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PubMed2025

Distinct spatial transcriptomic patterns of substantia Nigra in Parkinson disease and Parkinsonian subtype of multiple system atrophy.

To investigate transcriptomic signatures of Parkinson's disease (PD) and the Parkinsonian subtype of Multiple System Atrophy (MSA-P) in substantia nigra pars compacta (SNpc), we conducted transcriptome analysis using in-situ hybridization on paraffin-embedded SNpc tissues from post-mortem brains. The study included 2 MSA-P patients, 2 PD patients, and 2 healthy controls (HC), with 12 regions of interest (ROIs) selected from the dorsal to ventral and medial to lateral aspects of the SNpc. A total of 72 ROIs from 6 participants were analyzed, and differentially expressed genes (DEGs) were identified by comparing MSA-P, PD and HC groups. The MSA-P group showed 88 upregulated DEGs and 326 downregulated DEGs (adjusted 𝑝<0.05) compared to HC. The downregulated DEGs were significantly enriched in pathways related to ribosomal translation, immune processes, mitochondrial function, and autophagy. Notably, the dorsomedial quadrant was uniquely linked to antigen presentation, while other quadrants showed downregulation of protein synthesis. The PD group exhibited 165 upregulated DEGs and 350 downregulated DEGs (adjusted 𝑝<0.05) compared to HC, with downregulated DEGs associated with ribosomal translation, mitochondrial function, and the ubiquitin-proteasome system. In both MSA-P and PD, the upregulated DEGs were not associated with any pathways or biological process in gene enrichment analysis. In network propagation analysis, amyloid precursor protein was the most significant network hub among DEGs in both MSA-P and PD. Comparing the transcriptomic signatures of SNpc between MSA-P and PD, we found immune/inflammation, mitochondrial function and neural signaling related genes were significantly downregulated in MSA-P compared to PD. Overall, the transcriptomic signature of the SNpc in MSA-P and PD revealed overlapping but distinct features, including alterations in protein synthesis, immune processes, mitochondrial function, and protein degradation systems. Future studies with larger cohorts and functional validation are needed to further elucidate these findings.

Humans↗

PubMed2004

Research methodology: cancer cachexia syndrome.

Cachexia is a syndrome and therefore does not have a specific definition. Patients are characterized by the presence of anorexia, early satiety, weight loss, weakness, anaemia and oedema. These features occur to a variable extent in different patients and may change in severity during the course of a patient's illness. The multifactorial origin of cachexia precludes a uniform pathophysiological definition. Taken together these factors have hindered clinical studies both at a fundamental level and in terms of the introduction of effective therapy. The advent of novel therapeutic targets (e.g., ubiquitin-proteasome pathway) and biological response modifiers has opened possibilities for new clinical trials in cachexia. Regulatory authorities feel it is important not only to demonstrate efficacy in terms of patients' nutritional status (e.g., lean body mass) but also functional status (e.g., performance status). This article reviews current methods to assess the latter. Methods focused on measuring physical activity level (e.g., doubly labelled water technique or physical activity meters) promise objective data which can be readily interpreted in terms of clinically meaningful benefit.

Ambulatory Care↗

PubMed2006

Toxicoproteomics in liver injury and inflammation.

Toxicoproteomics, in applying proteomics to toxicology, seeks to identify critical proteins and pathways in biological systems responding to adverse chemical exposures and environmental stressors using global protein expression technologies. Toxicoproteomics is being exploited for the discovery of new biomarkers and toxicity signatures in target organs, such as liver, in major biological processes, such as inflammation, in mapping serum, plasma, and other biofluid proteomes, and in parallel proteomic and transcriptomic studies. The new field of toxicoproteomics is uniquely positioned toward discovery of new biomarkers and signatures of tissue injury and a better understanding of protein expression responses during toxicity and environmental disease.

Chemical and Drug Induced Liver Injury↗

PubMed2003

Lentivirus-delivered stable gene silencing by RNAi in primary cells.

Genome-wide genetic approaches have proven useful for examining pathways of biological significance in model organisms such as Saccharomyces cerevisiae, Drosophila melanogastor, and Caenorhabditis elegans, but similar techniques have proven difficult to apply to mammalian systems. Although manipulation of the murine genome has led to identification of genes and their function, this approach is laborious, expensive, and often leads to lethal phenotypes. RNA interference (RNAi) is an evolutionarily conserved process of gene silencing that has become a powerful tool for investigating gene function by reverse genetics. Here we describe the delivery of cassettes expressing hairpin RNA targeting green fluorescent protein (GFP) using Moloney leukemia virus-based and lentivirus-based retroviral vectors. Both transformed cell lines and primary dendritic cells, normally refractory to transfection-based gene transfer, demonstrated stable silencing of targeted genes, including the tumor suppressor gene TP53 in normal human fibroblasts. This report demonstrates that both Moloney leukemia virus and lentivirus vector-mediated expression of RNAi can achieve effective, stable gene silencing in diverse biological systems and will assist in elucidating gene functions in numerous cell types including primary cells.

Dendritic Cells↗

PubMed2000

A time-series analysis of acidic particulate matter and daily mortality and morbidity in the Buffalo, New York, region.

A component of particulate matter (PM) air pollution that may provide one biologically plausible pathway for the observed PM air pollution-health effect associations is aerosol acidity (H(+)). An increasing number of observational studies have demonstrated associations between H(+) and increased adverse health effects in the United States and abroad. Although studies have shown significant H(+) associations with increased morbidity in the United States, similar associations have yet to be shown with daily mortality. We considered a 2.5-year record of daily H(+) and sulfate measurements (May 1988-October 1990) collected in the Buffalo, New York, region in a time-series analysis of respiratory, circulatory, and total daily mortality and hospital admissions. Other copollutants considered included particulate matter [less than/equal to] 10 microm in aerodynamic diameter, coefficient of haze, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide. Various modeling techniques were applied to control for confounding of effect estimates due to seasonality, weather, and day-of-week effects. We found multiple significant pollutant-health effect associations--most strongly between SO(4)(2-) and respiratory hospital admissions (as indicated by its t-statistic). Additionally, H(+) and SO(4)(2-) demonstrated the most coherent associations with both respiratory hospital admissions [H(+): relative risk (RR) = 1. 31; 95% confidence interval (CI), 1.14-1.51; and SO(4)(2-): RR = 1. 18, CI, 1.09-1.28] and respiratory mortality (H(+): RR = 1.55, CI, 1. 09-2.20; and SO(4)(2-): RR = 1.24, CI, 1.01-1.52). Thus, acidic sulfate aerosols represent a component of PM air pollution that may contribute to the previously noted adverse effects of PM mass on human health, and the associations demonstrated in this study support the need for further investigations into the potential health effects of acidic aerosols.

Acids↗

PubMed2003

ArrayTrack--supporting toxicogenomic research at the U.S. Food and Drug Administration National Center for Toxicological Research.

The mapping of the human genome and the determination of corresponding gene functions, pathways, and biological mechanisms are driving the emergence of the new research fields of toxicogenomics and systems toxicology. Many technological advances such as microarrays are enabling this paradigm shift that indicates an unprecedented advancement in the methods of understanding the expression of toxicity at the molecular level. At the National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration, core facilities for genomic, proteomic, and metabonomic technologies have been established that use standardized experimental procedures to support centerwide toxicogenomic research. Collectively, these facilities are continuously producing an unprecedented volume of data. NCTR plans to develop a toxicoinformatics integrated system (TIS) for the purpose of fully integrating genomic, proteomic, and metabonomic data with the data in public repositories as well as conventional (Italic)in vitro(/Italic) and (Italic)in vivo(/Italic) toxicology data. The TIS will enable data curation in accordance with standard ontology and provide or interface a rich collection of tools for data analysis and knowledge mining. In this article the design, practical issues, and functions of the TIS are discussed through presenting its prototype version, ArrayTrack, for the management and analysis of DNA microarray data. ArrayTrack is logically constructed of three linked components: a) a library (LIB) that mirrors critical data in public databases; b) a database (MicroarrayDB) that stores microarray experiment information that is Minimal Information About a Microarray Experiment (MIAME) compliant; and c) tools (TOOL) that operate on experimental and public data for knowledge discovery. Using ArrayTrack, we can select an analysis method from the TOOL and apply the method to selected microarray data stored in the MicroarrayDB; the analysis results can be linked directly to gene information in the LIB.

Databases, Factual↗

PubMed2004

Cellular and genetic analysis of wound healing in Drosophila larvae.

To establish a genetic system to study postembryonic wound healing, we characterized epidermal wound healing in Drosophila larvae. Following puncture wounding, larvae begin to bleed but within an hour a plug forms in the wound gap. Over the next couple of hours the outer part of the plug melanizes to form a scab, and epidermal cells surrounding the plug orient toward it and then fuse to form a syncytium. Subsequently, more-peripheral cells orient toward and fuse with the central syncytium. During this time, the Jun N-terminal kinase (JNK) pathway is activated in a gradient emanating out from the wound, and the epidermal cells spread along or through the wound plug to reestablish a continuous epithelium and its basal lamina and apical cuticle lining. Inactivation of the JNK pathway inhibits epidermal spreading and reepithelialization but does not affect scab formation or other wound healing responses. Conversely, mutations that block scab formation, and a scabless wounding procedure, provide evidence that the scab stabilizes the wound site but is not required to initiate other wound responses. However, in the absence of a scab, the JNK pathway is hyperinduced, reepithelialization initiates but is not always completed, and a chronic wound ensues. The results demonstrate that the cellular responses of wound healing are under separate genetic control, and that the responses are coordinated by multiple signals emanating from the wound site, including a negative feedback signal between scab formation and the JNK pathway. Cell biological and molecular parallels to vertebrate wound healing lead us to speculate that wound healing is an ancient response that has diversified during evolution.

Alleles↗

PubMed2003

MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons.

We describe the discovery of a novel, 20 kDa, secreted human protein named mesencephalic astrocyte-derived neurotrophic factor, or MANF. The homologous, native molecule was initially derived from a rat mesencephalic type-1 astrocyte cell line and recombinant MANF subcloned from a cDNA encoding human arginine-rich protein. MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. The discovery of MANF marks a more systematic approach in the search for astrocyte-derived, secreted proteins that selectively protect specific neuronal phenotypes. Compared to glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), MANF was more selective in the protection of dopaminergic neurons at lower (0.05-0.25 ng/mL) and middle (0.5-2.5 ng/mL) concentrations: MANF>GDNF>BDNF. GDNF was more selective at higher concentrations (25-50 ng/ml): GDNF>MANF>BDNF. Two domains in MANF of 39-AA and 109-AA respectively, and eight cysteines are conserved from C. elegans to man. MANF is encoded by a 4.3 Kb gene with 4 exons, and is located on the short arm of human chromosome 3. The secondary structure is dominated by alpha-helices (47%) and random coils (37%). Studies to determine the localization of MANF in the brains of rat, monkey, and man, as well as the receptor, signaling pathways, and biologically active peptide mimetics are in progress. The selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson's disease.

Amino Acid Sequence↗

PubMed2004

Vascular endothelial growth factor and other signaling pathways in developmental and pathologic angiogenesis.

The field of angiogenesis received a huge boost in 2003 with the announcement of positive results in a phase III clinical trial using a vascular endothelial growth factor (VEGF)-blocking antibody for the treatment of cancer. Although the VEGF pathway has emerged as a central signaling pathway in normal and pathologic angiogenesis, several other pathways are also now recognized as playing essential roles. This review focuses on 2 specific areas. First, we summarize some of the work on newly discovered angiogenic signaling pathways by primarily describing the molecular biology of the pathways and the evidence for their involvement in vascular development. Second, we describe progress in therapeutic antiangiogenesis in cancer, particularly with agents that block the VEGF pathway.

Animals↗

PubMed2006

[Association between dietary carbohydrates and type 2 diabetes mellitus: epidemiological evidence].

The prevalence of type 2 diabetes has been escalating throughout the world and usual food consumption is regarded as one of the most important environmental determinants for chronic diseases. Thus, the role of type and quality of carbohydrates on the etiology of type 2 diabetes is still poorly understood. The present review discusses the available epidemiological evidence regarding the effect of the type and source of carbohydrate of the usual diet and the risk of type 2 diabetes in adults. Although epidemiological investigations support the hypothesis for a potential risk effect of high glycemic index and low fiber content diets for diabetes, the results are controversial and the benefit may be related to the magnesium content of the structure of the grains, suggesting the relevance of taking into account the food sources instead of nutrients on investigations of diet and risk of chronic diseases. The available evidence suggests that eating a diet rich in whole grain cereals and vegetables and low in refined grains, sucrose and fructose contents is beneficial in the prevention of diabetes. Thus, more clinical trials are required to support the associations and establish biologically plausible pathways.

Adult↗

PubMed2006

Up-regulation of bone morphogenetic proteins in cultured murine bone cells with use of specific electric fields.

BACKGROUND: Capacitively coupled electric stimulation has been successfully used in the treatment of bone nonunions and to effect spinal fusions. However, the pathway of biologic events whereby this is accomplished has not been fully elucidated. To determine whether bone morphogenetic proteins (BMPs) could be involved, the effect of electrical stimulation on BMP gene expression was investigated. METHODS: Postconfluent cultures of MC3T3-E1 bone cells were exposed to a series of capacitively coupled signals in which the duration, amplitude, frequency, and duty cycle were sequentially and systematically varied. The cellular response was measured by quantifying the mRNA levels of BMP-2 through BMP-8, as well as the BMP antagonists gremlin and noggin, with use of reverse transcription followed by real-time quantitative polymerase chain reaction. BMP-2 protein was measured by enzyme-linked immunosorbent assay, and alkaline phosphatase activity was measured by a specific colorimetric assay. RESULTS: The results showed that BMP-2 through BMP-8, gremlin, and noggin were all normally expressed by MC3T3-E1 cells, and could be significantly up-regulated by specific and selective capacitively coupled electric fields (p < 0.05). However, mRNA expression for BMP-2, 4, 5, 6, and 7 was consistently up-regulated several times higher than that for BMP-3 and BMP-8, gremlin, and noggin under identical conditions. Concomitantly, BMP-2 protein production and alkaline phosphatase activity were both significantly increased in the same electrically stimulated cultures (p = 0.001 and p < 0.01, respectively). CONCLUSIONS: These data clearly show that our optimal capacitively coupled signal (60 kHz, 20 mV/cm at a 50% duty cycle for twenty-four hours) can specifically, selectively, and simultaneously up-regulate the expression of a number of osteoinductive BMPs; other BMPs and antagonists are only moderately affected.

3T3 Cells↗

PubMed2001

Innovative biomechanics for directional hearing in small flies.

In humans and animals alike, the localization of sound constitutes a fundamental processing task of the auditory system. Directional hearing relies on acoustic cues such as the interaural amplitude and time differences and also, sometimes, the signal spectral composition. In small animals, such as insects, the auditory receptors are forcibly set close together, a design constraint imposing very short interaural distances. Due to the physics of sound propagation, the close proximity of the sound receivers results in vanishingly small amplitude and time cues. Yet, because of their directionality, small auditory systems embed original and innovative solutions that can be of inspirational value to some acute problems of technological miniaturization. Such ears are found in a parasitoid fly that acoustically locates its singing cricket host. Anatomically rather unconventional, the fly's auditory system is endowed with a directional sensitivity that is based on the mechanical coupling between its two hemilateral tympanal membranes. The functional principle permitting this directionality may be of particular relevance for technological applications necessitating sensors that are low cost, low weight, and low energy. Based on silicon-etching technology, early prototypes of sub-millimeter acoustic sensors provide evidence for directional mechanical responses. Further developments hold the promise of applications in hearing aid technology, vibration sensors, and miniature video-acoustic surveillance systems.

Animals↗

PubMed1989

Ultradian rhythms in cerebral laterality tested by a verbal dichotic listening paradigm.

Dichotic listening (DL) performance of normal (healthy) adults was tested every 15 minutes continuously during 8-12 hours of daytime. The dichotic material consisted of 8 blocks, each containing 40 pairs of monosyllabic, concrete nouns in German. The subjects heard one block per each 15-min trial. DL performances determined by the number of correct free recalls gave no evidence for periodic variations, neither of right nor of left-ear performance. However, when determined by the number of first, but correctly recalled nouns DL performance showed distinct periodicities of about 3-4 hours at least in some subjects. Such periodicities were obvious in both right and left-ear DL performance and oscillated in counter-phase. This suggests that competitive processing of dichotic verbal stimuli mediated by the cerebral hemispheres could be modulated by an endogenous oscillatory system. Some subjects slept in the laboratory after they had performed in a long-term dichotic listening task. Since sleep stage was scored by means of electroencephalographic recordings phase relationships between ultradian cycles of DL performance and the sleep cycle could be analyzed. These findings suggest that sleep cycle of about 1 1/2-2 hours and the 3-4 hour periodicities of DL performance are organized in an approximately 1:2 period ratio of an intrinsic multi-oscillatory system.

Auditory Pathways↗

PubMed1999

Truncated isoforms inhibit [3H]prazosin binding and cellular trafficking of native human alpha1A-adrenoceptors.

We have identified from human liver eight alpha(1A)-adrenoceptor (alpha(1A)-AR) splice variants that were also expressed in human heart, prostate and hippocampus. Three of these alpha(1A)-AR isoforms (alpha(1A-1)-AR, alpha(1A-2a)-AR and alpha(1A-3a)-AR) gave rise to receptors with seven transmembrane domains (7TMalpha(1A)-AR). The other five (alpha(1A-2b)-AR, alpha(1A-2c)-AR, alpha(1A-3c)-AR, alpha(1A-5)-AR and alpha(1A-6)-AR) led to truncated receptors lacking transmembrane domain VII (6TMalpha(1A)-AR). The 7TMalpha(1A)-AR isoforms transiently expressed in COS-7 cells bound [(3)H]prazosin with high affinity (K(d) 0.2 nM) and mediated a noradrenaline (norepinephrine)-induced increase in cytoplasmic free Ca(2+) concentration, whereas the 6TMalpha(1A)-AR isoforms were incapable of ligand binding and signal transduction. Immunocytochemical studies with N-terminal epitope-tagged alpha(1A)-AR isoforms showed that the 7TMalpha(1A)-AR isoforms were present both at the cell surface and in intracellular compartments, whereas the 6TMalpha(1A)-AR isoforms were exclusively localized within the cell. Interestingly, in co-transfected cells, each truncated alpha(1A)-AR isoform inhibited [(3)H]prazosin binding and cell-surface trafficking of the co-expressed 'original' 7TMalpha(1A-1)-AR. However, there was no modification of either the [(3)H]prazosin-binding affinity or the pharmacological properties of alpha(1A-1)-AR. Immunoblotting experiments revealed that co-expression of the alpha(1A-1)-AR with 6TMalpha(1A)-AR isoforms did not impair alpha(1A-1)-AR expression. Therefore the expression in human tissues of many truncated isoforms constitutes a new regulation pathway of biological properties of alpha(1A)-AR.

Amino Acid Sequence↗

PubMed2000

Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation.

Internalization and transport of a ligand-receptor complex are required to initiate cell body responses to target-derived neurotrophin. However, it is not known whether internalized receptors and cell surface receptors initiate the same signaling pathways and biological responses. Here we use a temperature-sensitive mutant of dynamin (G273D) to control the subcellular localization of activated NGF receptors (Trks). We show that dynamin function is required for ligand-dependent endocytosis of Trk receptors. In PC12 cells, nerve growth factor (NGF) stimulation promotes both survival and neuronal differentiation. These distinct biological responses to NGF are controlled by receptors signaling from different locations within the cell. Neuronal differentiation is promoted by catalytically active Trks within endosomes in the cell interior. In contrast, survival responses are initiated by activated receptors at the cell surface where they orchestrate prolonged activation of the kinase Akt. Thus, interactions between Trk receptor tyrosine kinases and intracellular signaling molecules are dictated both by phosphotyrosine motifs within the receptors and by the intracellular location of phosphorylated receptors.

Amino Acid Sequence↗

PubMed2000

Stimulus-based state control in the thalamocortical system.

Neural systems operate in various dynamic states that determine how they process information (Livingstone and Hubel, 1981; Funke and Eysel, 1992; Morrow and Casey, 1992; Abeles et al., 1995; Guido et al., 1995; Mukherjee and Kaplan, 1995; Kenmochi and Eggermont, 1997; Wörgötter et al., 1998; Kisley and Gerstein, 1999). To investigate the function of a brain area, it is therefore crucial to determine the state of that system. One grave difficulty is that even under well controlled conditions, the thalamocortical network may undergo random dynamic state fluctuations which alter the most basic spatial and temporal response properties of the neurons. These uncontrolled state changes hinder the evaluation of state-specific properties of neural processing and, consequently, the interpretation of thalamocortical function. Simultaneous extracellular recordings were made in the auditory thalamus and cortex of the ketamine-anesthetized cat under several stimulus conditions. By considering the cellular and network mechanisms that govern state changes, we develop a complex stimulus that controls the dynamic state of the thalamocortical network. Traditional auditory stimuli have ambivalent effects on thalamocortical state, sometimes eliciting an oscillatory state prevalent in sleeping animals and other times suppressing it. By contrast, our complex stimulus clamps the network in a dynamic state resembling that observed in the alert animal. It thus allows evaluation of neural information processing not confounded by uncontrolled variations. Stimulus-based state control illustrates a general and direct mechanism whereby the functional modes of the brain are influenced by structural features of the external world.

Acoustic Stimulation↗

PubMed2001

The CD40-CD40 ligand system: a potential therapeutic target in atherosclerosis.

Atherosclerosis is a leading cause of cardiovascular disease in the westernized world. This review highlights emerging evidence linking atherosclerosis to the CD40-CD40 ligand (CD154) pathway. Recently, atherosclerosis has been associated with chronic inflammation, linking it to the immune system. This novel viewpoint may serve as an additional target for therapeutic intervention. CD40 and CD154 are highly expressed in atherosclerotic human plaques. Recent data from preclinical animal models of atherosclerosis show that disruption of the CD40-CD154 pathway can prevent atherosclerotic progression and may reverse established lesions. Blockade of the CD40-CD154 pathway by biologicals or small molecules may prove valuable in the treatment of atherosclerosis.

Animals↗

PubMed2001

A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4.

Irinotecan (CPT-11) is an anticancer prodrug. It is converted by carboxylesterase to yield an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which acts as a topoisomerase I inhibitor. Several oxidative metabolites of CPT-11 have been identified in humans, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin (NPC), generated by cytochrome P-450 3A4 (CYP3A4). Other minor metabolites in which metabolic pathways and biologic activities have not been identified also exist. To further investigate the metabolism of CPT-11 in human liver, we analyzed metabolites of CPT-11 in human hepatic microsomes using a high-performance liquid chromatography/mass spectrometry (HPLC/MS) system and detected a new metabolite that was the major one produced in the microsomal system. HPLC-tandem mass spectrometry (HPLC/MS/MS) analysis indicated that this compound was an oxidation product formed by the loss of two hydrogen atoms from the terminal piperidine ring. Kinetic analyses indicated that a single enzyme generated the metabolite, and we have identified this enzyme in two in vitro systems. The formation of the new metabolite was significantly inhibited by SKF525A, ketoconazole, and an anti-CYP3A4 antibody and catalyzed specifically by CYP3A4 expressed in insect microsomes. A significant correlation was observed between the generation of this metabolite and the CYP3A4 content in individual human hepatic microsomes. These findings indicate that this newly detected metabolite is a CYP3A4-generated product that may be produced in hepatic microsomes of patients treated with CPT-11.

Animals↗