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PubMed2006

Preservation of mitochondrial structure and function after cardioplegic arrest in the neonate using a selective mitochondrial KATP channel opener.

BACKGROUND: Mitochondrial dysfunction may contribute to early postoperative neonatal heart dysfunction. Diazoxide, a mitochondrial-selective adenosine triphosphate-sensitive potassium-channel opener, is associated with mitochondrial preservation after cardioplegic arrest. We evaluated the mitochondrial-protective effect of diazoxide in terms of mitochondrial structure and function after neonatal cardioplegic arrest. METHODS: Newborn piglets (age, approximately 14 days) underwent cardiopulmonary bypass and 60 minutes of cardioplegic arrest using cold crystalloid cardioplegic solution (CCP, n = 5) or cold crystalloid cardioplegic solution with diazoxide (CCP+D, n = 5). After 6 hours of recovery, myocardium was harvested. Control myocardium from piglets that did not undergo cardiopulmonary bypass (non-CPB, n = 5) was obtained. RESULTS: Cardioplegic arrest was associated with translocation of Bax to the mitochondria, which was not prevented by diazoxide. Nevertheless, by electron microscopy, CCP-associated remodeling of mitochondrial structure was subjectively diminished in CCP+D hearts. In addition, CCP-associated mitochondrial permeabilization and cytochrome c release into the cytosol were prevented with CCP+D (p < 0.05). In vitro oxygen consumption of isolated mitochondria demonstrated deficient function of mitochondrial complex I in CCP, but it was preserved in the CCP+D myocardial mitochondria (p < 0.05). Complex II and IV activity was not different among groups. In parallel with impaired complex I function, the cardiac adenosine triphosphate content was diminished in CCP hearts, but well maintained in CCP+D hearts (p < 0.05). CONCLUSIONS: Although early apoptotic signaling events (Bax translocation) are not prevented by diazoxide, addition of the mitochondrial-selective adenosine triphosphate-sensitive potassium-channel opener to the cardioplegic solution is associated with protection of mitochondrial structural and functional integrity in a clinically relevant model of neonatal cardiac surgery. The mitochondrial-protective effects of diazoxide may contribute to improved postoperative myocardial function in the neonate.

Adenosine Triphosphate↗

PubMed2006

Phospholipid requirement and pH optimum for the in vitro enzymatic activity of the E. coli P-type ATPase ZntA.

Detergent solubilization and purification of the E. coli heavy metal P-type ATPase ZntA yields an enzyme with reduced hydrolytic activity in vitro. Here, it is shown that the in vitro hydrolytic activity of detergent solubilized ZntA is increased in the presence of negatively charged phospholipids and at slightly acidic pH. The protein-lipid interaction of ZntA was characterized by enzyme-coupled ATPase assays and fluorescence spectroscopy. Among the most abundant naturally occurring phospholipids, only phosphatidyl-glycerol lipids (PG) enhance the in vitro enzymatic ATPase activity of ZntA. Re-lipidation of detergent purified ZntA with 1,2-dioleoylphosphatidyl-glycerol (DOPG) increases the ATPase activity four-fold compared to the purified state. All other E. coli phospholipids fail to activate the ATPase. Among the phosphatidyl-glycerol family, highest activity was observed for 1,2-dioleoyl-PG followed by 1,2-dimyristoyl-PG, 1,2-dipalmitoyl-PG and 1,2-distearoyl-PG. Increasing intrinsic Trp fluorescence quantum yield upon relipidation of ZntA was used to determine a pH maximum for lipid binding at pH 6.7. The pH dependence of the lipid binding was confirmed by pH-dependent ATPase assays showing maximum activity at pH 6.7. The biophysical characterization of detergent solubilized membrane proteins crucially relies on the conformational stability and functional integrity of the protein under investigation. The present study describes how the E. coli ZntA P-type ATPase can be stabilized and functionally activated in a detergent solubilized system.

Adenosine Triphosphatases↗

PubMed2005

Critical role of actin in modulating BBB permeability.

A major obstacle in the treatment of degenerative manifestations and debilitating diseases in the central nervous system (CNS) lies in the impediment of drug delivery into these tissues. The impediment is due to a membrane barrier referred to as the blood-brain barrier (BBB). It is known that the BBB is a unique membranous structure in brain capillaries that tightly segregates the brain from systemic blood circulation. It is imperative to have a thorough understanding of the molecular components and their integrated function of this barrier to develop effective therapeutics for CNS disorders and diseases. Although there are other cell and biochemical properties that underlie this barrier function, it is well established that the barrier is mainly made up of the physical elements of tight junction (TJ) complex. The major constituents of TJ, such as occludin, claudins, zonula occludens (ZOs) and junctional adhesion molecule (JAM) have been subjects of intensive studies and reviews. However, after examining currently proposed models, we have come to believe that a cytoskeletal component-actin may play a critical role in interacting TJ molecular constituents and modulating functional TJ complex. In this review, we will discuss the correlation of temporal and spatial distribution and remodeling of actin filaments with altering integrity of TJ complexes in various systems and present a hypothesis to depict its potential role in modulating BBB permeability.

Actins↗

PubMed2007

Influenza virus host resistance model.

Host resistance (HR) models are used to evaluate the effect of a test article on clearance of an infectious microorganism in order to assess total immunocompetence. HR models serve as biomarkers of net immunological health or immunological well-being. Immunotoxicity can result either in an impaired clearance of an infectious agent, increased susceptibility to an opportunistic microorganism, prevention of immunization, or exacerbation of latent viral infections. The purpose of immunotoxicity testing is to obtain data that is meaningful for safety assessment, and for immunosuppression the major objective is to determine the significance with respect to increased susceptibility to infectious disease. Host resistance models provide the only sure method of examining the influence of test articles on the functional integrity of the immune system and its ability to eliminate pathogenic microorganisms and tumor cells. They provide the means to directly assess the functional reserve of the immune system. Clearance of influenza virus requires an intact and functional immune system that incorporates a cascade of immune responses. Mechanistic studies can be included in the influenza virus host resistance model by measuring the effect of a test article on innate immunity (cytokine and interferon production, macrophage function, and natural killer (NK) cell function) and acquired or adaptive immunity (cytotoxic T lymphocyte (CTL) activity as well as influenza-specific IgM and/or IgG antibody).

Animals↗

PubMed2002

Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion.

The formation of axon trajectories requires integration of local adhesive interactions with directional information from attractive and repulsive cues. Here, we show that these two types of information are functionally integrated; activation of the transmembrane receptor Roundabout (Robo) by its ligand, the secreted repulsive guidance cue Slit, inactivates N-cadherin-mediated adhesion. Loss of N-cadherin-mediated adhesion is accompanied by tyrosine phosphorylation of beta-catenin and its loss from the N-cadherin complex, concomitant with the formation of a supramolecular complex containing Robo, Abelson (Abl) kinase and N-cadherin. Local formation of such a receptor complex is an ideal mechanism to steer the growth cone while still allowing adhesion and growth in other directions.

Animals↗

PubMed1999

The patterns of small bowel motility: physiology and implications in organic disease and functional disorders.

The physiology and pathophysiology of small bowel motility are reviewed with particular focus on the motility patterns and periods that are detected by intraluminal manometry. Motility patterns are groups of phasic pressure waves resulting from contractions of the circular muscle layer of the small bowel that are organized by the enteric nervous system. Phase III of the migrating motor complex, the hallmark of the fasting motility period, thus reflects enteric neuromuscular function. Response to meal challenge also involves the CNS, reflexes beyond the gut and endocrine responses. Although specific disease diagnosis cannot be made by motility studies of the small bowel, the functional integrity is revealed. The normal occurrence of the essential patterns and periods of motility and the absence of distinctly abnormal patterns evidence preserved function, whereas the opposite indicates clinically significant dysmotility. Certain motility patterns are occasionally seen both in health and disease, and increased prevalence indicates a moderate dysfunction of yet unclear significance. Bacterial overgrowth with Gram-negative bacilli is the consequence of severe small bowel dysmotility, and a diagnosis that can be predicted by a motility study. Testing can be useful in the clinical management of paediatric and adult patients also by predicting the prognosis and response to enteral nutrition and medical therapy. Further studies are, however, needed to take full advantage of motility testing in clinical practise.

Central Nervous System↗

PubMed1992

Benefits and obstacles of health status assessment in ambulatory settings. The clinician's point of view. The Dartmouth Primary Care COOP Project.

In the past decade physicians have identified the need to expand patient assessment to include global function and quality of life. During the same period, the busy clinic has evolved into the location where this assessment seems most appropriate. Integrating functional health assessment into a busy clinical practice is difficult because the necessary steps require time, thought, recording, and follow-up. Attention to the office ecosystem is very important before any patient care management method is introduced. The clinician must transform the results of health status screening into a specific functional diagnosis. The clinician has to understand the sensitivity, specificity, and predictive value of the measure for a preliminary diagnosis to be made. Often, additional measurements must be taken to establish a specific diagnosis. These steps encompass assessment linkage. Once the specific cause for the dysfunction is recognized, the clinician then has to determine the need for special resources. This is called the resource linkage. By following the steps outlined in this paper, the clinician should be able to overcome many obstacles for functional health status assessment in busy ambulatory settings.

Activities of Daily Living↗

PubMed2004

p38 Mitogen-activated protein kinase inhibitor protects the epidermis against the acute damaging effects of ultraviolet irradiation by blocking apoptosis and inflammatory responses.

The primary function of the epidermis is to provide a protective barrier against numerous environmental insults, including ultraviolet radiation (UVR). UVR, particularly in the UVB spectrum, is a potent carcinogen known to damage DNA directly or through the generation of free radicals. Although in the long term, protective measures such as apoptosis and inflammation may prove beneficial in safeguarding the epidermis against the propagation of potentially tumorigenic cells, after high-dose UV irradiation these biologic events may be acutely detrimental to the architectural and functional integrity of the tissue owing to rampant cell death and inflammatory responses, which can culminate in epidermal erosion and consequently loss of barrier functions. The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated by UVR and herein we identify p38 MAPK as a key modulator of these physiologic events. Mice treated with the p38 MAPK inhibitor SB202190 are protected against several detrimental effects of acute UV irradiation, namely, sunburn cell/apoptosis, inflammation, and a hyperproliferation response. Based on our results, selectively blocking p38 activation with the SB202190 inhibitor could prove beneficial in treating victims from severe sunburn or exposure to other chemical agents known to trigger the p38 pathway.

Acute Disease↗

PubMed1985

An animal model for neuron-specific spinal cord lesions by the microinjection of N-methylaspartate, kainic acid, and quisqualic acid.

It has been shown that N-methylaspartate (NMA), kainic acid (KA), and quisqualic acid (QA) can produce preferential neuronal damage in various parts of the striatum, hippocampus, and thalamus with relative sparing of axons in transit. Thus far, the evidence that axons in transit escape destruction has been based largely on histological observations. To test the functional integrity of axons in passage, we made unilateral lesions with these agents in the cervical spinal cord of rats and compared the subsequent functional deficits with those seen after spinal cord hemisections. Observations were made in 14 rats. In each case, a laminectomy at the C6-C7 level was performed under general anesthesia. Animals receiving microinjections of KA, QA, or NMA showed motor and sensory deficits only in the ipsilateral forepaw and remained able to use the hindpaws normally. By contrast, animals undergoing spinal cord hemisection developed obvious motor deficits in the ipsilateral hindpaw in addition to the deficits in the forepaw. Histological observations of the spinal cords confirmed an extensive gray matter destruction with relative preservation of the long tracts in animals injected with KA, QA, and NMA. In addition, it was noted that spinal cord neurons appear relatively less sensitive to KA and more sensitive to QA than neurons in the thalamus, striatum, or hippocampus. The possible application of these findings for the production of dorsal root entry zone lesions will be discussed.

Animals↗

PubMed2002

Deletion of Stat3 blocks mammary gland involution and extends functional competence of the secretory epithelium in the absence of lactogenic stimuli.

The transcription factor Stat3 is activated through tyrosine phosphorylation by many cytokines and is a fundamental mediator of their signals. In the mammary gland, Stat3 activity increases sharply shortly after weaning, and involution is delayed in mice, that contain a mutant Stat3 lacking 33 amino acids including the key tyrosine residue. We have now generated a more extensive mutation of Stat3 through the deletion of exons 15-21 in mammary epithelium. This resulted in the loss of 245 amino acids including the DNA binding and SH2 domains, and Stat3 protein was undetectable. Pregnancy-mediated mammary development and lactation were normal in these mice. Involution was delayed and, remarkably, Stat3-null mammary epithelium maintained its functional integrity and competence even 6 d after weaning, whereas control mammary tissue was rendered nonfunctional within 2 d. The lack of remodeling and functional stasis of the epithelium correlated with the disruption of proteinase activity. Our data demonstrate that mammary tissue can retain its functional competence in the absence of external lactogenic stimuli and demonstrate a delay in the initiation of the irreversible stage of involution.

Alleles↗

PubMed2005

Metabolic activity: a novel indicator of neuronal survival in the murine dopaminergic cell line CAD.

Apoptosis is implicated in many neurodegenerative diseases, including Parkinson's disease (PD). Neuroprotective strategies targeting apoptosis need to preserve functional integrity of the saved cells to be effective. The aim of the present study was to evaluate a novel approach for analyzing neuronal function that monitors cellular metabolic responses to receptor activation using the microphysiometer. N-Acetyl-sphingosine (C2-ceramide) induced cell death of the neuronal cell line, Cath.a-differentiated (CAD) cells, which resemble catecholaminergic cells of the CNS, and provide a useful in vitro model for the cells affected in PD. C2-ceramide also suppressed the metabolic response of CAD cells to muscarinic receptor activation. Pretreatment with the caspase inhibitor Boc-Asp-(OMe)-fluoromethylketone (BAF) plus neurotrophin-3 (NT-3) reduced C2- ceramide-induced CAD cell death, delaying cell death more effectively than either agent alone; and, most significantly, BAF and NT-3 enabled the cells remaining 24 h after toxin treatment to generate a normal metabolic response to the muscarinic agonist carbachol. On the basis of these results, we suggest that measuring metabolic responses to receptor activation is a useful method for following neuronal viability after toxin treatment and that the combination of caspase inhibitors and neurotrophic factors might be a plausible strategy for improving neuronal survival, with critical preservation of metabolic function.

Amino Acid Chloromethyl Ketones↗

PubMedDate not supplied

Threshold-duration function of the acoustic reflex in man.

The threshold-duration function of the acoustic reflex was investigated in 5 male and 5 female adult, normal-hearing humans and in 3 adult male subjects with hearing loss of cochlear etiology. Reflex threshold was obtained at stimulus durations of 10, 20, 50, 100, 200, and 500 msec and at frequencies of 500, 1 000, 2 000, 3 000, and 4 000 Hz. Three commercially available acoustic bridges were employed, the Madsen ZO-70 and Grason-Stadler 1720 electroacoustic bridges, and the Grason-Stadler-Zwislocki model 3 mechanical-acoustic bridge. A probe-tone frequency of 220 Hz was used in all measures. The reflex threshold-duration function for normal-hearing subjects was found to encompass a much greater range of intensity than the psychophysically assessed auditory threshold temporal integration function. A sex difference was found which may be explained by subclinical noise-induced cochlear pathology in the male subjects with subsequent truncation of the reflex threshold-duration function. The function was also found to be truncated in the 3 subjects with hearing loss diagnosed to be of cochlear etiology. The implications of these findings for control of stimulus duration in clinical reflex measurement was discussed.

Acoustic Stimulation↗

PubMed2006

Neuroprotection in schizophrenia.

Longitudinal and structural neuroimaging studies show that patients with schizophrenia that converted to psychosis were found to have progressive gray matter loss in the cortex. Gray matter loss was also associated with functional decline. While the underlying mechanisms of gray matter loss remain uncertain, evidence of improved outcomes suggests neuroprotection, the maintenance of the functional integrity of the brain in response to neurobiological stress, in schizophrenia is possible. In order to protect against gray matter loss and slow functional decline following the onset of psychosis, new data suggests that an appropriate antipsychotic chosen at first episode can modify the rate of structural deterioration, which can lead to improved outcome.

Antipsychotic Agents↗

PubMed1992

von Willebrand factor interacts with malignant hematopoietic cell lines: evidence for the presence of specific binding sites and modification of von Willebrand factor structure and function.

von Willebrand factor (vWf) mediates the adherence of platelets to exposed vascular subendothelium. During hematogenous metastasis in certain model systems, platelets are also deposited at endothelial surfaces in heterotypic aggregates with tumor cells. The role of vWf in this metastatic event was investigated by examining the interaction between purified iodine 125-labeled vWf and the human tumor cell lines, U937 and CA46. vWf-tumor cell binding was specific, partially reversible, and saturable at 4 degrees C. At 37 degrees C, however, U937 cell binding sites could not be saturated, suggesting endocytosis as a possible mechanism of interaction. When constant amounts of vWf were added, interactions with tumor cells were complete after 60 minutes, but rapidly dissociated over the next 2 hours. With the addition of specific proteinase inhibitors, vWf remained in stable association with tumor cells throughout a 3-hour time course. Loss of vWf antigen in supernatant samples complemented the 125I-labeled vWf bound directly to tumor cells. However, disproportionately large reductions in vWf functional activity were observed and correlated with alterations in multimeric structure. These data suggest an initial binding of vWf to some tumor cells, followed by a time-dependent loss of structural and functional integrity. VWf may contribute to tumor cell arrest within the microvasculature and may influence other tumor cell-subendothelial interactions as the adhesive function of vWf is subsequently modified.

Amino Acid Sequence↗

PubMed1994

Helping the elderly stay active: a technique for detecting disability in the primary care office.

The inability to perform essential activities of daily living such as cooking, shopping, dressing and bathing is termed functional disability. These deficits can prevent elders from enjoying independent, active lifestyles. The development of functional disability is a gradual process. Early identification and intervention by the primary care physician can often reduce functional decline. Screening for functional decline has traditionally been performed by either questionnaire or direct observation of tasks. This paper reviews methods which have been proposed to integrate functional disability screening into office practice. A method which incorporates both questionnaire and direct observation is recommended by the authors. The method of screening proposed targets specific areas prone to dysfunction. It focuses on simple screens of vision, hearing, arm and leg function, urinary incontinence, mental status, depression, nutrition, activities of daily living, environmental hazards, and social support systems. Appropriate methods of follow up evaluation and treatment are provided. This fifteen minute technique is a practical and applicable means of screening elderly patients for functional deficits in the primary care office.

Activities of Daily Living↗

PubMed1996

The membrane attack complex of complement induces interleukin-8 and monocyte chemoattractant protein-1 secretion from human umbilical vein endothelial cells.

Cell surface assembly of the membrane attack complex (MAC) of complement occurs in a variety of pathophysiological settings. Depending upon the density and size distribution of pores formed by the MAC and the functional integrity of membrane regulators of complement activation, the MAC can either cause direct cell lysis or transduce cell activation. We have examined the functional capacity of sublytic concentrations of MAC to induce the secretion of specific alpha- and beta-chemokines from human umbilical vein endothelial cells (HUVECs). Endothelial cell activation by the MAC has particular relevance to complement-dependent inflammatory processes including ischemia-reperfusion injury and acute lung injury. Assembly of sublytic concentrations of the MAC on HUVECs resulted in the sequential secretion of both neutrophil and monocyte chemotactic activities. Analysis of conditioned medium from MAC-bearing HUVECs revealed that the neutrophil chemotactic activity was largely attributable to interleukin (IL)-8, whereas the monocyte chemotactic activity, which was detected later (peak at 8 hours versus 4 hours), was largely attributable to MCP-1. This temporal pattern of MAC-induced secretion of IL-8 and MCP-1 was confirmed using IL-8- and MCP-1-specific enzyme-linked immunosorbent assays. Northern hybridization analysis of HUVECs revealed that MAC deposition was accompanied by an increase in IL-8 and MCP-1 mRNA levels. These data indicate that assembly of sublytic concentrations of the MAC on HUVECs can induce the sequential secretion of both neutrophil and monocyte chemotactic activities and that the former is largely attributable to IL-8 whereas the latter is largely attributable to MCP-1.

Cell Membrane↗

PubMed1998

Hypoxia and smooth muscle function: key regulatory events during metabolic stress.

Hypoxia rapidly reduces force in many smooth muscles and we review recent data that shed light on the mechanisms involved. As many regulated cellular processes are integrated to co-ordinate smooth muscle contractility, the processes responsible for decreased force output with altered metabolism are also likely to be many, acting in concert, rather than the actions of one altered parameter. Nevertheless the aim of this study is to elucidate the hierarchical series of events that contribute to reduced smooth muscle force production during altered metabolism. We conclude that in many phasic smooth muscles the decrease in force can be attributed to impaired electro-mechanical coupling whereby the Ca2+ transient is reduced. A direct effect of hypoxia on the Ca2+ channel may be of key importance. In tonic vascular smooth muscles KATP channels may also play a role in the integrated functional responses to hypoxia. There are also many examples of force being reduced, in tonically activated preparations, without a fall in steady-state Ca2+; indeed it usually increases. We examine the roles of altered [ATP], pH, myosin phosphorylation, inorganic phosphate and proteolytic activity on the [Ca2+]-force relationship during hypoxia. We find no defining force-inhibitory role for any one factor acting alone, and suggest that force most probably falls as a result of the combination of myriad factors.

Animals↗

PubMed1995

Expression and radiolabeling of human C-reactive protein in baculovirus-infected cell lines and Trichoplusia ni larvae.

Human C-reactive protein (CRP) is a member of the pentraxin family of proteins which are molecules composed of five identical subunits arranged in a planar configuration. In the present study a human CRP cDNA clone was ligated into the baculovirus vector pVL1393 which was used to establish a recombinant strain of BaculoGold Autographa californica multiple nuclear polyhedrosis virus containing the coding and leader sequence for human CRP (designated AcMNPV-CRP). Synthesis and secretion of CRP were studied after infection of TN5B1-4 and Sf-9 cells with AcMNPV-CRP. Accumulation of CRP but not other proteins in the medium over the course of infection suggested that CRP was actively secreted. Analysis by gel filtration chromatography and by SDS-PAGE demonstrated an intact pentamer composed of subunits of the appropriate molecular mobility. The structural integrity of the recombinant protein was further established by the ability of the product to bind to phosphocholine in a calcium-dependent manner, a property which is restricted to the intact pentamer. Functional studies of complement activation, binding to mononuclear phagocytic cells, and reactivity with a panel of monoclonal antibodies were also consistent with structural and functional integrity of the recombinant molecule. Infection of Trichoplusia ni larvae with AcMNPV-CRP also resulted in the production of functional recombinant protein. This method has the advantage of producing larger amounts of protein at lower cost than tissue culture. An additional advantage is the ability to metabolically label CRP through feeding the larvae on an [35S]methionine-containing diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗