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Armstrong Jansen posted an update 6 months, 2 weeks ago
100 differentially expressed proteins were identified between the sham operation and model groups, salvianolate reversed the expression of 25 of those proteins, that were mainly involved in the metabolism of extracellular collagen matrix and the response to growth factor stimulation. Type I collagen, type V collagen, chymase, β-myosin heavy chain, and A-Raf differential expression were consistent in western blotting. In conclusion, salvianolate had a protective effect on myocardial tissues of rats with myocardial infarction. Several proteins including type I collagen, type V collagen, chymase, β-myosin, and A-Raf may be salvianolate targets for treatment of myocardial infarction.The unfolded protein response (UPR) is an emerging target pathway for cancer treatment owing to its ability to induce cell death. In our previous analysis of UPR-modulating small molecules, we had reported that piperazine oxalate derivative compounds (AMC-01-04) are able to promote increased phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2α). In this study, we found that AMC-04 induces apoptotic cell death via the activation of UPR in human breast and liver cancer cells. AMC-04 upregulated the expression of activating transcription factor-4 (ATF4)-C/EBP homologous protein (CHOP) and death receptor 5 (DR5) in cancer cells, as revealed by microarray analysis, small-interference RNA assay, and western blotting. From a mechanistic perspective, cytotoxic UPR pathway activation by AMC-04 is mediated by reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (p38 MAPK) signaling. A chemical informatics approach predicted that AMC-04 modulates histone methyltransferase activity. Based on biochemical analysis, the activity of histone methyltransferases, including SUV39H1, SUV39H2, SETDB1, and EHMT1, was inhibited by AMC-04. Furthermore, chemical inhibition of the identified target proteins induced UPR activation and apoptotic cell death, suggesting that inhibition of histone methyltransferases is a promising strategy for cancer therapy. Taken together, we showed that the small molecule AMC-04 modulates epigenetic enzyme activity and mediates the link between cytotoxic UPR and histone modifications.
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. selleck inhibitor Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Recently, we demonstrated that aldehyde dehydrogenase 1B1 (ALDH1B1) knockdown dramatically reduced colon tumor growth in a mouse xenograft model. The purpose of the present preliminary study is to examine the effect of loss of ALDH1B1 in CRC development in an inducible colon-specific Apc mouse model.
Apc
Cdx2
mice develop uni-allelic inactivation of Apc specifically in colon epithelial cells following tamoxifen treatment. Aldh1b1
KO mice were crossed with Apc
Cdx2
mice. Six-month-old male Apc
Cdx2
/Aldh1b1
, and Apc
Cdx2
/Aldh1b1
mice were treated with tamoxifen (50mg/kg, i.p.) for three consecutive days. Apc
/Aldh1b1
and Apc
/Aldh1b1
mice were treated with corn oil (i.e., tamoxifen vehicle control) for three consecutive days. Eighteen days later, mice were sacrificed and their colons examined microscopically, macroscopically and histologically for the presence of adenoma.
All Apc
Cdx2
/Aldh1b1
and Apc
Cdx2
/Aldh1b1
mice treated with tamoxifen developed colorectal adenoma. The Apc
Cdx2
/Aldh1b1
mice showed a significant decrease in the total volume of all ileal and colonic adenomas, and decreased incidence of large colonic adenoma compared to Apc
Cdx2
/Aldh1b1
mice. Immunohistochemical analysis of p53 and β-catenin showed a trend toward decreased expression score in colonic adenomas of Apc
Cdx2
/Aldh1b1
mice.
The present preliminary study suggests that deletion of ALDH1B1 may protect against the full development of colorectal cancer. Further mechanistic studies are required to elucidate how ALDH1B1 contributes for colorectal cancer.
The present preliminary study suggests that deletion of ALDH1B1 may protect against the full development of colorectal cancer. Further mechanistic studies are required to elucidate how ALDH1B1 contributes for colorectal cancer.To promote the recovery of cells that undergo intracellular ice formation (IIF), it is imperative that the recrystallization of intracellular ice is minimized. Hepatocytes are more prone to IIF than most mammalian cells, and thus we assessed the ability of novel small molecule carbohydrate-based ice recrystallization inhibitors (IRIs) to permeate and function within hepatocytes. HepG2 monolayers were treated with N-(4-chlorophenyl)-d-gluconamide (IRI 1), N-(2-fluorophenyl)-d-gluconamide (IRI 2), or para-methoxyphenyl-β-D-glycoside (IRI 3) and fluorescent cryomicroscopy was used for real time visualization of intracellular ice recrystallization. Both IRI 2 and IRI 3 reduced rates of intracellular recrystallization, whereas IRI 1 did not. IRI 2 and IRI 3, however, demonstrated a marked reduction in efficiency in the presence of the most frequently used permeating cryoprotectants (CPAs) glycerol, propylene glycol (PG), dimethyl sulfoxide (DMSO), and ethylene glycol (EG). Nevertheless, IRI 3 reduced rates of intracellular recrystallization relative to CPA-only controls in the presence of glycerol, PG, and DMSO. Interestingly, IRI preparation in trehalose, a commonly used non-permeating CPA, did not impact the activity of IRI 3. However, trehalose did increase the activity of IRI 1 while decreasing that of IRI 2. While this study suggests that each of these compounds could prove relevant in hepatocyte cryopreservation protocols where IIF would be prominent, CPA-mediated modulation of intracellular IRI activity is apparent and warrants further investigation.
Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa.
We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin.