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PubMed2005

The ubiquitin proteasome pathway from bench to bedside.

The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.

Antineoplastic Agents↗

PubMed2002

Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes.

The B-cell lymphoproliferative malignancies B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share characteristics, including overlapping chromosomal aberrations with deletions on chromosome bands 13q14, 11q23, 17p13, and 6q21 and gains on chromosome bands 3q26, 12q13, and 8q24. To elucidate the biochemical processes involved in the pathogenesis of B-CLL and MCL, we analyzed the expression level of a set of genes that play central roles in apoptotic or cell proliferation pathways and of candidate genes from frequently altered genomic regions, namely ATM, BAX, BCL2, CCND1, CCND3, CDK2, CDK4, CDKN1A, CDKN1B, E2F1, ETV5, MYC, RB1, SELL, TFDP2, TNFSF10, and TP53. Performing real-time quantitative reverse transcription polymerase chain reaction in a panel of patients with MCL and B-CLL and control samples, significant overexpression and underexpression was observed for most of these genes. Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types. Overexpression in these malignancies suggests ETV5 as a new candidate for a pathogenic factor in B-cell lymphomas. Characteristic deregulation of multiple genes analyzed in this study could be combined in a comprehensive picture of 2 distinctive pathomechanisms in B-CLL and MCL. In B-CLL, the expression parameters are in strong favor of protection of the malignant cells from apoptosis but did not provide evidence for promoting cell cycle. In contrast, in MCL the impairment of apoptosis induction seems to play a minor role, whereas most expression data indicate an enhancement of cell proliferation.

Adult↗

PubMed2004

Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.

BACKGROUND: The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. RESULTS: The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1-3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2-4.2). CONCLUSIONS: Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism.

Adolescent↗

PubMed2002

Genome scans and microarrays: converging on genes for schizophrenia?

Systematic genome-wide scans to date have shown that genes of major effect are not common causes of schizophrenia, but independent linkage studies looking for schizophrenia susceptibility genes are converging on a number of key chromosomal locations. Microarray expression analysis may identify new candidate genes and pathways, and a number of intriguing preliminary findings have already been reported.

Chromosome Mapping↗

PubMed2005

Cytokine therapy.

Cytokines are a unique class of intercellular regulatory proteins that play a crucial role in initiating, maintaining, and regulating immunologic homeostatic and inflammatory processes. Indeed, measurement of cytokine profiles in patients provides a useful indication of disease status. Due to their multiple functions, including regulatory and effector cellular function in many diseases, these molecules, their receptors, and their signal transduction pathways are promising candidates for therapeutic interference. The therapeutic administration of cytokines, modulation of cytokine action, or at times gene therapy is being used for a wide range of infectious and autoimmune diseases, in immunocompromised patients with AIDS, and in neoplasia.

Autoimmune Diseases↗

PubMedDate not supplied

Effect of the serotonin receptor agonist, buspirone, on immune function in HIV-infected individuals: a six-month randomized, double-blind, placebo-controlled trial.

PURPOSE: Previous studies have shown that agents modulating the cAMP/PKA pathway have a beneficial effect on immune reconstitution in HIV-infected individuals. Here we evaluate the effect of buspirone on immune function as measured by CD4 and CD8 T-cell counts, CD4/CD8 T-cell ratio, HIV viral load, and response to pokeweed mitogen (PWM) in antiretroviral naive HIV-1-infected individuals. METHOD: Twenty-three HIV-infected patients with CD4 T-cell counts above 300 per microL were enrolled in a 6-month double-blinded placebo controlled trial. No patients received antiretroviral therapy during the study. Blood samples were drawn prior to treatment, after 1 week, 1 month, 3 months, and 6 months, and as a follow-up sample 1 month after completion of study. RESULTS: A significant decrease in CD8+ T-cell counts (p =.02) and an increase in CD4/CD8 ratio (p =.0003) in buspirone-treated patients compared to placebo-treated patients was observed. There were no significant differences in CD4 T-cell counts, HIV viral load, or proliferative response to PWM between those receiving placebo and those receiving buspirone. CONCLUSION: Buspirone treatment leads to significant changes in CD8 T-cell count and in CD4/CD8 ratio. Thus, agents affecting the adenosine 3', 5'-cyclic monophosphate/protein kinase A type 1 (cAMP/PKA-1) pathway may be candidates for positive immune modulation in patients with HIV-1 infection.

Adult↗

PubMed2005

Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer.

Pancreatic cancer, the fourth leading cause of cancer death in the United States, is frequently associated with the amplification and deletion of specific oncogenes and tumor-suppressor genes (TSGs), respectively. To identify such novel alterations and to discover the underlying genes, we performed comparative genomic hybridization on a set of 22 human pancreatic cancer cell lines, using cDNA microarrays measuring approximately 26,000 human genes (thereby providing an average mapping resolution of <60 kb). To define the subset of amplified and deleted genes with correspondingly altered expression, we also profiled mRNA levels in parallel using the same cDNA microarray platform. In total, we identified 14 high-level amplifications (38-4934 kb in size) and 15 homozygous deletions (46-725 kb). We discovered novel localized amplicons, suggesting previously unrecognized candidate oncogenes at 6p21, 7q21 (SMURF1, TRRAP), 11q22 (BIRC2, BIRC3), 12p12, 14q24 (TGFB3), 17q12, and 19q13. Likewise, we identified novel polymerase chain reaction-validated homozygous deletions indicating new candidate TSGs at 6q25, 8p23, 8p22 (TUSC3), 9q33 (TNC, TNFSF15), 10q22, 10q24 (CHUK), 11p15 (DKK3), 16q23, 18q23, 21q22 (PRDM15, ANKRD3), and Xp11. Our findings suggest candidate genes and pathways, which may contribute to the development or progression of pancreatic cancer.

Cell Line, Tumor↗

PubMed2000

A QTL on pig chromosome 4 affects fatty acid metabolism: evidence from an Iberian by Landrace intercross.

Three Iberian boars were bred to 31 Landrace sows to produce 79 F1 pigs. Six F1 boars were mated to 73 F1 sows. The F2 progeny from 33 full-sib families (250 individuals) were genotyped for seven microsatellites spanning the length of chromosome 4. Least squares procedures for interval mapping were used to detect quantitative trait loci (QTL). A permutation test was used to establish nominal significance levels associated with QTL effects, and resulting probability levels were corrected to a genomewide basis. Observed QTL effects were (genomewide significance, position of maximum significance in centimorgans): percentage of linoleic acid in subcutaneous adipose tissue (< 0.01, 81); backfat thickness (< 0.01, 83); backfat weight (< 0.01, 80); longissimus muscle area (0.02, 83); live weight (0.19, 88); and percentage of oleic acid in subcutaneous adipose tissue (0.25, 81). Gene action was primarily additive. The Iberian genotypes were fatter, slower growing, and had lower linoleic and higher oleic acid contents than Landrace genotypes. The interval from 80 to 83 cM contains the FAT1 and A-FABP loci that have been shown previously to affect fat deposition in pigs. This is the first report of a QTL affecting fatty acid composition of subcutaneous adipose tissue in pigs and provides a guide for the metabolic pathways affected by candidate genes described in this region of chromosome 4.

Adipose Tissue↗

PubMed1999

Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments.

There are few candidates for biochemical pathways that either initiate or amplify catabolic processes involved in osteoarthritis (OA). Perhaps, one of the most likely sources for such pathways may be within the extracellular matrix itself. This review focuses on an example of how specific degradation products of the extracellular matrix of cartilage, produced during proteolytic damage, have the potential to enhance OA-like processes. In this example, these products can induce or activate other factors, such as catabolic cytokines, that amplify the damage. The damage, in turn, enhances levels of the degradation products themselves, as in a positive feedback loop. Since these products are derived from the cartilage matrix, they could be considered barometers of the health of the cartilage that signal to the chondrocyte, through outside to inside signaling, the health or status of the surrounding matrix. The best example and most characterized system is that of fragments of the matrix protein, fibronectin (Fn), although as discussed later, other recently discovered fragment systems may also have the potential to regulate cartilage metabolism. In the case of Fn fragments (Fn-fs), the Fn-fs enhance levels of catabolic cytokines as in OA and, thus, are potentially earlier damage mediators than catabolic cytokines. The Fn-fs up-regulate matrix metalloproteinase (MMP) expression, significantly enhance degradation and loss of proteoglycan (PG) from cartilage and temporarily suppress PG synthesis, all events observed in OA. However, this Fn-f system may be involved in normal cartilage homeostasis as well. For example, low concentrations of Fn-fs enhance anabolic activities and could play a role in normal homeostasis. This system may also be involved in not only amplifying damage but also coupling damage to repair. For example, high concentrations of Fn-fs that might arise in OA temporarily offset the anabolic response of lower Fn-f concentrations and cause short-term enhanced catabolic events that are followed by slowly increasing anabolic responses. Such effects would be expected for mediators with roles in regulation of metabolism in both normal or diseased cartilage. Other products of matrix degradation have also been shown to regulate cartilage metabolism. A common mechanistic theme to these systems may be that they perturb the cartilage matrix and directly or indirectly alter function of specific receptors involved in metabolism. These concepts illustrate the potential of the cartilage matrix to regulate its composition in both health and disease.

Animals↗

PubMed2006

Pharmacogenomics: challenges and opportunities.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Clinical Medicine↗

PubMed2003

A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity.

Norepinephrine (NE) transporters (NETs) terminate noradrenergic synaptic transmission and represent a major therapeutic target for antidepressant medications. NETs and related transporters are under intrinsic regulation by receptor and kinase-linked pathways, and clarification of these pathways may suggest candidates for the development of novel therapeutic approaches. Syntaxin 1A, a presynaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, interacts with NET and modulates NET intrinsic activity. NETs colocalize with and bind to syntaxin 1A in both native preparations and heterologous systems. Protein kinase C activation disrupts surface NET/syntaxin 1A interactions and downregulates NET activity in a syntaxin-dependent manner. Syntaxin 1A binds the NH(2) terminal domain of NET, and a deletion of this domain both eliminates NET/syntaxin 1A associations and prevents phorbol ester-triggered NET downregulation. Whereas syntaxin 1A supports the surface trafficking of NET proteins, its direct interaction with NET limits transporter catalytic function. These two contradictory roles of syntaxin 1A on NET appear to be linked and reveal a dynamic cycle of interactions that allow for the coordinated control between NE release and reuptake.

Animals↗

PubMed2005

[Suicide attempt, psychopathology and genetics].

BACKGROUND: There is compelling evidence that suicidal behaviour has a heritable component and is associated with disturbances in serotonergic mechanisms. Thus genes coding for proteins of the serotonergic pathways are leading candidates for investigating possible associations. METHOD: We studied three serotonergic gene polymorphisms (5-HTTLPR S/L, TPH A779C, 5-HT1B G861C) in a sample of 114 unrelated suicide attempters (mainly non-violent methods), in 112 patients, 23 siblings and 56 healthy controls. Genotyping was done using polymerase chain reaction (PCR) based assays. The primary analyses compared allele and genotype frequencies between patients and controls and to test for presence of linkage disequilibrium using the family based association test (FBAT). The genotypes were further related to clinical characteristics and to psychological traits. RESULTS: There was a trend towards an increase in the L-allele frequency of the 5-HTTLPR in suicidal patients (p=0.066, OR=1,57, 95%CI 0,96-2,52). No other polymorphisms were associated with suicidal behaviour and the FBAT showed no excess transmission of any allele from parents to the offsprings. We found a slight reduction in "Novelty Seeking Scores" in patients having at least one S-allele (one-way ANOVA F=3,90, p=0.024). All the other traits were not related to any of the genotypes. CONCLUSION: Our data extend the evidence that genetic factors do not play a major role in non-violent suicidal behaviour. The 5-HTTLPR S/L variants may have an impact on personality traits.

Adult↗

PubMed2026

Transcriptomic analysis provides molecular insights into the innate immune defense of Mactra veneriformis against Vibrio alginolyticus infection.

Mactra veneriformis is an economically important bivalve mollusc in China, but its aquaculture is frequently threatened by Vibrio infections, particularly Vibrio alginolyticus. To investigate the molecular immune response of M. veneriformis to V. alginolyticus, we performed RNA-seq analysis of hepatopancreatic tissues collected at 48 h post-infection, the peak mortality time point, with PBS-injected individuals used as controls. Infection with V. alginolyticus caused severe histopathological damage in the hepatopancreas and resulted in a cumulative mortality of 53.3% over 14 d, compared with 3.3% in the control group. Transcriptomic analysis identified 2623 differentially expressed genes (DEGs), including 1585 significantly up-regulated genes and 1038 down-regulated genes. KEGG enrichment analysis demonstrated that DEGs were significantly enriched in immune related and metabolism pathways, including the JAK-STAT signaling pathway, RIG-I-like receptor (RLR) signaling pathway, and cytochrome P450 (CYP450) signaling pathway. Collectively, these findings revealed candidate immune related genes (tlr3, tlr5, myd88, nfkb1, il-17d, and ifi44l), a putative TLR-MyD88-NF-κB signaling axis, and KEGG signaling pathways, including JAK-STAT, RLR and CYP450, that may be involved in the innate immune response of M. veneriformis to V. alginolyticus infection. These results provide a transcriptomic basis for understanding host-pathogen interactions in this species and highlight candidate genes and pathways for future functional validation and potential application in disease-resistance breeding.

Animals↗

PubMed1995

Multiple strategies for directed growth cone extension and navigation of peripheral neurons.

Leeches have a diverse constellation of peripheral neural elements that are challenged to extend growth cones in highly specific ways in a constantly changing embryonic environment. Two major systems are reviewed here. In one, peripheral afferents extend growth cones toward the central nervous system (CNS), forming common pathways, and then segregate into particular tracts within the CNS. A majority of these afferents depend on CNS-derived guidance cues and projections from the CNS to guide their way. However, not all of the nerves are established this way and at least one of the peripheral nerves is likely to be pioneered by sensillar sensory afferents. The distribution of particular antigens (such as the lan3-2 antigen) suggests the identity of molecules involved in homophilic adhesion along common pathways, whereas others (such as the lan4-2 and 3-6 antigens) are candidates for mediating specific pathway choices. In the second system, the myo-organizing Comb cell (C cell) projects multiple growth cones simultaneously along oblique trajectories not influenced by segmental or midline boundaries. Its parallel growth cones exhibit space-filling as well as directional growth and are guided by local cues to extend in discrete phases that are coordinated with the development of the environment. Both systems exhibit highly directed outgrowth orchestrated by a hierarchy of cues, establish patterns of neurites used to direct later migrating cells, and seem to be regulated temporally and spatially by interactions with the embryonic environment. These systems illustrate the strengths of examining neural development in vivo across several levels of analysis.

Animals↗

PubMed2002

Conversion of 7 alpha-hydroxycholesterol to bile acid in human subjects: is there an alternate pathway favoring cholic acid synthesis?

Despite the fact that most human subjects synthesize about twice as much cholic acid as chenodeoxycholic acid, available evidence suggests that 7 alpha-hydroxycholesterol, the first intermediate in the major pathway for bile acid synthesis, is converted about equally to these two bile acids. Synthesis through the main alternate pathway can not explain this discrepancy because 27-hydroxycholesterol, the first intermediate in that pathway, is converted preferentially to chenodeoxycholic acid. To examine the validity of these contradictory observations, we administered (24-(14)C)-cholic acid and (24-(14)C)-chenodeoxycholic acid together with (7 beta-(3)H)-7 alpha-hydroxycholesterol on one occasion and (22,23-(3)H)-27-hydroxycholesterol on a separate occasion to eight normal human subjects. Synthesis of the two primary bile acids was determined by means of standard isotope dilution kinetics of the carbon 14-specific activities of biliary bile acids. Conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol and (22,23-(3)H)-27-hydroxycholesterol to bile acid was calculated from the tritium/carbon 14 ratio in cholic and chenodeoxycholic acid. For synthesis, the mean +/- SEM cholic/chenodeoxycholic ratio was 1.82 +/- 0.26. For apparent conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol to bile acid, the mean +/- SEM cholic/ chenodeoxycholic ratio was 1.02 +/- 0.09, whereas for (22,23(3)H)-27-hydroxycholesterol, the mean +/- SEM cholic/chenodeoxycholic ratio was 0.38 +/- 0.03. These data imply that, on average, more than 40% of cholic acid in these subjects was synthesized through a pathway that bypassed initial 7 alpha-hydroxylation. However, consideration of all potential candidates for such a pathway raises doubts that any of them contributes substantially to bile acid synthesis.

Adult↗

PubMed2004

Biosynthesis of pantothenate.

Pantothenate is an essential metabolite for all biological systems, however, the biosynthetic pathway is limited to plants, eubacteria and archaea. This suggests that the pathway is a strong candidate for the discovery of novel antibiotic and herbicidal compounds. The enzymology of this short pathway in both bacteria and plants is discussed in detail. In addition a short survey of studies of the whole pathway, and a discussion of both the metabolism and the transport of pantothenate are included.

Amino Acid Sequence↗

PubMed2003

Systems-wide chicken DNA microarrays, gene expression profiling, and discovery of functional genes.

The goal of our current consortium project is to launch a new era--functional genomics of poultry--by providing genomic resources [expressed sequence tags (EST) and DNA microarrays] and by examining global gene expression in target tissues of chickens. DNA microarray analysis has been a fruitful strategy for the identification of functional genes in several model organisms (i.e., human, rodents, fruit fly, etc.). We have constructed and normalized five tissue-specific or multiple-tissue chicken cDNA libraries [liver, fat, breast, and leg muscle/epiphyseal growth plate, pituitary/hypothalamus/pineal, and reproductive tract (oviduct/ovary/testes)] for high-throughput DNA sequencing of EST. DNA sequence clustering was used to build contigs of overlapping sequence and to identify unique, non-redundant EST clones (unigenes), which permitted printing of systems-wide chicken DNA microarrays. One of the most promising genetic resources for gene exploration and functional gene mapping is provided by two sets of experimental lines of broiler-type chickens developed at INRA, France, by divergent selection for extremes in growth traits (fast-growing versus slow-growing; fatness versus leanness at a similar growth rate). We are using DNA microarrays for global gene expression profiling to identify candidate genes and to map growth, metabolic, and regulatory pathways that control important production traits. Candidate genes will be used for functional gene mapping and QTL analysis of F2 progeny from intercrosses made between divergent genetic lines (fat x lean lines; fast-growing x slow-growing lines). Using our first chicken liver microarray, we have already identified several interesting differentially expressed genes in commercial broilers and in divergently selected broiler lines. Many of these candidate genes are involved in the lipogenic pathway and are controlled in part by the thyrotropic axis. Thus, genome-wide transcriptional profiling is a powerful tool used to visualize the cascade of genetic circuits that govern complex biological responses. Global gene expression profiling and QTL scans should enable us to functionally map the genetic pathways that control growth, development, and metabolism of chickens. This emerging technology will have broad applications for poultry breeding programs (i.e., use of molecular markers) and for future production systems (i.e., the health and welfare of birds and the quality of poultry products).

Animal Husbandry↗

PubMed2005

Potential candidates for ischemic preconditioning-associated vascular growth pathways revealed by antibody array.

Our understanding of the phenomenon of myocardial vascular growth is very limited even though various studies have been conducted in several different models, because the focus in each has been on a select very few number of proteins as the possible growth factors. In the present study, we used the ischemic preconditioning (IP) model in the form of four in vivo repetitive cycles of coronary artery occlusion, each followed by reperfusion as the model to stimulate vascular growth, and performed the protein profiling using high-throughput antibody array technology. Rats were divided into two groups: control + left anterior descending coronary artery (LAD) occlusion (CMI), and IP+ LAD occlusion (IPMI). The antibody array experiment performed to compare the expression of 512 proteins between the IPMI and CMI samples revealed significant upregulation of growth proteins like TGF-beta, BMX, granulocyte-monocyte colony-stimulating factor, signal transducer and activator of transcription 3, alpha- and beta-catenins, ubiquitin-conjugating enzyme UbcH6, nexilin, and PKC-epsilon and -lambda. JNK1 and c-Src tyrosine kinase were expectedly found to be downregulated. Western blot experiments validated the changes in expression of these proteins. Therefore, this study puts forward the above-mentioned proteins as valid participants in the vascular growth signals that are known to be triggered by ischemic preconditioning of heart.

Animals↗