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The activated carbon from Leucaena leucocephala seed shell was prepared by chemical activation, characterized and used as adsorbent for the removal of hexavalent chromium [Cr(VI)] from aqueous solution via batch mode adsorption. The variables affecting the adsorption process, initial adsorbate concentration, pH, adsorbent dosage and temperature were optimized using central composite design (CCD) of the response surface methodology (RSM) at fixed contact time of 60 min. Equilibrium adsorption isotherm and kinetic were also studied. The analysis of variance (ANOVA) revealed that all the variables studied had significant effects on the removal efficiency of Cr(VI). The obtained data showed that 71.49 mg/L initial Cr(VI) concentration, 4.22 solution pH, 0.57 g adsorbent dosage and 26.2 C temperature resulted in 95.62% adsorption. Equilibrium adsorption isotherm and kinetic studies showed that Freundlich isotherm and pseudo-second-order kinetic model fitted well to the experimental data. The activated carbon from Leucaena leucocephala seed shell was found to be efficient for Cr(VI) adsorption.
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Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.
Non-receptor TKs (NRTKs) are intracellular cytoplasmic proteins that relay intracellular signals [9, 11] and can either be bound to the cell membrane or are nuclear-specific [9]. NRTKs display a broad role in cell signaling. This includes the regulation of gene expression e.g. via IL-6 mediated phosphorylation of the membrane-bound TK (Janus kinase) activating the signal transducer and activator of transcription (STAT) [12]. In addition, inhibition of cell growth e.g. via the stimulation of nuclear TKs (such as Abl) resulting in transcription factor Rb activation [13]. NRTK, such as focal adhesion kinase (FAK), can also regulate cell adhesion and proliferation [14] and are important components of signal transduction pathways, including Fyn [15] and Acks [16]. Furthermore, Acks play a vital role in cell growth via the induction of Janus kinase (JAK) and SRC machinery [17]. Tec family kinases are also associated with intracellular signaling mechanisms [18], as well as SYK which are involved in executing immune response between cell receptors and intracellular signaling [19,20,21]. Moreover, NRTKs exhibit considerable variability in their structural make up, due to a kinase domain and possession of some protein-protein interacting domains (e.g. SH2, SH3, and PH domain) [4, 22] and additional signaling. Although RTK are activated by ligand-binding, activation of NRTK involves a much more complex mode of action, incorporating heterologous protein-protein interaction, enabling transphosphorylation [23].
Oncogenic NRTK mutations can be of two types, those due to point mutations, duplications or deletions and insertions, and those involving the development of a fusion gene resulting from a chromosomal rearrangement (e.g. most famously BCR-ABL). NRTK aberrant activation caused by either of these two ways is importance huge cause in the development of many hematological malignancies. Consequently, signal transduction therapy [3] and kinase inhibitors [27] have been sought after to target mutated kinases including those found to be deregulated in various hematological diseases, including lymphomas, leukemias and myelomas. A number of compounds have since been discovered which have been shown to inhibit the activity of NRTKs, which are remarkably well tolerated, considering these compounds typically target a number of kinases, including those both normal and mutant [3].
This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations which give rise to such altered expression. This review further aims to showcase how the development of novel natural compounds are able to target kinases and perhaps in combination with other forms of therapy show great promise for the treatment of hematological malignancies. With particular interest in disease states associated with aggressive phenotype and the development of resistance to conventional chemotherapy, we highlight in vivo studies and clinical trials carried out targeting NRTKs with the use of natural products.
Aberrant activation of Fes is not connected with human cancers. Regardless, studies show that hyper-activation of Fes kinase is critical in maintaining the deregulated proliferation in human lymphoid malignancies elicited by constitutively active forms of mutated surface receptors (internal tandem duplication containing FLT3 and KIT D816V) [50]. Four somatic mutations within the kinase domain of Fes was reported in colorectal cancers, but none of them are gain-of-function mutations [51]. Similarly Fer mutations in small cell lung cancer has been reported [52] Over expression of human c-fps/fes using retroviral vector can transform fibroblasts and other established mouse cells [53] and it requires Ras, Rac, and Cdc42 [47].
Constitutive activation of JAKs has been reported in many cancers including various hematological malignancies. Deregulated JAK activity arises by numerous means, including aberrant cytokine production via autocrine/paracrine mechanism, activating point mutations within JAKs or any other oncogene upstream of signaling cascade.
Through past several years, a number of JAK mutations that lead to activation of constitutively active or hyperactive JAK activity have been identified [64]. The genetic alteration of JAK family has been reported in all members. It is a well known fact that JAK mutations is linked with development of hematological malignancies [59, 65]. The majority of these alterations are point mutations [59]. JAK2V617F mutation is one of the most studies genetic alteration in JAK family [59]. JAK2V617F mutation is mainly found in primary myelofibrosis or essential thrombocythemia patients. These patients have an incidence of 50% to 60% JAK2V617F mutational freqency and majority (95%) reported polycythemia vera [66]. Another point JAK1 mutation, A634D has been reported in the pseudokinase domain [67]. This mutation has been shown to cause a prominent effect on signaling functions [67]. JAK1 mutation has been found to involve in the development of AML [68] JAK1 mutations are commonly found in T-cell ALL (18%) and with a lesser frequency in B-cell ALL (B-ALL). Constitutive activation of STAT5 has been linked with mutation of JAK1 [65, 69, 70]. JAK1 mutation-mediated activation of STAT5 is also reported in AML patients. JAK3 member of JAK family is found only in hematopoietic lineage. Point mutations leading to aberrant activation of JAK3 have been reported in various leukemia/lymphomas [71]. Juvenile myelomonocytic leukemia (JMML) patients with secondary mutations in JAK3 have poor prognosis and clinical outcome. In JMML 12% of JAK3 gene has been found to be mutated [72]. Mutation of JAK3 is reported in 15% acute megakaryoblastic leukemia [73]. T-cell lymphoma patients (Extranodal nasal-type natural killer) (21%) were reported to have JAK3 mutations (A573V or V722I) in the pseudokinase domain [74]. These mutations can lead to constitutive JAK3 activation conferring invasive growth and survival advantages. In aggressive T-ALL, JAK3 mutation has been found to be significantly associated [75]. Mutation inTYK2 kinase have been reported in T-ALL (21%) and play a role in promote cell survival via activation of STAT1 as well BCL2 upregulation expression [76]. 2ff7e9595c