Homeodomain-leucine zipper (HD-Zip) proteins, a group of homeobox transcription factors, participate in various aspects of normal plant growth and developmental processes as well as environmental responses. To date, no overall analysis or expression profiling of the HD-Zip gene family in soybean (Glycine max) has been reported.
Methods and Findings
An investigation of the soybean genome revealed 88 putative HD-Zip genes. These genes were classified into four subfamilies, I to IV, based on phylogenetic analysis. In each subfamily, the constituent parts of gene structure and motif were relatively conserved. A total of 87 out of 88 genes were distributed unequally on 20 chromosomes with 36 segmental duplication events, indicating that segmental duplication is important for the expansion of the HD-Zip family. Analysis of the Ka/Ks ratios showed that the duplicated genes of the HD-Zip family basically underwent purifying selection with restrictive functional divergence after the duplication events. Analysis of expression profiles showed that 80 genes differentially expressed across 14 tissues, and 59 HD-Zip genes are differentially expressed under salinity and drought stress, with 20 paralogous pairs showing nearly identical expression patterns and three paralogous pairs diversifying significantly under drought stress. Quantitative real-time RT-PCR (qRT-PCR) analysis of six paralogous pairs of 12 selected soybean HD-Zip genes under both drought and salinity stress confirmed their stress-inducible expression patterns.
This study presents a thorough overview of the soybean HD-Zip gene family and provides a new perspective on the evolution of this gene family. The results indicate that HD-Zip family genes may be involved in many plant responses to stress conditions. Additionally, this study provides a solid foundation for uncovering the biological roles of HD-Zip genes in soybean growth and development.
A short half-life and low levels of growth factors in an injured microenvironment necessitates the sustainable delivery of growth factors and stem cells to augment the regeneration of injured tissues. Our aim was to investigate the ability of VEGF165 expressing bone marrow mesenchymal stem cells (BMMSCs) to differentiate into hepatocytes when cultured with hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in vitro. We isolated, cultured and identified rabbit BMMSCs, then electroporated the BMMSCs with VEGF165-pCMV6-AC-GFP plasmid. G418 was used to select transfected cells and the efficiency was up to 70%. The groups were then divided as follows: Group A was electroporated with pCMV6-AC-GFP plasmid + HGF + EGF and Group B was electroporated with VEGF165-pCMV6-AC-GFP plasmid +HGF + EGF. After 14 days, BMMSCs were induced into short spindle and polygonal cells. Alpha-fetoprotein (AFP) was positive and albumin (ALB) was negative in Group A, while both AFP and ALB were positive in group B on day 10. AFP and ALB in both groups were positive on day 20, but the quantity of AFP in group B decreased with prolonged time and was about 43.5% less than group A. The quantity of the ALB gene was increased with prolonged time in both groups. However, there was no significant difference between group A and B on day 10 and 20. Our results demonstrated that VEGF165-pCMV6-AC-GFP plasmid modified BMMSCs still had the ability to differentiate into hepatocytes. The VEGF165 gene promoted BMMSCs to differentiate into hepatocyte-like cells under the induction of HGF and EGF, and reduced the differentiation time. These results have implications for cell therapies.
Stem cells; Differentiation; VEGF165; Hepatocyte growth factor; Epidermal growth factor
Elevated lipoprotein(a) [Lp(a)] levels predict cardiovascular events incidence in patients with coronary artery disease (CAD). Genetic variants in the rs3798220, rs10455872 and rs6415084 single-nucleotide polymorphisms (SNPs) in the Lp(a) gene (LPA) correlate with elevated Lp(a) levels, but whether these SNPs have prognostic value for CAD patients is unknown. The present study evaluated the association of LPA SNPs with incidence of subsequent cardiovascular events in CAD patients after percutaneous coronary intervention (PCI).
TaqMan SNP genotyping assays were performed to detect the rs6415084, rs3798220 and rs10455872 genotypes in 517 Chinese Han patients with CAD after PCI. We later assessed whether there was an association of these SNPs with incidence of major adverse cardiovascular events (MACE: cardiac death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization). Serum lipid profiles were also determined using biochemical methods.
Only the rs6415084 variant allele was associated with higher Lp(a) levels [41.3 (20.8, 74.6) vs. 18.6 (10.3, 40.9) mg/dl, p < 0.001]. During a 2-year follow-up period, 102 patients suffered MACE, and Cox regression analysis demonstrated that elevated Lp(a) (≥30 mg/dl) levels correlated with increased MACE (adjusted HR, 1.69; 95% CI 1.13-2.53), but there was no association between LPA genetic variants (rs6415084 and rs3798220) and MACE incidence (p > 0.05).
Our data did not support a relationship between genetic LPA variants (rs6415084 and rs3798220) and subsequent cardiovascular events after PCI in Chinese Han CAD patients.
Coronary artery disease; Lipoprotein(a); Major adverse cardiovascular events; Percutaneous coronary intervention; Single-nucleotide polymorphism
Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis, a significant cause of morbidity in China and the Philippines. Here we present a draft genomic sequence for the worm, which is the first reported for any flatworm, indeed for the superphylum Lophotrochozoa. The genome provides a global insight into the molecular architecture and host interaction of this complex metazoan pathogen, revealing that it can exploit host nutrients, neuroendocrine hormones and signaling pathways for growth, development and maturation. Having a complex nervous system and a well developed sensory system, S. japonicum can accept stimulation of the corresponding ligands as a physiological response to different environments, such as fresh water or the tissues of its intermediate and mammalian hosts. Numerous proteinases, including cercarial elastase, are implicated in mammalian skin penetration and haemoglobin degradation. The genomic information will serve as a valuable platform to facilitate development of new interventions for schistosomiasis control.
The relative proportions of components in a pheromone blend play a major role in sexual recognition in moths. Two sympatric species, Helicoverpa armigera and Helicoverpa assulta, use (Z)-11-hexadecenal (Z11–16: Ald) and (Z)-9-hexadecenal (Z9–16: Ald) as essential sex pheromone components but in very different ratios, 97∶3 and 7∶93 respectively. Using wind tunnel tests, single sensillum recording and in vivo calcium imaging, we comparatively studied behavioral responses and physiological activities at the level of antennal sensilla and antennal lobe (AL) in males of the two species to blends of the two pheromone components in different ratios (100∶0, 97∶3, 50∶50, 7∶93, 0∶100). Z11–16: Ald and Z9–16: Ald were recognized by two populations of olfactory sensory neurons (OSNs) in different trichoid sensilla on antennae of both species. The ratios of OSNs responding to Z11–16:Ald and Z9–16:Ald OSNs were 100∶28.9 and 21.9∶100 in H. armigera and H. assulta, respectively. The Z11–16:Ald OSNs in H. armigera exhibited higher sensitivity and efficacy than those in H. assulta, while the Z9–16:Ald OSNs in H. armigera had the same sensitivity but lower efficacy than those in H. assulta. At the dosage of 10 µg, Z11–16: Ald and Z9–16: Ald evoked calcium activity in 8.5% and 3.0% of the AL surface in H. armigera, while 5.4% and 8.6% of AL in H. assulta, respectively. The calcium activities in the AL reflected the peripheral input signals of the binary pheromone mixtures and correlated with the behavioral output. These results demonstrate that the binary pheromone blends were precisely coded by the firing frequency of individual OSNs tuned to Z11–16: Ald or Z9–16: Ald, as well as their population sizes. Such information was then accurately reported to ALs of H. armigera and H. assulta, eventually producing different behaviors.
Odorant-binding proteins (OBPs) are soluble proteins, whose role in olfaction of insects is being recognized as more and more important. We have cloned, expressed and purified an OBP (HarmOBP7) from the antennae of the moth Helicoverpa armigera. Western blot experiments indicate specific expression of this protein in the antennae of adults. HarmOBP7 binds both pheromone components Z-11-hexadecenal and Z-9-hexadecenal with good affinity. We have also performed a series of binding experiments with linear aldehydes, alcohols and esters, as well as with other compounds and found a requirement of medium size for best affinity. The affinity of OBP7, as well as that of a mutant lacking the last 6 residues does not substantially decrease in acidic conditions, but increases at basic pH values with no significant differences between wild-type and mutant. Binding to both pheromone components, instead, is negatively affected by the lack of the C-terminus. A second mutant, where one of the three lysine residues in the C-terminus (Lys123) was replaced by methionine showed reduced affinity to both pheromone components, as well as to their analogues, thus indicating that Lys123 is involved in binding these compounds, likely forming hydrogen bonds with the functional groups of the ligands.
Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN.
Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated.
Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-β1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-α activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC-βII and ERK phosphorylation, but had no effect on PKC-α or PKC-βI phosphorylation.
Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN.
The complete molecule of the title complex, [Co(C14H9Br2FNO)2], is generated by crystallographic twofold symmetry, with the CoII atom lying on the rotation axis. The coordination of the metal atom by the two N,O-bidentate ligands results in a squashed CoN2O2 tetrahedron. The six-membered chelate ring is an envelope, with the metal atom as the flap. The dihedral angle between the planes of the aromatic rings within each ligand is 84.1 (6)°.
Chronic kidney disease (CKD) is recognized worldwide as a public health problem, and its prevalence increases as the population ages. However, the applicability of formulas for estimating the glomerular filtration rate (GFR) based on serum creatinine (SC) levels in elderly Chinese patients with CKD is limited.
Materials and methods
Based on values obtained with the technetium-99m diethylenetriaminepentaacetic acid (99mTc-DTPA) renal dynamic imaging method, 319 elderly Chinese patients with CKD were enrolled in this study. Serum creatinine was determined by the enzymatic method. The GFR was estimated using the Cockroft–Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Jelliffe-1973 equation, and the Hull equation.
The median of difference ranged from −0.3–4.3 mL/min/1.73 m2. The interquartile range (IQR) of differences ranged from 13.9–17.6 mL/min/1.73 m2. Accuracy with a deviation less than 15% ranged from 27.6%–32.9%. Accuracy with a deviation less than 30% ranged from 53.6%–57.7%. Accuracy with a deviation less than 50% ranged from 74.9%–81.5%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from the standard glomerular filtration rate (sGFR). Bland–Altman analysis demonstrated that the mean difference ranged from −3.0–2.4 mL/min/1.73 m2. However, the agreement limits of all the equations, except the CG equation, exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m2. When the overall performance and accuracy were compared in different stages of CKD, GFR estimated using the CG equation showed promising results.
Our study indicated that none of these equations were suitable for estimating GFR in the elderly Chinese population investigated. At present, based on overall performance, as well as performance in different CKD stages, the CG equation may be the most accurate for estimating GFR in elderly Chinese patients with CKD.
elderly; equation; glomerular filtration rate; serum creatinine; Chinese
A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.
Odorant-binding proteins (OBPs) mediate both perception and release of semiochemicals in insects. These proteins are the ideal targets for understanding the olfactory code of insects as well as for interfering with their communication system in order to control pest species. The two sibling Lepidopteran species Helicoverpa armigera and H. assulta are two major agricultural pests. As part of our aim to characterize the OBP repertoire of these two species, here we focus our attention on a member of this family, OBP10, particularly interesting for its expression pattern. The protein is specifically expressed in the antennae of both sexes, being absent from other sensory organs. However, it is highly abundant in seminal fluid, is transferred to females during mating and is eventually found on the surface of fertilised eggs. Among the several different volatile compounds present in reproductive organs, OBP10 binds 1-dodecene, a compound reported as an insect repellent. These results have been verified in both H. armigera and H. assulta with no apparent differences between the two species. The recombinant OBP10 binds, besides 1-dodecene, some linear alcohols and several aromatic compounds. The structural similarity of OBP10 with OBP1 of the mosquito Culex quinquefasciatus, a protein reported to bind an oviposition pheromone, and its affinity with 1-dodecene suggest that OBP10 could be a carrier for oviposition deterrents, favouring spreading of the eggs in these species where cannibalism is active among larvae.
STGC3 is a potential tumor suppressor that inhibits the growth of the nasopharyngeal carcinoma cell line CNE2; the expression of this protein is reduced in nasopharyngeal carcinoma compared with normal nasopharyngeal tissue. In this study, we investigated the tumor-suppressing activity of STGC3 in nude mice injected subcutaneously with Tet/pTRE-STGC3/CNE2 cells. STGC3 expression was induced by the intraperitoneal injection of doxycycline (Dox). The volume mean of Tet/pTRE-STGC3/CNE2+Dox xenografts was smaller than that of Tet/pTRE/CNE2+Dox xenografts. In addition, Tet/pTRE-STGC3/CNE2+Dox xenografts showed an increase in the percentage of apoptotic cells, a decrease in Bcl-2 protein expression and an increase in Bax protein expression. A proteomic approach was used to assess the protein expression profile associated with STGC3-mediated apoptosis. Western blotting confirmed the differential up-regulation of prohibitin seen in proteomic analysis. These results indicate that overexpression of STGC3 inhibits xenograft growth in nude mice by enhancing apoptotic cell death through altered expression of apoptosis-related proteins such as Bcl-2, Bax and prohibitin. These data contribute to our understanding of the function of STGC3 in human nasopharyngeal carcinoma and provide new clues for investigating other STGC3-associated tumors.
CNE2 cell line; nasopharyngeal carcinoma; nude mouse; STGC3; Tet-on; two-dimensional electrophoresis
The epidermal growth factor receptor (EGFR) is usually overexpressed in nasopharyngeal carcinoma (NPC) and is associated with pathogenesis of NPC. However, the downstream signaling proteins of EGFR in NPC have not yet been completely understood at the system level. The aim of this study was identify novel downstream proteins of EGFR signaling pathway in NPC cells.
We analyzed EGFR-regulated phosphoproteome in NPC CNE2 cells using 2D-DIGE and mass spectrometry analysis after phosphoprotein enrichment. As a result, 33 nonredundant phosphoproteins including five known EGFR-regulated proteins and twenty-eight novel EGFR-regulated proteins in CNE2 were identified, three differential phosphoproteins were selectively validated, and two differential phosphoproteins (GSTP1 and GRB2) were showed interacted with phospho-EGFR. Bioinformatics analysis showed that 32 of 33 identified proteins contain phosphorylation modification sites, and 17 identified proteins are signaling proteins. GSTP1, one of the EGFR-regulated proteins, associated with chemoresistance was analyzed. The results showed that GSTP1 could contribute to paclitaxel resistance in EGF-stimulated CNE2 cells. Furthermore, an EGFR signaling network based on the identified EGFR-regulated phosphoproteins were constructed using Pathway Studio 5.0 software, which includes canonical and novel EGFR-regulated proteins and implicates the possible biological roles for those proteins.
The data not only can extend our knowledge of canonical EGFR signaling, but also will be useful to understand the molecular mechanisms of EGFR in NPC pathogenesis and search therapeutic targets for NPC.
A high content molecular fragmentation for the analysis of phosphatidylcholines (PC) was achieved utilizing a two-stage [trap (first generation fragmentation) and transfer (second generation fragmentation)] collision-induced dissociation (CID) in combination with travelling-wave ion mobility spectrometry (TWIMS). The novel aspects of this work reside in the fact that a TWIMS arrangement was used to obtain a high level structural information including location of fatty acyl substituents and double bonds for PCs in plasma, and the presence of alkali metal adduct ions such as [M + Li]+ was not required to obtain double bond positions. Elemental compositions for fragment ions were confirmed by accurate mass measurements. A very specific first generation fragment ion m/z 577 (M-phosphoryl choline) from the PC [16:0/18:1 (9Z)] was produced, which by further CID generated acylium ions containing either the fatty acyl 16:0 (C15H31CO+, m/z 239) or 18:1 (9Z) (C17H33CO+, m/z 265) substituent. Subsequent water loss from these acylium ions was key in producing hydrocarbon fragment ions mainly from the α-proximal position of the carbonyl group such as the hydrocarbon ion m/z 67 (+H2C-HC = CH-CH = CH2). Formation of these ions was of important significance for determining double bonds in the fatty acyl chains. In addition to this, and with the aid of 13C labeled lyso-phosphatidylcholine (LPC) 18:1 (9Z) in the ω-position (methyl) TAP fragmentation produced the ion at m/z 57. And was proven to be derived from the α-proximal (carboxylate) or distant ω-position (methyl) in the LPC.
Electronic supplementary material
The online version of this article (doi:10.1007/s13361-011-0172-2) contains supplementary material, which is available to authorized users.
Ion mobility; Mass spectrometry; Phosholipids; Time-of-flight; Fatty acids; Double bond position; CID fragmentation
The haemagglutinin (HA) glycoprotein of influenza A virus is a major antigen that initiates humoral immunity against infection; however, the cellular immune response against HA is poorly understood. Furthermore, HA-derived cytotoxic T-lymphocyte (CTL) epitopes are relatively rare in comparison to other internal gene products. Here, CTL epitopes of the HA serotype H5 protein were screened. By using in silico prediction, in vitro refolding and a T2 cell-binding assay, followed by immunization of HLA-A2.1/Kb transgenic mice, an HLA-A*0201-restricted decameric epitope, RI-10 (H5 HA205–214, RLYQNPTTYI), was shown to elicit a robust CTL epitope-specific response. In addition, RI-10 and its variant, KI-10 (KLYQNPTTYI), were also demonstrated to be able to induce a higher CTL epitope-specific response than the influenza A virus dominant CTL epitope GL-9 (GILGFVFTL) in peripheral blood mononuclear cells of HLA-A*0201-positive patients who had recovered from H5N1 virus infection. Furthermore, the crystal structures of RI-10–HLA-A*0201 and KI-10–HLA-A*0201 complexes were determined at 2.3 and 2.2 Å resolution, respectively, showing typical HLA-A*0201-restricted epitopes. The conformations of RI-10 and KI-10 in the antigen-presenting grooves in crystal structures of the two complexes show significant differences, despite their nearly identical sequences. These results provide implications for the discovery of diagnostic markers and the design of novel influenza vaccines.
Behavioral and electrophysiological responses of larvae of the polyphagous moth species Helicoverpa armigera to two plant-derived allelochemicals were studied, both in larvae that had been reared on a diet devoid of these compounds and in larvae previously exposed to these compounds. In dual-choice cotton leaf disk and pepper fruit disk arena assays, caterpillars reared on a normal artificial diet were strongly deterred by strychnine and strophanthin-K. However, caterpillars reared on an artificial diet containing strychnine were insensitive to strychnine and strophanthin-K. Similarly, caterpillars reared on an artificial diet containing strophanthin-K were also desensitized to both deterrent chemicals. Electrophysiological tests revealed that the deterrent-sensitive neurons in taste sensilla on the maxillae of caterpillars reared on each deterrent-containing diet displayed reduced sensitivity to the two chemicals compared with the caterpillars reared on normal diets. We conclude that the experience-dependent behavioral plasticity was partly based on the reduced sensitivity of taste receptor neurons and that the desensitization of taste receptor neurons contributed to the cross-habituation to the two chemicals.
Deterrent neuron; Sensilla styloconica; Food experience; Acquired insensitivity; Cross-habituation
Cholesterol deposition in arterial wall drives atherosclerosis. The key goal of this study was to examine the relationship between plaque cholesterol content and patient characteristics that typically associate with disease state and lesion vulnerability. Quantitative assays for free cholesterol, cholesteryl ester, triglyceride, and protein markers in atherosclerotic plaque were established and applied to plaque samples from multiple patients and arterial beds (Carotid and peripheral arteries; 98 lesions in total).
We observed a lower cholesterol level in restenotic than primary peripheral plaque. We observed a trend toward a higher level in symptomatic than asymptomatic carotid plaque. Peripheral plaque from a group of well-managed diabetic patients displayed a weak trend of more free cholesterol deposition than plaque from non-diabetic patients. Plaque triglyceride content exhibited less difference in the same comparisons. We also measured cholesterol in multiple segments within one carotid plaque sample, and found that cholesterol content positively correlated with markers of plaque vulnerability, and negatively correlated with stability markers.
Our results offer important biological validation of cholesterol as a key lipid marker for plaque severity. Results also suggest cholesterol is a more sensitive plaque marker than routine histological staining for neutral lipids.
Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation.
Methods and Findings
We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and β-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFκB.
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.
In the title compound, C23H24NO4
+·Br−, the butyl chain is disordered between two conformations; the occupancies refined to 0.735 (7) and 0.265 (7). The dihedral angle between the naphthalene ring system and the phenyl ring is 11.6 (2)°. In the crystal structure, the cations are packed via π–π interactions into stacks propagating in the  direction. Weak intermolecular C—H⋯O and C—H⋯Br hydrogen bonds contribute further to the crystal packing stability.
While adipogenesis is known to be controlled by a complex network of transcription factors, less is known about the transcriptional cascade that initiates this process. We report here the characterization of KLF4 as an essential early regulator of adipogenesis. KLF4 is expressed in 3T3-L1 cells within 30 minutes after exposure to a standard adipogenic cocktail of insulin, glucocorticoids and IBMX. A knockdown of KLF4 inhibits adipogenesis and downregulates C/EBPβ levels. KLF4 binds directly to the C/EBPβpromoter as shown by CHIP and gel shift assays, and together with Krox20, cooperatively transactivates a C/EBPβ reporter. A C/EBPβ knockdown increases the levels of KLF4 and Krox20 suggesting that C/EBPβ normally supresses Krox20 and KLF4 expression via a tightly controlled negative feedback loop. KLF4 is specifically induced in response to cAMP, which by itself can partially activate adipogenesis. The data suggest that KLF4 functions as an immediate-early regulator of adipogenesis to induce C/EBPβ.
High-throughput technologies for DNA sequencing and for analyses of transcriptomes, proteomes and metabolomes have provided the foundations for deciphering the structure, variation and function of the human genome and relating them to health and disease states. The increased efficiency of DNA sequencing opens up the possibility of analyzing a large number of individual genomes and transcriptomes, and complete reference proteomes and metabolomes are within reach using powerful analytical techniques based on chromatography, mass spectrometry and nuclear magnetic resonance. Computational and mathematical tools have enabled the development of systems approaches for deciphering the functional and regulatory networks underlying the behavior of complex biological systems. Further conceptual and methodological developments of these tools are needed for the integration of various data types across the multiple levels of organization and time frames that are characteristic of human development, physiology and disease. Medical genomics has attempted to overcome the initial limitations of genome-wide association studies and has identified a limited number of susceptibility loci for many complex and common diseases. Iterative systems approaches are starting to provide deeper insights into the mechanisms of human diseases, and to facilitate the development of better diagnostic and prognostic biomarkers for cancer and many other diseases. Systems approaches will transform the way drugs are developed through academy-industry partnerships that will target multiple components of networks and pathways perturbed in diseases. They will enable medicine to become predictive, personalized, preventive and participatory, and, in the process, concepts and methods from Western and oriental cultures can be combined. We recommend that systems medicine should be developed through an international network of systems biology and medicine centers dedicated to inter-disciplinary training and education, to help reduce the gap in healthcare between developed and developing countries.
In the zwitterionic title compound, C18H17Br4N3O2, the two salicylaldimine groups form a dihedral angle of 51.94 (2)° and the dihedral angle between the aromatic ring planes is 51.14 (2)°. One of the C atoms adjacent to the aza N atom is disordered over two positions; the site-occupancy factors are 0.51 (1) and 0.49 (1). There are two strong intramolecular N—H⋯O hydrogen bonds in the molecule.