of Canada MC application which is intended for brachytherapy applications. The dosimetric dataset recommended by Task Group 43 update (TG43U1) is calculated using egs_brachy for an unbounded phantom.

Implementation and Evaluation of Phantomless Intensity Modulated Radiotherapy Delivery Verification Using FractionCHECK.

Introduction: The objective was to implement the DynaLog file-based automated FractionCHECKTM software which verifies the delivery accuracy of all patient treatments without any measuring devices and evaluate this tool for dynamic IMRT delivery verification of 40 cases. The present work was aimed to find the generalized results with user-defined tolerances of all treatment deliveries and asses the delivery results in terms of Pass/Warn/fail analysis. In addition to this, an in-depth analysis of mean RMS error of each BANK of the MLC's and mean 95th Percentile error of all the leaves and percentage of pixels passing Gamma between the planned and delivered fluences for all 40 dynamic IMRT cases.

Physical and Radiobiological Evaluation of Accelerated Intensity Modulated Radiotherapy for Locally Advanced Head and Neck Cancer and Comparison with Short-Term Clinical Outcomes.

Objective: The present study aims to evaluate the accelerated intensity modulated radiotherapy (IMRT) of head and neck (HandN) treatments using physical indices and radiobiological models with its clinical correlation using histogram analysis in radiation therapy (HART). The radiobiological evaluation in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP) indices were compared with acute toxicity. Materials and Methods: A total of twenty patients with stage III and IV of HandN cases treated with accelerated IMRT using 6MV photons were chosen for the study.

Depletion of Gram-Positive Bacteria Impacts Hepatic Biological Functions During the Light Phase.

Living organisms display internal biological rhythms, which are an evolutionarily conserved adaptation to the environment that drives their rhythmic behavioral and physiological activities. The gut microbiota has been proposed, in association with diet, to regulate the intestinal peripheral clock. However, the effect of gut dysbiosis on liver remains elusive, despite that germfree mice show alterations in liver metabolic functions and the hepatic daily rhythm.

Evaluation of optically stimulated luminescence dosimeter for exit dose dosimetry in radiation therapy.

Aim: The aim of this study was to assess and analyze the exit dose in radiotherapy using optically stimulated luminescence dosimeter (OSLD) with therapeutic photon beams.

Materials And Methods: Measurements were carried out with OSLD to estimate the exit dose in phantom for different field sizes, various phantom thicknesses, and with added backscatter material. The data obtained were validated with ionization chamber data where applicable.

Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism.

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle.

Dosimetric characterization of optically stimulated luminescence dosimeter with therapeutic photon beams for use in clinical radiotherapy measurements.

Aim: The modern radiotherapy techniques impose new challenges for dosimetry systems with high precision and accuracy in in vivo and in phantom dosimetric measurements. The knowledge of the basic characterization of a dosimetric system before patient dose verification is crucial. This incites the investigation of the potential use of nanoDot optically stimulated luminescence dosimeter (OSLD) for application in radiotherapy with therapeutic photon beams.

Response of Nanodot Optically Stimulated Luminescence Dosimeters to Therapeutic Electron Beams.

Response of AlO:C-based nanoDot optically stimulated luminescence (OSL) dosimeter was studied for the dosimetry of 6, 9, 12, 16, and 20 MeV therapeutic electron beams. With reference to ionization chamber, no change in the response was observed with the change in the energy of electron beams for the field size from 6 cm × 6 cm to 25 cm × 25 cm, dose rates from 100 MU/min to 600 MU/min, and the linearity in the response up to 300 cGy. The fading of the transient signal was higher for 20 MeV electron beam than that of 6 MeV electron beam by about 5% as compared to value at 20 min after irradiation.

Dosimetric evaluation of newly developed well-type ionization chamber for use in the calibration of brachytherapy sources.

The well-type ionization chamber has been designed for convenient use in brachytherapy source strength calibration. The chamber has a volume of 240 cm, weight of 2.5 kg, and is open to atmospheric conditions.

Roles of Peroxisome Proliferator-Activated Receptor β/δ in skeletal muscle physiology.

More than two decades of studying Peroxisome Proliferator-Activated Receptors (PPARs) has led to an understanding of their implications in various physiological processes that are key for health and disease. All three PPAR isotypes, PPARα, PPARβ/δ, and PPARγ, are activated by a variety of molecules, including fatty acids, eicosanoids and phospholipids, and regulate a spectrum of genes involved in development, lipid and carbohydrate metabolism, inflammation, and proliferation and differentiation of many cell types in different tissues. The hypolipidemic and antidiabetic functions of PPARα and PPARγ in response to fibrate and thiazolidinedione treatment, respectively, are well documented.

The effect of influence quantities and detector orientation on small-field patient-specific IMRT QA: comparison of measurements with various ionization chambers.

Intensity-modulated radiation therapy (IMRT) requires a patient-specific quality assurance (QA) program to validate the treatment plan and a high level of dosimetric accuracy in the treatment delivery. Dosimetric verification generally consists of both absolute- and relative-dose measurements in a phantom using ionization chambers. Measurements were carried out with three different ionization chambers (Scanditronix FC 65G, Exradin A18, and PTW PinPoint 31014) to assess the effects of influence quantities such as the stability, pre- and post-irradiation leakage, stem effect, polarity, and ion recombination on the IMRT point-dose verification with two different orientations.

Dosimetric Performance of Newly Developed Farmer-Type Ionization Chamber in Radiotherapy Practice.

Dose measurement with ionization chamber is essential to deliver accurate dose to the tumor in radiotherapy. The cylindrical Farmer-type ionization chamber is recommended by various dosimetry protocols for dose measurement of radiotherapy beams. The air-equivalent graphite wall Farmer-type ionization chamber (FAR 65 GB) of active volume 0.

Inactivation of PPARβ/δ adversely affects satellite cells and reduces postnatal myogenesis.

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a ubiquitously expressed gene with higher levels observed in skeletal muscle. Recently, our laboratory showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935-12951, 2012) that PPARβ/δ modulates myostatin activity to induce myogenesis in skeletal muscle.