Luteolin Is a Novel P90 Ribosomal S6 Kinase (RSK) Inhibitor That Suppresses Notch4 Signaling by Blocking the Activation of Y-Box Binding Protein-1 (YB-1).

Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1).

Oncotarget. 2013 Feb; 4(2): 329-45
Reipas KM, Law JH, Couto N, Islam S, Li Y, Li H, Cherkasov A, Jung K, Cheema AS, Jones SJ, Hassell JA, Dunn SE

Triple-negative breast cancers (TNBC) are notoriously difficult to treat because they lack hormone receptors and have limited targeted therapies. Recently, we demonstrated that p90 ribosomal S6 kinase (RSK) is essential for TNBC growth and survival indicating it as a target for therapeutic development. RSK phosphorylates Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, highly expressed in TNBC (~70% of cases) and associated with poor prognosis, drug resistance and tumor initiation. YB-1 regulates the tumor-initiating cell markers, CD44 and CD49f however its role in Notch signaling has not been explored. We sought to identify novel chemical entities with RSK inhibitory activity. The Prestwick Chemical Library of 1120 off-patent drugs was screened for RSK inhibitors using both in vitro kinase assays and molecular docking. The lead candidate, luteolin, inhibited RSK1 and RSK2 kinase activity and suppressed growth in TNBC, including TIC-enriched populations. Combining luteolin with paclitaxel increased cell death and unlike chemotherapy alone, did not enrich for CD44(+) cells. Luteolin’s efficacy against drug-resistant cells was further indicated in the primary x43 cell line, where it suppressed monolayer growth and mammosphere formation. We next endeavored to understand how the inhibition of RSK/YB-1 signaling by luteolin elicited an effect on TIC-enriched populations. ChIP-on-ChIP experiments in SUM149 cells revealed a 12-fold enrichment of YB-1 binding to the Notch4 promoter. We chose to pursue this because there are several reports indicating that Notch4 maintains cells in an undifferentiated, TIC state. Herein we report that silencing YB-1 with siRNA decreased Notch4 mRNA. Conversely, transient expression of Flag:YB-1(WT) or the constitutively active mutant Flag:YB-1(D102) increased Notch4 mRNA. The levels of Notch4 transcript and the abundance of the Notch4 intracellular domain (N4ICD) correlated with activation of P-RSK(S221/7) and P-YB-1(S102) in a panel of TNBC cell lines. Silencing YB-1 or RSK reduced Notch4 mRNA and this corresponded with loss of N4ICD. Likewise, the RSK inhibitors, luteolin and BI-D1870, suppressed P-YB-1(S102) and thereby reduced Notch4. In conclusion, inhibiting the RSK/YB-1 pathway with luteolin is a novel approach to blocking Notch4 signaling and as such provides a means of inhibiting TICs. HubMed – drug

New insights into the mechanism of drug-induced dyskinesia.

CNS Spectr. 2013 Feb; 18(1): 15-20
Loonen AJ, Ivanova SA

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/ or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson’s disease,and it occurs spontaneously as a symptom of Huntington’s disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the corticostriato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway,which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here,we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia. HubMed – drug

Clinical and epidemiological characteristics of Korean patients with hepatitis C virus genotype 6.

Clin Mol Hepatol. 2013 Mar; 19(1): 45-50
Seong MH, Kil H, Kim JY, Lee SS, Jang ES, Kim JW, Jeong SH, Kim YS, Bae SH, Lee YJ, Lee HC, Yun H, Kang BH, Kim K

The distribution of hepatitis C virus (HCV) genotypes varies geographically. In Korea, genotypes 1 and 2 comprise more than 90% of HCV infections, while genotype 6 is very rare. This study compared the clinical and epidemiological characteristics of patients with genotype 6 HCV infection with those infected with HCV genotypes 1 and 2.This was a prospective, multicenter HCV cohort study that enrolled 1,173 adult patients, of which 930 underwent HCV genotype analysis, and only 9 (1.0%) were found to be infected with genotype 6 HCV. The clinical and epidemiological parameters of the genotypes were compared.The patients with genotype 6 HCV had a mean age of 41.5 years, 77.8% were male, and they had no distinct laboratory features. A sustained virologic response (SVR) was observed in four (67%) of six patients who received antiviral therapy. Risk factors such as the presence of a tattoo (n=6, 66.7%), more than three sexual partners (n=3, 33.3%), and injection drug use (n=3, 33.3%) were more common among genotype 6 patients than among genotypes 1 or 2.The epidemiology and treatment response of patients infected with genotype 6 HCV differed significantly from those with genotypes 1 or 2, warranting continuous monitoring. HubMed – drug

Prevalence and antibiogram study of Salmonella and Staphylococcus aureus in poultry meat.

Asian Pac J Trop Biomed. 2013 Feb; 3(2): 163-168
Akbar A, Anal AK, Ansari FA

To evaluate the presence and antibiogram pattern of Salmonella and Staphylococcus aureus (S. aureus) in retail poultry meat products.Foodborne pathogens (Salmonella and S. aureus) were isolated from poultry meat and confirmed with the help of biochemical and immunological test. Antibiogram of the isolates were examined by following CLSI methods.A total number of 209 poultry meat samples were collected and studied in this study. Out of which, 5.26% were found contaminated with Salmonella while 18.18% were found contaminated with S. aureus. All the Salmonella and S. aureus isolates were found resistant to at least one antibiotic. About 72.72% of the Salmonella isolates showed resistance to tetracycline, while S. aureus isolates were also found highly resistant to tetracycline equal to 44.73%. One of the Salmonella isolates showed multi-drug resistance to almost six antibiotics out of nine antibiotics used in the study. Multidrug resistant S. aureus isolates were also found in the study.The study confirmed the presence of Salmonella and S. aureus in retail poultry meat. It is a potential threat to consumer health. To reduce the risk of contamination, good hygiene practices are necessary from processing to storage. HubMed – drug