Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lactate minimum test (LACmin) has been considered an important indicator of endurance exercise capacity and a single session protocol can predict the maximal steady state lactate (MLSS). The objective of this study was to determine the best swimming protocol to induce hyperlactatemia in order to assure the LACmin in rats (Rattus norvegicus), standardized to four different protocols (P) of lactate elevation. The protocols were P1: 6 min of intermittent jumping exercise in water (load of 50% of the body weight - bw); P2: two 13% bw load swimming bouts until exhaustion (tlim); P3: one tlim 13% bw load swimming bout; and P4: two 13% bw load swimming bouts (1st 30 s, 2nd to tlim), separated by a 30 s interval. The incremental phase of LACmin beginning with initial loads of 4% bw, increased in 0.5% at each 5 min. Peak lactate concentration was collected after 5, 7 and 9 min (mmol L(-1)) and differed among the protocols P1 (15.2+/-0.4, 14.9+/-0.7, 14.8+/-0.6) and P2 (14.0+/-0.4, 14.9+/-0.4, 15.5+/-0.5) compared to P3 (5.1+/-0.1, 5.6+/-0.3, 5.6+/-0.3) and P4 (4.7+/-0.2, 6.8+/-0.2, 7.1+/-0.2). The LACmin determination success rates were 58%, 55%, 80% and 91% in P1, P2, P3 and P4 protocols, respectively. The MLSS did not differ from LACmin in any protocol. The LACmin obtained from P4 protocol showed better assurance for the MLSS identification in most of the tested rats.
Comp Biochem Physiol A Mol Integr Physiol 2007 Dec
PMID:Protocols for hyperlactatemia induction in the lactate minimum test adapted to swimming rats. 1796 36

As in vivo 31P-Nuclear Magnetic Resonance spectroscopy is currently the state of the art method to measure continuously intracellular pH (pH(i)) and energy status of muscle tissue, we used this method to study the recovery from exhaustive exercise. The biochemical changes during recovery are not well understood and it was suggested that post-exercise mortality could be caused by low pH(i); other studies however indicate that energy depletion might be more important. To analyse the mechanism of post-exercise recovery pH(i), ATP, P(i), and PCr must be measured at the same time, which is possible using in vivo 31P-NMR. Common carp and rainbow trout of about 100 g were exercised to exhaustion in a swim tunnel. After swimming 10 h at 1.5 body lengths (BL)/s (aerobic control), 50% of the fish were forced to swim at 6 BL/s until exhaustion. Recovery of energy rich phosphates was found to be faster in carp (1.2-1.9 h) than in trout (1.5-2.3 h). The same applied for the recovery from acidosis, which took 1.75 h in carp and 5.75 h in trout. In parallel experiments the energy phosphates and lactate levels were measured in liver, red muscle, and white muscle. Exhaustion caused a significant drop in the energy status of red and white muscle tissue of trout and carp (corroborates NMR data), while no change at all was observed in liver tissue. The lactate levels were increased in the muscle but not in liver and blood. While all experimental animals looked healthy after exhaustion, 40-50% of the carp as well as trout died during the recovery phase. The energy status of those individuals measured by 31P-NMR was much lower than that of the survivors, while in contrast there was no difference in pH(i). Thus, it appears that not acidosis but depletion of high energy phosphates disabled muscle function and therefore may have been the cause of death of the non-survivors.
Comp Biochem Physiol A Mol Integr Physiol 2008 Jan
PMID:Depletion of high energy phosphates implicates post-exercise mortality in carp and trout; an in vivo 31P-NMR study. 1805 39

The phenotype and function of antigen-specific CD8 T cells are closely associated with the efficacy of a therapeutic vaccination. Here we showed that multiple immunizations with LCMV gp33-41 peptide (KAV) in Freund's adjuvant could induce KAV-specific CD8 T cells with low expression of CD127 and CD62L molecules. The inhibitory receptor PD-1 was also expressed on a substantial part of KAV-specific CD8 T cells, and its expression level on KAV-specific CD8 T cells in spleen and lymph nodes was much higher when compared to those in peripheral blood. Furthermore, KAV-specific CD8 T cells could specifically kill KAV-pulsed target cells in vivo but the efficiency was low. These data suggest that prime-boost vaccination schedule with peptide in Freund's adjuvant can elicit antigen-specific CD8 T cells of effector-like phenotype with partial functional exhaustion, which may only provide short-term protection against the pathogen.
Cell Mol Immunol 2007 Dec
PMID:Phenotypic and functional analysis of LCMV gp33-41-specific CD8 T cells elicited by multiple peptide immunization in mice revealed the up-regulation of PD-1 expression on antigen-specific CD8 T cells. 1816 54

We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
Hum Mol Genet 2008 Jun 01
PMID:Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. 1829 49

It is firmly established that poor metabolic control in diabetes inhibits beta cell function. Chronic hyperglycaemia is probably the most important factor, exerting both primary negative effects (by glucose per se and/or metabolites) and secondary ones (by beta cell exhaustion). Dyslipidemia in diabetes aggravates the glucose effects both by inducing insulin resistance and by direct effects on beta cells. Much experimental and some clinical evidence indicates that therapies that promote "beta cell rest" such as early and intensive insulin treatment and K-ATP channel blockers can be beneficial.
Mol Cell Endocrinol 2009 Jan 15
PMID:Impact of metabolic abnormalities for beta cell function: clinical significance and underlying mechanisms. 1862 Oct 94

Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.
Mol Cancer 2009 Jan 08
PMID:Senescence induction; a possible cancer therapy. 1913 11

The filoviruses, Ebola (EBOV) and Marburg (MARV), are among the deadliest of human pathogens, causing acute diseases typified by rapidly fatal hemorrhagic fevers. Upon filoviral infection, innate immune cells become paralyzed and lose the capacity to properly co-stimulate and activate filovirus-specific, T-cell responses. Deleterious inflammation and upregulation of co-inhibitory molecules expressed by monocytic lineage cells (e.g., dendritic cells) and their co-inhibitory receptors on T- and B-cells may lead to incomplete humoral and T-cell immunity, anergy, exhaustion, apoptosis, and subsequent immune subversion. Hence, the dysregulation of inflammatory and co-inhibitory molecules may be exploited by filoviruses to further deteriorate host immune responses, ultimately leading to fulminant infections in susceptible species. Thus, in light of accumulating scientific observations, the challenge is now to characterize the molecular mechanisms that may result in rational strategies leading to new therapeutics and vaccines.
Curr Mol Med 2009 Mar
PMID:Potential factors induced by filoviruses that lead to immune supression. 1927 25

Ten years after the first clinical application of Rituximab, an anti-CD20 recombinant monoclonal antibody, immunotherapy has become common practice in oncology wards. Thanks to the great diversity of the immune system and the powerful methodology of genetic engineering, the pharmacologic potential of antibody-based therapy is far from exhaustion. The recent application of Trastuzumab, an antibody to a receptor tyrosine kinase, in adjuvant breast cancer therapy marks the beginning of a new phase in cancer treatment. Here we discuss molecular mechanisms of antibody-based therapy, the emerging ability to target minimal disease and the therapeutic potential of combining antibodies with other modalities.
Mol Oncol 2007 Jun
PMID:Cancer therapeutic antibodies come of age: targeting minimal residual disease. 1938 86

The estrogen receptor ERalpha is emerging as a key molecule involved in glucose and lipid metabolism. The main functions of pancreatic beta-cells are the biosynthesis and release of insulin, the only hormone that can directly decrease blood glucose levels. Estrogen receptors ERalpha and ERbeta exist in beta-cells. The role of ERbeta is still unknown, yet ERalpha plays an important role in the regulation of insulin biosynthesis, insulin secretion and beta-cell survival. Activation of ERalpha by 17beta-estradiol (E2) and the environmental estrogen bisphenol-A (BPA) promotes an increase of insulin biosynthesis through a non-classical estrogen-activated pathway that involves phosphorylation of ERK1/2. The activation of ERalpha by physiological concentrations of E2 may play an important role in the adaptation of the endocrine pancreas to pregnancy. However, if ERalpha is over stimulated by an excess of E2 or the action of an environmental estrogen such as BPA, it will produce an excessive insulin signaling. This may provoke insulin resistance in the liver and muscle, as well as beta-cell exhaustion and therefore, it may contribute to the development of type II diabetes.
Mol Cell Endocrinol 2009 May 25
PMID:The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. 1943 49

Inflammation in patients defined as frail by Fried's phenotypic definition may be related to sarcopenia. This study aimed to investigate inflammation in older patients across different frailty criteria. Frailty status was determined in 110 patients aged over 75 years (mean 83.9 years) according to function (dependent, intermediate, independent); Fried (three or more items of exhaustion, weight loss, slow walking speed, low handgrip strength, low physical activity) and Frailty Index (a measure of accumulated deficits). With increasing patient frailty as defined by function and by Fried phenotype, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C-reactive protein (CRP) increased significantly. Albumin was lowest in the frailest subjects by each definition. The greatest differences were seen between intermediate and dependent groups and between the pre-frail and frail. Adjustment for multiple covariates (age, sex, BMI category, smoking status, number of co-morbidities and number of prescribed medications) did not account for any of the observed differences in levels of inflammatory markers. The Frailty Index correlated significantly with log-transformed CRP (r= 0.221, P < 0.05), log-transformed IL-6 (r= 0.369, P < 0.01), TNF-alpha (r= 0.379, P < 0.01) and inversely with albumin (r=- 0.545, P < 0.01). This study provides further evidence linking inflammation and frailty in older people, an association that seems consistent across different frailty measures.
J Cell Mol Med 2009 Sep
PMID:Inflammation and frailty measures in older people. 1943 6


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