Selective electrochemical determination of dopamine at p-nitroaniline film-hole modified glassy carbon electrodes

Herein, we report determination of dopamine (DA) at modified glassy carbon electrode (GCE) with a film produced by reduction of diazonium generated from p-nitroaniline (PNA). Pores were created purposely by stripping pre-deposited gold nanoparticles (AuNPs) in the modifier film. The modified electrodes were characterized electrochemically by common redox probes: hydroquinone (HQ), hexacyanoferrate [(Fe(CN)6)]3- and hexamine ruthenium(III) [Ru(NH3)6]3+. Comparison was made for the cyclic voltammetric and amperometric response of DA using the modified electrodes against the bare GCE in phosphate buffer solution (PBS) of pH 7.5. The bare and modified GCE showed a linear response to DA in the concentration range of 0.2-2.2 mM and 5-35 µM with detection limit of 0.015 mM and 0.6112 µM, respectively. The modified electrode showed high sensitivity, well selectivity, good anti-interference ability, durable stability and good electrode reproducibility for determining DA. The reported modified electrode is a promising sensor for use in electroanalysis of DA. KEY WORDS: Diazonium, p-Nitroaniline, Gold nanoparticles, Dopamine, Ascorbic acid, Glassy carbon electrode Bull. Chem. Soc. Ethiop. 2017, 31(3), 361-372DOI: http://dx.doi.org/10.4314/bcse.v31i3.

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as standalone or in combination with targeted drugs.Peer reviewe

Classical cadherins control survival through the gp130/Stat3 axis

Stat3 (Signal Transducer and Activator of Transcription-3) is activated by a number of receptor and nonreceptor tyrosine kinases. We recently demonstrated that engagement of E-cadherin, a calcium-dependent, cell to cell adhesion molecule which is often required for cells to remain tightly associated within the epithelium, also activates Stat3.We nowexamined the effect of two other classical cadherins, cadherin-11 and N-cadherin,whose expression often correlateswith the epithelial to mesenchymal transition occurring in metastasis of carcinoma cells, upon Stat3 phosphorylation and activity. Our results indicate that engagement of these two cadherins also, can trigger a dramatic surge in Stat3 activity. This activation occurs through upregulation ofmembers of the IL6 family of cytokines, and it is necessary for cell survival, proliferation and migration. Interestingly, our results also demonstrate for the first time that, in sharp contrast to Stat3, the activity of Erk (Extracellular Signal Regulated kinase) was unaffected by cadherin-11 engagement. Further examination indicated that, although IL6 was able to activate Erk in sparsely growing cells, IL6 could not induce an increase in Erk activity levels in densely growing cultures. Most importantly, cadherin-11 knock-down did allow Erk activation by IL6 at high densities, indicating that it is indeed cadherin engagement that prevents Erk activation by IL6. The fact that the three classical cadherins tested so far, E-cadherin, N-cadherin and cadherin11,which are present in essentially all tissues, actually activate Stat3 regardless of their role in metastasis, argues for Stat3 as a central survival, rather than invasion factor

Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein

We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound <b>13a</b>, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5–SH2 domain complexation events <i>in vitro</i>, silences activated STAT5 in leukemic cells, as well as STAT5′s downstream transcriptional targets, including <i>MYC</i> and <i>MCL1</i>, and, as a result, leads to apoptosis. We believe <b>13a</b> represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials

Elevated PIN1 expression by C/EBPα-p30 blocks C/EBPα-induced granulocytic differentiation through c-Jun in AML

10.1038/leu.2010.37Leukemia245914-92

The presence of C/EBP alpha and its degradation are both required for TRIB2-mediated leukaemia

peer-reviewedC/EBP alpha (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP alpha p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP alpha, TRIB2 was unable to induce AML. Only in the presence of C/EBP alpha p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP alpha p42 requires site-specific direct interaction between TRIB2 and C/EBP alpha p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP alpha p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP alpha. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP alpha p42 is required for TRIB2-mediated AML.peer-reviewe