Abstract Radiation-induced toxicity limits the delivery of high-dose radiation to head and neck lesions. The aim of this study was to investigate the effectiveness of epicatechin (EC), a minor ...component of green tea extract, on radiation-induced ototoxicity in vitro and in vivo . The effect of EC on radiation-induced cytotoxicity was analyzed in the organ of Corti-derived cell lines, HEI-OC1 and UB-OC1. The cell viability, apoptosis, reactive oxygen species generation, and mitochondrial membrane potential as well as changes in the signal pathway related to apoptosis were investigated. Then, the therapeutic effects of hearing protection and drug toxicity of EC were explored in a zebrafish and rat model. Radiation-induced apoptosis and altered mitochondrial membrane potential in HEI-OC1 and UB-OC1 were observed. EC inhibited radiation-induced apoptosis and intracellular reactive oxygen species generation. EC markedly attenuated the radiation-induced embryotoxicity and protected against radiation-induced loss and changes of auditory neuromast in the zebrafish. In addition, intratympanic administration of EC was protective against radiation-induced hearing loss in the rat model, as determined by click-evoked auditory brainstem ( P <0.01). EC significantly reduced the expression of p-JNK, p-ERK cleaved caspase-3, and cleaved PARP compared to their significant increase after radiation treatment. The results of this study suggest that EC significantly inhibited radiation-induced apoptosis in auditory hair cells and may be a safe and effective candidate treatment for the prevention of radiation-induced ototoxicity.
Abstract Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain and exhibits potent neuroprotective properties. However, little information on its role in ...Alzheimer's disease (AD) is known. The neuroprotective effect and mechanisms of NRG1 in SH-SY5Y cells overexpressing the Swedish mutant form of amyloid precursor protein (Swe-APP) and primary cortical neuronal cells treated with amyloid beta peptide1–42 (Aβ1–42 ) were investigated in this study. NRG1 attenuated Swe-APP- or Aβ1–42 -induced lactate dehydrogenase (LDH) release in a concentration-dependent manner. The mitigating effects of NRG1 on neuronal cell death were blocked by ErbB4 inhibition, a key NRG1 receptor, which suggests a role of ErbB4 in the neuroprotective function of NRG1. Moreover, NRG1 reduced the number of Swe-APP- and Aβ1–42 -induced TUNEL-positive SH-SY5Y cells and primary cortical neurons, respectively. NRG1 reduced the accumulation of reactive oxygen species and attenuated Swe-APP-induced mitochondrial membrane potential loss. NRG1 also induced the upregulation of the expression of the anti-apoptotic protein, Bcl-2, and decreased caspase-3 activation. Collectively, our results demonstrate that NRG1 exerts neuroprotective effects via the ErbB4 receptor, which suggests the neuroprotective potential of NRG1 in AD.
We report here the first successful synthesis of cold antihydrogen atoms employing a cusp trap, which consists of a superconducting anti-Helmholtz coil and a stack of multiple ring electrodes. This ...success opens a new path to make a stringent test of the CPT symmetry via high precision microwave spectroscopy of ground-state hyperfine transitions of antihydrogen atoms.
Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, ...both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic’ ischemia. We discuss diagnostic and therapeutic consequences of these predictions.
Emerging evidence supports that osteogenic differentiation of skeletal progenitors is a key determinant of overall bone formation and bone mass. Despite extensive studies showing the function of ...mitogen-activated protein kinases (MAPKs) in osteoblast differentiation, none of these studies show in vivo evidence of a role for MAPKs in osteoblast maturation subsequent to lineage commitment. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks
(MEK1) and
(MEK2), in mature osteoblasts and osteocytes, markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partially reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.
Psoriasis is a chronic inflammatory immune‐mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4‐methylhistamine (4‐MH) plays an important role in immunomodulation of ...inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4‐MH on the development of imiquimod (IMQ)‐induced psoriasis‐like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg). Histological analysis of the skin revealed that 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis and lymphocytes infiltration. Treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF‐α, IFN‐α, and IL‐27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL‐17A and IL‐23) did not change in response to treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg). Furthermore, the number of CD4+CD25+FoxP3+ regulatory T (Treg) cells was significantly increased by treatment with 4‐MH (40 mg/kg). Taken together, these results imply that H4R agonist 4‐MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro‐inflammatory cytokines, and recruited CD4+CD25+FoxP3+ Treg cells.
. Objectives: To characterize mesenchymal stem cell‐like cells isolated from human amniotic fluid for a new source of therapeutic cells. Materials: Fibroblastoid‐type cells obtained from amniotic ...fluid at the time of birth. Methods: The ability of ex vivo expansion was investigated until senescence, and stem cell‐like characteristics were analyzed by examining differentiation potential, messenger RNA expression and immunophenotypes. Results and Conclusions: A morphologically homogenous population of fibroblastoid‐type (HAFFTs) cells, similar to mesenchymal stem cells from bone marrow (BM‐MSCs), was obtained at the third passage. The cells became senescent after 27 passages over a period of 8 months while undergoing 66 population doublings. Under appropriate culture conditions, by the 8th passage they differentiated into adipocytes, osteocytes, chondrocytes and neuronal cells, as revealed by oil red O, von Kossa, Alcian blue and anti‐NeuN antibody staining, respectively. Immunophenotype analyses at the 17th passage demonstrated the presence of TRA‐1–60; SSEA‐3 and‐4; collagen types I, II, III, IV and XII; fibronectin; α‐SMA; vimentin; desmin; CK18; CD44; CD54; CD106; FSP; vWF; CD31; and HLA ABC. Reverse transcriptase–polymerase chain reaction analysis of the HAFFTs from passages 6–20 showed consistent expression of Rex‐1, SCF, GATA‐4, vimentin, CK18, FGF‐5 and HLA ABC genes. Oct‐4 gene expression was observed up to the 19th passage but not at the 20th passage. HAFFTs showed telomerase activity at the 5th passage with a decreased level by the 21st passage. Interestingly, BMP‐4, AFP, nestin and HNF‐4α genes showed differential gene expression during ex vivo expansion. Taken together, these observations suggest that HAFFTs are pluripotent stem cells that are less differentiated than BM‐MSCs, and that their gene expression profiles vary with passage number during ex vivo expansion.
Carbapenemase-producing Enterobacteriaceae (CPE) can lead to life-threatening outcomes with rapid spread of the carbapenemase gene in solid organ transplantation (SOT) recipients because of ...limitations of available antibiotics. We examined the characteristics and importance of CPE acquisition in SOT recipients with large numbers of CPE isolates.
Between November 2015 and October 2016, 584 CPE isolates were found in 37 recipients and verified by carbapenemase gene multiplex polymerase chain reaction (PCR). One hundred recipients with at least 2 negative results in carbapenemase PCR for stool surveillance and no CPE isolates in clinical samples were retrospectively included.
Most CPE isolates were Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (546, 93.5%). The most frequent transplantation organ was lung (43.3%), and the most common sample with CPE isolates other than stool was respiratory tract (22.6%). The median time between SOT and first CPE acquisition was 7 days. All-cause mortality was significantly higher in recipients with CPE than in those without CPE (24.3% vs 10.0%; P = .03). In multivariate regression analysis, stool colonization of vancomycin-resistant Enterococci and/or Clostridium difficile during 30 days before SOT (odds ratio OR, 3.28; 95% CI, 1.24–8.68; P = .02), lung transplantation (OR, 4.50; 95% CI, 1.19–17.03; P = .03), and intensive care unit stay ≥2 weeks (OR, 6.21; 95% CI, 1.72–22.45; P = .005) were associated with acquisition of CPE.
Early posttransplantation CPE acquisition may affect the clinical outcome of SOT recipients. Careful screening for CPE during the early posttransplantation period would be meaningful in recipients with risk factors.
•Infection or colonization by KPC-producing K. pneumoniae was associated with high mortality in solid organ transplantation recipients. The median time between solid organ transplantation and first carbapenemase-producing Enterobacteriaceae (CPE) acquisition was 7 days.•Stool colonization of vancomycin-resistant Enterococci and/or Clostridium difficile during 30 days before solid organ transplantation, lung transplantation, and intensive care unit stay ≥2 weeks were associated with acquisition of CPE.•Careful screening for CPE during the early posttransplantation period is important in recipients with risk factors.
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