Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings.
View Article and Find Full Text PDFOsteoporosis (OP) is typically brought on by disruption of bone homeostasis. Excessive oxidative stress and mitochondrial dysfunction are believed to be the primary mechanisms underlying this disorder. Therefore, in order to restore bone homeostasis effectively, targeted treatment of oxidative stress and mitochondrial dysfunction is necessary.
View Article and Find Full Text PDFThis white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working Group for the characterization of absorption, distribution, metabolism, and excretion of oligonucleotide (ON) therapeutics in nonclinical studies. In general, the recommended approach is similar to that for small molecule drugs. However, some differences in timing and/or scope may be warranted due to the greater consistency of results across ON classes as compared with the diversity among small molecule classes.
View Article and Find Full Text PDFMeasurement of plasma oxalate (POx) is challenging, but critical, for management of patients with primary hyperoxaluria type 1. A novel LC-MS/MS assay was developed, validated and used to quantify POx in patients with primary hyperoxaluria type 1. Samples (100 μl of plasma in KEDTA) were spiked with internal standard (C-labeled oxalic acid), acidified and cleaned by protein precipitation before analysis using anion HPLC-ESI-MS/MS.
View Article and Find Full Text PDFTherapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months.
View Article and Find Full Text PDFCerium (IV)-based metal-organic frameworks (MOFs) are highly desirable due to their unique potential in fields such as redox catalysis and photocatalysis. However, due to the high reduction potential of Ce species in solution, it is still a great challenge to synthesize Ce -MOFs with novel structures, which are extremely dominated by the hexanuclear Ce-O cluster inorganic building units (IBUs). Herein, a Ce-O IBU chain containing Ce -MOF, CSUST-3 (CSUST: Changsha University of Science and Technology), was successfully prepared using the kinetic stabilization study of UiO-66(Ce)-NDC (H NDC=2,6-naphthalenedicarboxylic acid).
View Article and Find Full Text PDFThe aim of this study was to investigate the abnormities in functional connectivity (FC) within each modular network and between modular networks in patients with systemic lupus erythematosus (SLE). Twelve meaningful modular networks were identified via independent component analysis from 41 patients and 40 volunteers. Parametric tests were used to compare the intra- and intermodular FC between the groups.
View Article and Find Full Text PDFGivosiran is an -acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t; less than 4 hours).
View Article and Find Full Text PDFIntroduction: Recent animal studies showed that isoflurane exposure may lead to the disturbance of hippocampal neurogenesis and later cognitive impairment. However, much less is known about the effect of isoflurane exposure on the neurons generated form tertiary dentate matrix, even though a great increase of granule cell population during the infantile period is principally derived from this area.
Methods: To label the new cells originated from the tertiary dentate matrix, the mice were injected with BrdU on postnatal day 6 (P6).
Developing reliable and user-friendly electroencephalography (EEG) electrodes remains a challenge for emerging real-world EEG applications. Classic wet electrodes are the gold standard for recording EEG; however, they are difficult to implement and make users uncomfortable, thus severely restricting their widespread application in real-life scenarios. An alternative is dry electrodes, which do not require conductive gels or skin preparation.
View Article and Find Full Text PDFUsing resting-state functional magnetic resonance imaging and graph theory approaches to investigate the topological characteristics of functional networks and their potential correlations with clinical information in patients with systemic lupus erythematosus (SLE). A total of 41 patients and 35 volunteers were consecutively recruited. Detailed clinical data of all participants were recorded.
View Article and Find Full Text PDFAdvancements in RNA interference therapeutics have triggered development of improved bioanalytical methods for oligonucleotide metabolite profiling and high-throughput quantification in biological matrices. HPLC coupled with high-resolution mass spectrometry (LC-HRMS) methods were developed to investigate the metabolism of a REVERSIR™ molecule Plasma and tissue samples were extracted using solid-phase extraction followed by LC-HRMS analysis for metabolite profiling and quantification. The method was qualified from 10 to 5000 ng/ml (plasma) and 100 to 50000 ng/g (liver and kidney).
View Article and Find Full Text PDFNF-κB activating protein (NKAP) is a highly conserved protein involved in transcriptional repression, immune cell development, maturation, acquisition of functional competency and maintenance of hematopoiesis. In the present study, the function of NKAP in the progress of Ewing sarcoma (ES) was investigated. It was identified that NKAP is highly expressed in ES cells when compared with human mesenchymal stem cells (MSCs).
View Article and Find Full Text PDFSmall interfering RNAs (siRNAs) represent a new class of medicines that are smaller (∼16,000 Da) than biologic therapeutics (>150,000 Da) but much larger than small molecules (<900 Da). Current regulatory guidance on drug-drug interactions (DDIs) from the European Medicines Agency, Food and Drug Administration, and Pharmaceutical and Medical Devices Agency provides no recommendations for oligonucleotide therapeutics including siRNAs; therefore, small molecule guidance documents have historically been applied. Over ∼10 years, in vitro DDI investigations with siRNAs conjugated to a triantennary -acetylgalactosamine [(GalNAc)-siRNA] ligand have been conducted during nonclinical drug development to elucidate the potential clinical DDI liability.
View Article and Find Full Text PDFFor oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2'-F-monomer metabolites was low and transient in rats and humans.
View Article and Find Full Text PDFPurpose: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [C]-ixazomib.
Methods: After administration of a single 4.1-mg oral dose of [C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35.
Background: Brain consists of plenty of complicated cytoarchitecture. Gaussian-model based diffusion tensor imaging (DTI) is far from satisfactory interpretation of the structural complexity. Diffusion kurtosis imaging (DKI) is a tool to determine brain non-Gaussian diffusion properties.
View Article and Find Full Text PDFThe ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade.
View Article and Find Full Text PDFAfr J Tradit Complement Altern Med
September 2017
Background: The current study was designed to evaluate the effect of Platycodin D (PD), triterpenoid saponins extracted from the roots of (PG) on alcohol-induced fatty liver (AFL) and investigate the possible mechanism.
Methods And Materials: A rat model was set up by feeding ethanol and fish oil to experimental rats, which then were treated with PD of 10, 20, 30 mg/kg body weight/day for 4 weeks, respectively, whereafter, liver function enzymes, endotoxin of serum and liver lipid were assayed by biochemical methods, cytokines, histochemistry of hepatic tissue, the protein expression of CD14 and TLR4, the mRNA expression of MD-2, MyD 88 and TRAF-6 were assayed.
Results: Treatment with PD on AFL rats significantly decreased the levels of serum ALT, AST and TBIL, coefficient of liver index and the hepatic tissue contents of TG, additionally and dramatically decreased serum endotoxin levels, down-regulated MD-2 and CD14 levels, as well as the mRNA expression of TLR4, MyD88 and TRAF-6, accordingly suppressed NF-κB: p65 as well as endotoxin-mediated inflammatory factors such as TNF-α and IL-6.
Background: Metabolite identification without radiolabeled compound is often challenging because of interference of matrix-related components.
Results: A novel and an effective background subtraction algorithm (A-BgS) has been developed to process high-resolution mass spectral data that can selectively remove matrix-related components. The use of a graphics processing unit with a multicore central processing unit enhanced processing speed several 1000-fold compared with a single central processing unit.
Antibody-drug conjugates (ADCs) play an increasingly important role for targeted cancer treatment. One class of ADCs has attracted particular interest in drug development. These ADCs employ a cleavable chemistry linkage for drugs and utilize the reduced interchain disulfide cysteine residues for conjugation.
View Article and Find Full Text PDFBackground: The purpose of this meta-analysis was to evaluate the clinical significance of diffusion-weighted imaging in assessing the status of axillary lymph nodes in patients with breast cancer.
Methods: We searched the PubMed, Cochrane, and EMBASE databases, selected studies by inclusion and exclusion criteria, and assessed the quality of selected studies. We explored the source of heterogeneity; calculated sensitivity, specificity, positive and negative likelihood ratios, and pretest probability.