Bookermckenzie6967
A new methodology for the pH-triggered degradation of polymers or for the release of drugs under visible light irradiation based on the cyclization of ortho-hydroxy-cinnamates (oHC) to coumarins is described. The key oHC structural motif can be readily incorporated into the rational design of novel photocleavable polymers via click chemistry. This main-chain moiety undergoes a fast photocleavage when irradiated with 455 nm light provided that a suitable base is added. A series of polyethylene glycol-alt-ortho-hydroxy cinnamate (polyethylene glycol (PEG)n -alt-oHC)-based polymers are synthesized and the time-dependent visible-light initiated cleavage of the photoactive monomer and polymer is investigated in solution by a variety of spectroscopic and chromatographic techniques. The photo-degradation behavior of the water-soluble poly(PEG2000 -alt-oHC) is investigated within a broad pH range (pH = 2.1-11.8), demonstrating fast degradation at pH 11.8, while the stability of the polymer is greatly enhanced at pH 2.1. Moreover, the neat polymer shows long-term stability under daylight conditions, thus allowing its storage without special precautions. In addition, two water-soluble PEG-based drug-carrier molecules (mPEG2000 -oHC-benzhydrol/phenol) are synthesized and used for drug delivery studies, monitoring the process by UV-vis spectroscopy in an ON/OFF intermittent manner.
Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Krüppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown.
KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor γ (PPARγ) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis.
KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPARγ promoter activity. Inhibition of PPARγ blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPARγ-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPARγ downregulation.
KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.
KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.
To perform dynamic T
mapping using a 2D variable flip angle (VFA) method, a correction for the slice profile effect is needed. In this work we investigated the impact of flip angle selection and excitation RF pulse profile on the performance of slice profile correction when applied to T
mapping over a range of T
values.
A correction of the slice profile effect is proposed, based on Bloch simulation of steady-state signals. With this correction, Monte Carlo simulations were performed to assess the accuracy and precision of 2D VFA T
mapping in the presence of noise, for RF pulses with time-bandwidth products of 2, 3 and 10 and with flip angle pairs in the range [1°-90°]. To evaluate its performance over a wide range of T
, maximum errors were calculated for six T
values between 50 ms and 1250 ms. The method was demonstrated using in vitro and in vivo experiments.
Without corrections, 2D VFA severely underestimates T
. Slice profile errors were effectively reduced with the correction based on simulations, both in vitro and in vivo. Linsitinib molecular weight The precision and accuracy of the method depend on the nominal T
values, the FA pair, and the RF pulse shape. FA pairs leading to <5% errors in T
can be identified for the common RF shapes, for T
values between 50 ms and 1250 ms.
2D VFA T
mapping with Bloch-simulation-based correction can deliver T
estimates that are accurate and precise to within 5% over a wide T
range.
2D VFA T1 mapping with Bloch-simulation-based correction can deliver T1 estimates that are accurate and precise to within 5% over a wide T1 range.
This scoping review was undertaken to synthetize and appraise the literature on the potential mechanisms of action of functional electrical stimulation therapy in combination with task-specific training (FEST + TST) in the rehabilitation following stroke, spinal cord injury, traumatic brain injury, or multiple sclerosis.
The literature search was performed using multiple databases (including APA, PsycInfo, Medline, PubMed, EMBASE, CCRCT, and Cochrane Database of Systematic Reviews) from 1946 to June 2020. The literature search used the following terms (spinal cord injury, paraplegia, tetraplegia, quadriplegia, stroke, multiple sclerosis, traumatic brain injury, or acquired brain injury) AND (functional electrical stimulation or FES). The search included clinical and preclinical studies without limits to language.
Of the 8209 titles retrieved from the primary search, 57 publications fulfilled the inclusion and exclusion criteria for this scoping review. While most publications were clinical studies (n=50CNS injury or disease, the results of this review underline an important knowledge gap with regards to the actual mechanism of action of FEST + TST.
