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PubMed1997

Cellular metabolic homeostasis during large-scale change in ATP turnover rates in muscles.

The term homeostasis traditionally refers to the maintenance of a relatively constant internal milieu in the face of changing environmental conditions or changing physiological function. Tissues such as skeletal and cardiac muscles must sustain very large-scale changes in ATP turnover rate during equally large changes in work. In many skeletal muscles, these changes can exceed 100-fold. In unique biological circumstances (for example, during periods of oxygen limitation, vasoconstriction and hypometabolism), tissues such as skeletal muscles may be obliged to sustain further decreases in ATP turnover rates and operate for varying periods at seriously suppressed ATP turnover rates. Examination of a number of cellular and whole-organism systems identifies ATP concentration as a key parameter of the interior milieu that is nearly universally "homeostatic'; it is common to observe no change in ATP concentration even while the change in its turnover rate can increase or decrease by two orders of magnitude. A large number of other intermediates of cellular metabolism are also regulated within narrow concentration ranges, but none seemingly as precisely as is [ATP]. In fact, the only other metabolite in aerobic energy metabolism that is seemingly as "homeostatic' is oxygen-at least in working muscles. The central regulatory question is how such homeostasis of key intermediates in pathways of energy supply and energy demand is achieved.

Adenosine Triphosphate↗
PubMed2000

The molecular mechanisms of messenger RNA nuclear export.

In eukaryotic cells, the nuclear membrane creates a barrier between the nucleus and the cytoplasm. Whereas RNA synthesis occurs in the nucleus, they mostly function in the cytoplasm; thus export of RNA molecules from the nucleus to the cytoplasm is indispensable for normal function of the cells. The molecular mechanisms involved in each kind of cellular RNA export is gradually understood. The focus of this review will be mRNA export. mRNAs are multiformed. In order to ensure that this variety of mRNA molecules are all exported, cells are probably equipped with multiple export pathways. A number of proteins is predicted to be involved in mRNA export. Ascertaining which proteins play crucial roles in the pathways is the key point in the study of mRNA export.

Active Transport, Cell Nucleus↗
PubMed2002

Mechanisms of hyperammonemia.

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.

Amino Acids↗
PubMed2006

Bortezomib for multiple myeloma.

The ubquitin-proteasome pathway is a key regulator of homeostasis within cells, degrading misfolded or redundant proteins, and also those involved in mediating transcription, cell-cycle progression and apoptosis. Inhibition of the 26S proteasome results in accumulation of such proteins and ultimately leads to cell death. Malignant cells are more susceptible to proteasome inhibition due to their higher proliferation rates, protein production and their dependence on anti-apoptotic molecules for cell survival. Bortezomib has recently gained European Commission approval for the treatment of relapsed multiple myeloma on the basis of clinical trials demonstrating its efficacy, tolerability and superiority to high-dose dexamethasone. Preclinical data demonstrates the ability to synergise with other chemotherapeutic agents and overcome drug resistance, and hence combination studies are underway. This review describes the pharmacology, toxicity, preclinical and clinical activity of bortezomib, predominantly in the setting of multiple myeloma.

Animals↗
PubMed2004

Requirement for the RIIbeta isoform of PKA, but not calcium-stimulated adenylyl cyclase, in visual cortical plasticity.

The cAMP-dependent protein kinase (PKA) signaling pathway plays a key role in visual cortical plasticity. Inhibitors that block activation of all PKA regulatory subunits (RIalpha,RIbeta, RIIalpha, RIIbeta) abolish long-term potentiation (LTP) and long-term depression (LTD) in vitro and ocular dominance plasticity (ODP) in vivo. The details of this signaling cascade, however, including the source of PKA signals and which PKA subunits are involved, are unknown. To investigate these issues we have examined LTP, LTD, and ODP in knock-out mice lacking either the two cortically expressed Ca2+-stimulated adenylyl cyclases (AC1 and AC8) or the predominant neocortical subunit of PKA (RIIbeta). Here we show that plasticity remains intact in AC1/AC8-/- mice, whereas ODP and LTD, but not LTP, are absent in RIIbeta-/- mice. We conclude that (1) plasticity in the visual cortex does not require the activity of known Ca2+-stimulated adenylyl cyclases, (2) the PKA dependence of ODP and LTD, but not LTP, is mediated by RIIbeta-PKA, and (3) multiple isoforms of PKA contribute to LTD.

Adenylyl Cyclases↗
PubMed2005

Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of tau phosphorylation.

Alzheimer's disease is cytopathologically characterized by loss of synapses and neurons, neuritic amyloid plaques consisting of beta-amyloid (Abeta) peptides, and neurofibrillary tangles consisting of hyperphosphorylated tau protein in susceptible brain regions. Abeta, which triggers a cascade of pathogenic events including tau phosphorylation and neuronal excitotoxicity, is proteolytically derived from beta-amyloid precursor protein (APP); the pathological and physiological functions of APP, however, remain undefined. Here we demonstrate that the level of tau phosphorylation in cells and brains deficient in APP is significantly higher than that in wild-type controls, resulting from activation of cyclin-dependent kinase 5 (CDK5) but not glycogen synthase kinase 3, the two major tau kinases. In addition, we show that overexpression of APP or its non-amyloidogenic homolog amyloid precursor-like protein 1 suppresses both basal and stress-induced CDK5 activation. The ectodomain of APP, sAPPalpha, is responsible for inhibiting CDK5 activation. Furthermore, neurons derived from APP-deficient mice exhibit reduced metabolism and survival rates and are more susceptible to excitotoxic glutamate-induced apoptosis. These neurons also manifest significant defects in neurite outgrowth compared with neurons from the wild-type littermates. The observed neuronal excitotoxicity/apoptosis is mediated through a mechanism involving CDK5 activation. Our study defines a novel neuroprotective function for APP in preventing tau hyperphosphorylation via suppressing overactivation of CDK5. We suggest that CDK5 activation, through a calcium/calpain/p25 pathway, plays a key role in neuronal excitotoxicity and represents an underlying mechanism for the physiological functions of APP.

Amyloid beta-Protein Precursor↗
PubMed2006

Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration.

A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-5-188WH), a selective inhibitor of proinflammatory cytokine production by activated glia, suppressed the human amyloid-beta (Abeta) 1-42-induced upregulation of interleukin-1beta, tumor necrosis factor-alpha, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Abeta decreased the numbers of activated astrocytes and microglia and the cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain proinflammatory cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.

Administration, Oral↗
PubMed2001

The IGF system and breast cancer.

The IGF system components have been implicated in breast cancer progression. IGF-I and IGF-II are mitogenic and anti-apoptotic peptides that influence the proliferation of various cell types including normal and transformed breast epithelial cells. The IGF system is a key growth regulatory pathway in breast cancer. As various components of the IGF system have been directly or indirectly implicated in breast cancer, it is essential to gain a better understanding of these in order to develop more specific therapeutic strategies for treating breast cancer.

Breast Neoplasms↗
PubMed2025

Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San in a chronic unpredictable mild stress mouse model of depression.

OBJECTIVE: To reveal the antidepressant mechanisms of Jiawei DanZhiXiaoYaoSan (,JD) in chronic unpredictable mild stress (CUMS)-induced depression in mice. METHODS: Using the CUMS mouse model of depression, the antidepressant effects of JD were assessed using the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Tandem mass tag (TMT)-based quantitative proteomic analysis of the brain was performed following JD treatment. Hierarchical clustering, Gene Ontology function annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interactions (PPIs) were used to analyze differentially expressed proteins (DEPs), which were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: Behavioral tests confirmed the anti-depressant effects of JD, and bioinformatics analysis revealed 59 DEPs, including 33 up-regulated and 26 down-regulated proteins, between the CUMS and JD-M groups. KEGG and PPI analyses revealed that neuro-filament proteins and the Ras signaling pathway may be key targets of JD in the treatment of depression. qRT-PCR and Western blotting results demonstrated that CUMS reduced the protein expression of neurofilament light (NEFL) and medium (NEFM) and inhibited the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2), whereas JD promoted the phosphorylation of ERK1/2 and up-regulated the protein expression of NEFL and NEFM. CONCLUSIONS: The antidepressant mechanism of JD may be related to the up-regulation of p-ERK1/2 and neurofilament proteins.

Animals↗
PubMed2004

A benefit-risk assessment of basiliximab in renal transplantation.

Interleukin-2 (IL-2) and its receptor (IL-2R) play a central role in T lymphocyte activation and immune response after transplantation. Research on the biology of IL-2R allowed the identification of key signal transduction pathways involved in the generation of proliferative and antiapoptotic signals in T cells. The alpha-chain of the IL-2R is a specific peptide against which monoclonal antibodies have been raised, with the aim of blunting the immune response by means of inhibiting proliferation and inducing apoptosis in primed lymphocytes. Indeed, basiliximab, one of such antibodies, has proved to be effective in reducing the episodes of acute rejection after kidney and pancreas transplantation. The use of basiliximab was associated with a significant reduction in the incidence of any treated rejection episodes after kidney transplantation in the two major randomised studies (placebo 52.2% vs basiliximab 34.2% at 6 months, European study; placebo 54.9% vs basiliximab 37.6% at 1 year, US trial). Basiliximab and equine antithymocyte globulin (ATG) administration resulted in a similar rate of biopsy-proven acute rejection at 6 months (19% for both) and at 12 months (19% and 20%, respectively). The use of basiliximab appears not to be associated with an increased incidence of adverse events as compared with placebo in immunosuppressive regimens, including calcineurin inhibitors, mycophenolate mofetil or azathioprine and corticosteroids, and its safety profile is superior to ATG. Moreover, a similar occurrence of infections is noted in selected studies (65.5% after basiliximab vs 65.7% of controls), including cytomegalovirus infection (17.3% vs 14.5%), and cytokine-release syndrome is not observed. Finally, economic analysis demonstrated lower costs of overall treatment in patients treated with basiliximab. Therefore, the use of basiliximab entails a very low risk, allows safe reduction of corticosteroid dosage and reduces the short- and mid-term rejection rates. However, the improvement in the long-term survival of kidney grafts in patients treated according to modern immunosuppressive protocols is still to be demonstrated. These conclusions are based on a systematic review of the scientific literature, indexed on Medline database, concerning the mechanism of action, therapeutic activity, safety and pharmacoeconomic evaluation of basiliximab in renal transplantation.

Antibodies, Monoclonal↗
PubMed2004

B cell responses to oxidative stress.

B-lymphocytes are exposed to a reduction/oxidation environment during activation or inflammatory process, and the antioxidant systems are functional to protect themselves against harmful reactive oxygen species (ROS). The crucial roles of thioredoxin-2 (Trx-2) and a DNA repair enzyme APE/Ref-1 in mitochondria are reported in B-lymphocytes. Furthermore, ROS stimulate different signaling pathways in many cellular responses. Their effects often cause some diseases or are utilized for the treatment of other diseases. For example, the cells derived from Fanconi anemia (FA) patients are intolerant of oxidative stress and the therapeutic effect of anti-CD20 monoclonal antibody rituximab on B cell lymphoproliferative disorders is due to the generation of ROS. To clarify the oxidative stress-induced signaling pathways, we stimulated a B cell line with various concentrations of H(2)O(2). As a result, a protein tyrosine kinase, Syk was involved in the induction of G2/M arrest and protection of cells from apoptosis. Syk might inhibit the activation of caspase-9 through Akt thereby protecting cells from oxidative stress-induced apoptosis. On the other hand, Syk-dependent PLC-gamma2 activation was required for acceleration towards apoptosis following oxidative stress. These findings suggest that oxidative stress-induced Syk activation triggers the activation of different pathways, such as pro-apoptotic or survival pathways, and that the balance of these pathways is a key factor in determining the fate of the cells exposed to oxidative stress. In contrast, the stimulation with the millimolar concentrations of H(2)O(2) rapidly led to necrosis in which tyrosine phosphorylation of FAK was involved at the downstream of Lyn and Syk.

Antibodies, Monoclonal↗
PubMed2004

Metabonomics: its potential as a tool in toxicology for safety assessment and data integration.

The functional genomic techniques of transcriptomics and proteomics promise unparalleled global information during the drug development process. However, if these technologies are used in isolation the large multivariate data sets produced are often difficult to interpret, and have the potential of missing key metabolic events (e.g. as a result of experimental noise in the system). To better understand the significance of these megavariate data the temporal changes in phenotype must be described. High resolution 1H NMR spectroscopy used in conjunction with pattern recognition provides one such tool for defining the dynamic phenotype of a cell, organ or organism in terms of a metabolic phenotype. In this review the benefits of this metabonomics/metabolomics approach to problems in toxicology will be discussed. One of the major benefits of this approach is its high throughput nature and cost effectiveness on a per sample basis. Using such a method the consortium for metabonomic toxicology (COMET) are currently investigating approximately 150 model liver and kidney toxins. This investigation will allow the generation of expert systems where liver and kidney toxicity can be predicted for model drug compounds, providing a new research tool in the field of drug metabolism. The review will also include how metabonomics may be used to investigate co-responses with transcripts and proteins involved in metabolism and stress responses, such as during drug induced fatty liver disease. By using data integration to combine metabolite analysis and gene expression profiling key perturbed metabolic pathways can be identified and used as a tool to investigate drug function.

Animals↗
PubMed2006

Molecular symmetry: a structural property frequently present in new cytotoxic and proapoptotic drugs.

In recent years, a large number of new potent symmetrical cytotoxic agents that act through different mechanisms have been described. Apoptosis induction is one of the most representative of these mechanisms. Recent articles have revealed that the activation of apoptosis pathways is the key mechanism by which cytotoxic tumor cells are killed. The present review highlights the importance of the molecular symmetry of several chemical structures and their relation with cytotoxic and apoptotic activity.

Antineoplastic Agents↗
PubMed2002

Metabonomic applications in toxicity screening and disease diagnosis.

Biofluid NMR spectroscopy is a powerful tool providing a comprehensive metabolic profile of the low molecular weight components in biofluids that reflect concentrations and fluxes of endogenous metabolites involved in key intermediary cellular pathways, thereby giving an indication of an organisms physiological or pathophysiological status [1]. The interaction of pharmacological agents with cells and tissues can also be monitored using recently developed high resolution magic-angle spinning (HRMAS) NMR spectroscopic technology for biological matrices [1]. However, recent developments in both spectrometer and software technology has resulted in improved capacity for sample handling, leading to a rapid growth in the size of toxicological spectral databases, and increased the complexity of the biological spectral data generated. Thus more emphasis has been placed on the need to develop improved automated procedures for data processing and interpretation. By harnessing chemometric tools for analysis of complex spectral data, the toxicological consequences of xenobiotic exposure can be evaluated efficiently on line. Automation of spectral processing procedures and the construction of mathematically based 'expert systems' for the prediction of drug-induced toxicity founded on IH NMR spectral profiles have now been achieved. Chemometric analysis of biological NMR spectra has provided the main analytical platform for metabonomic analysis, providing a systems approach to evaluating pathophysiological or genetic influences on the metabolic status of an organism [1]. This technology is currently being given high-priority in the pharmaceutical industry with respect to development of efficient high throughput toxicity screening systems for lead candidate selection. In this article, we review the recent developments in metabonomics and consider their application in toxicological screening, disease diagnosis and functional genomics.

Animals↗
PubMed2006

Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia.

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.

Allosteric Regulation↗
PubMed2005

Oxidative-nitrosative stress as a contributing factor to cardiovascular disease in subjects with diabetes.

In diabetes, clear evidence has emerged for the presence of oxidative-nitrosative stress, which may be a consequence of a glucose-mediated imbalance of systemic antioxidant buffering capacity, coupled with increased production of free radical species. Although multiple metabolic pathways have been identified, which may contribute to oxidative stress in diabetes, the principal pathogenetic pathways and their key down-stream targets remain to be established. Evidence links oxidative stress in particular, to elevations of postprandial glucose and lipids, which also have recently emerged as major risk factors for cardiovascular events. Indeed, considerable evidence suggests that increased oxidative stress in diabetes may play an important role in the development or progression of cardiovascular disease by a number of different mechanisms, including alterations of cardiovascular sympathetic nervous system tone and integrity, elevation of acute phase reactants, disruption of endothelial function and facilitation of myocardial injury. Despite the disappointments of recent large scale clinical trials evaluating the efficacy of antioxidants in cardiovascular disease, many therapeutic agents which have been used successfully in diabetic subjects at high risk for cardiovascular disease have a mechanism of action which includes an antioxidant capacity. Therefore, incorporating an antioxidant action in future therapeutic approaches to combat cardiovascular disease complicating diabetes, appears to remain justified and warrants further evaluation.

Animals↗
PubMed2005

Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists?

There is increasing evidence to suggest that chronic activation of the endothelin-1 system can lead to heterologous desensitization of the glucose-regulatory and mitogenic actions of insulin with subsequent development of glucose intolerance, hyperinsulinemia, impaired endothelial function and exacerbation of cardiovascular disease. Effects are mediated through a variety of mechanisms that include attenuation of key insulin signalling pathways and decreased tyrosine phosphorylation of insulin receptor substrates IRS-1, SHC and G alpha q/11. Other actions involve hemodynamic changes leading to reduced delivery of insulin and glucose to peripheral tissues as well as enhanced hepatic glycogenolysis, decreased glucose-transporter translocation and modulation of various adipokines that regulate insulin action. Overall the data suggest that ET-1 antagonists may provide an effective means of improving cardiac dysfunction and favourably influencing glucose tolerance in obese humans and patients with early insulin sensitivity where there is clear evidence for activation of the ET-1 system. Although most effects of ET-1 that modulate mechanisms leading to glucose intolerance appear to involve the ETA receptor subtype recent data indicates that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. Prospective trials are needed to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional therapies such as insulin sensitizers and to evaluate effects of combined treatments on the development of insulin resistance and the progression of diabetes. Early screening of patients at risk for evidence of ET-1 activation would help to identify subjects who may benefit most from such treatment.

Animals↗
PubMed2003

Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?

In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-kappaB, p38 mitogen-activated protein kinase, NH(2)-terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.

Animals↗