The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.     

Coumarins from Malaysian Micromelum minutum

In a continuation of our study of the Rutaceae, detailed chemical investigation on Micromelum minutum (Rutaceae) collected from Sepilok, Sabah, Malaysia gave four new coumarins. The structures of the coumarins have been fully characterised by spectroscopic methods as 3",4"-dihydrocapnolactone 1, 2',3'-epoxyisocapnolactone 2, 8-hydroxyisocapnolactone-2',3'-diol 3 and 8-hydroxy-3",4"-dihydrocapnolactone-2',3'-diol 4.     

Role of cytochrome P450 3A in the metabolism of mefloquine in human and animal hepatocytes

We studied mefloquine metabolism in cells and microsomes isolated from human and animal (monkey, dog, rat) livers. In both hepatocytes and microsomes, mefloquine underwent conversion to two major metabolites, carboxymefloquine and hydroxymefloquine. In human cells and microsomes these metabolites only were formed, as already demonstrated in vivo, while in other species several unidentified metabolites were also detected. After a 48 hr incubation with human and rat hepatocytes, metabolites accounted for 55-65% of the initial drug concentration, whereas in monkey and dog hepatocytes, mefloquine was entirely metabolized after 15 and 39 hrs, respectively. The consumption of mefloquine was less extensive in microsomes, and unchanged drug represented 60% (monkey) to 85-100% (human, dog, rat) of the total radioactivity after 5 hr incubations. The involvement of the cytochrome P450 3A subfamily in mefloquine biotransformation was suggested by several lines of evidence. Firstly, mefloquine metabolism was strongly increased in hepatic microsomes from dexamethasone-pretreated rats, and also in human and rat hepatocytes after prior treatment with a cytochrome P450 3A inducer. Secondly, mefloquine biotransformation in rifampycin-induced human hepatocytes was inhibited in a concentration-dependent manner by the cytochrome P450 3A inhibitor ketoconazole and thirdly, a strong correlation was found between erythromycin-N-demethylase activity (mediated by cytochrome P450 3A) and mefloquine metabolism in human microsomes (r=0.81, P < 0.05, N=13). Collectively, these findings concerning the role of cytochrome P450 3A in mefloquine metabolism may have important in vivo consequences especially with regard to the choice of agents used in multidrug antimalarial regimens.     

Stress “Deafness” Reveals Absence of Lexical Marking of Stress or Tone in the Adult Grammar

A Sequence Recall Task with disyllabic stimuli contrasting either for the location of prosodic prominence or for the medial consonant was administered to 150 subjects equally divided over five language groups. Scores showed a significant interaction between type of contrast and language group, such that groups did not differ on their performance on the consonant contrast, while two language groups, Dutch and Japanese, significantly outperformed the three other language groups (French, Indonesian and Persian) on the prosodic contrast. Since only Dutch and Japanese words have unpredictable stress or accent locations, the results are interpreted to mean that stress “deafness” is a property of speakers of languages without lexical stress or tone markings, as opposed to the presence of stress or accent contrasts in phrasal (post-lexical) constructions. Moreover, the degree of transparency between the locations of stress/tone and word boundaries did not appear to affect our results, despite earlier claims that this should have an effect. This finding is of significance for speech processing, language acquisition and phonological theory.     

Surgical Clipping versus Endovascular Intervention for the Treatment of Subarachnoid Hemorrhage Patients in New York State

Object

Randomized trials have demonstrated a survival benefit for endovascular treatment of ruptured cerebral aneurysms. We investigated the association of surgical clipping and endovascular coiling with outcomes in subarachnoid hemorrhage (SAH) patients in a real-world regional cohort.

Methods

We performed a cohort study involving patients with ruptured cerebral aneurysms, who underwent surgical clipping, or endovascular coiling from 2009–2013 and were registered in the Statewide Planning and Research Cooperative System (SPARCS) database. An instrumental variable analysis was used to investigate the association of treatment technique with outcomes.

Results

Of the 4,098 patients undergoing treatment, 2,585 (63.1%) underwent coiling, and 1,513 (36.9%) underwent clipping. Using an instrumental variable analysis, we did not identify a difference in inpatient mortality [marginal effect (ME), -0.56; 95% CI, -1.03 to 0.02], length of stay (LOS) (ME, 1.72; 95% CI, -3.39 to 6.84), or the rate of 30-day readmissions (ME, -0.30; 95% CI, -0.82 to 0.22) between the two treatment techniques for patients with SAH. Clipping was associated with a higher rate of discharge to rehabilitation (ME, 0.63; 95% CI, 0.24 to 1.01). In sensitivity analysis, mixed effect regression, and propensity score adjusted regression models demonstrated identical results.

Conclusions

Using a comprehensive all-payer cohort of patients in New York State presenting with aneurysmal SAH we did not identify an association of treatment method with mortality, LOS or 30-day readmission. Clipping was associated with a higher rate of discharge to rehabilitation.     

Androgen receptor regulation of the versican gene through an androgen response element in the proximal promoter

Versican, one of the key components of prostatic stroma, plays a central role in tumor initiation and progression. Here, we investigated promoter elements and mechanisms of androgen receptor (AR)-mediated regulation of the versican gene in prostate cancer cells. Using transient transfection assays in prostate cancer LNCaP and cervical cancer HeLa cells engineered to express the AR, we demonstrate that the synthetic androgen R1881 and dihydrotestosterone stimulate expression of a versican promoter-driven luciferase reporter vector (versican-Luc). Further, both basal and androgen-stimulated versican-Luc activities were significantly diminished in LNCaP cells, when AR gene expression was knocked down using a short hairpin RNA. Methylation-protection footprinting analysis revealed an AR-protected element between positions +75 and +102 of the proximal versican promoter, which strongly resembled a consensus steroid receptor element. Electrophoretic mobility shift and supershift assays revealed strong and specific binding of the recombinant AR DNA binding domain to oligonucleotides corresponding to this protected DNA sequence. Site-directed mutagenesis of the steroid receptor element site markedly diminished R1881-stimulated versican-Luc activity. In contrast to the response seen using LNCaP cells, R1881 did not significantly induce versican promoter activity and mRNA levels in AR-positive prostate stromal fibroblasts. Interestingly, overexpression of beta-catenin in the presence of androgen augmented versican promoter activity 10- and 30-fold and enhanced versican mRNA levels 2.8-fold in fibroblasts. In conclusion, we demonstrate that AR transactivates versican expression, which may augment tumor-stromal interactions and may contribute to prostate cancer progression.     

The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress

Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1alpha markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1alpha or XBP1, disruption of PERK activity, or inhibition of eIF2alpha phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.     

Atheroprotective and hepatoprotective effects of trans-chalcone through modification of eNOS/AMPK/KLF-2 pathway and regulation of COX-2, Ang-II,and PDGF mRNA expression in NMRI mice fed HCD

Molecular Biology Reports - The effects of trans-chalcone on atherosclerosis and NAFLD have been investigated. However, the underlying molecular mechanisms of these effects are not completely...