Biomedical subjects

X Chen

Publications and source records attributed to X Chen.

At least 937 records · Page 52Linked to original sources

PubMed1998

ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease.

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

Animals↗

PubMed1998

Identification and characterization of protease-resistant SecA fragments: secA has two membrane-integral forms.

We have identified and characterized the protease-resistant SecA fragments (X. Chen, H. Xu, and P. C. Tai, J. Biol. Chem. 271:29698-29706, 1996) through immunodetection with region-specific antibodies, chemical extraction, and sequencing analysis. The 66-, 36-, and 27-kDa proteolytic fragments in the membranes all start at Met1, whereas the 48-kDa fragment starts at Glu361. The overlapping of the sequences of the 66- and 48-kDa fragments indicates that they are derived from different SecA molecules. These two fragments were generated differently in response to ATP hydrolysis and protein translocation. Furthermore, the presence of membrane is required for the generation of the 48-kDa fragment but not for that of the 66-kDa fragment. These data suggest that there are two different integral forms of SecA in the membrane: SecA(S) and SecA(M). The combination of these two forms of SecA has several membrane-interacting domains. Both forms of SecA are integrated in the membrane, since both the 48- and 66-kDa fragments could be derived from urea- or Na2CO3-washed membranes. Moreover, all fragments are resistant to extraction with a high concentration of salt or with heparin, but the membrane-specific 48-kDa SecA domain is more sensitive to Na2CO3 or urea extraction. This suggests that this domain may interact with other membrane proteins in an aqueous microenvironment and therefore may form a part of the protein-conducting channel.

Adenosine Triphosphatases↗

PubMed1998

Small abundant DNA binding proteins from the thermoacidophilic archaeon Sulfolobus shibatae constrain negative DNA supercoils.

Major DNA binding proteins, designated Ssh7, were purified from the thermoacidophilic archaeon Sulfolobus shibatae. The Ssh7 proteins have an apparent molecular mass of 6.5 kDa and are similar to the 7-kDa DNA binding proteins from Sulfolobus acidocaldarius and Sulfolobus solfataricus in N-terminal amino acid sequence. The proteins constitute about 4.8% of the cellular protein. Upon binding to DNA, the Ssh7 proteins constrain negative supercoils. At the tested Ssh7/DNA mass ratios (0 to 1.65), one negative supercoil was taken up by approximately 20 Ssh7 molecules. Our results, together with the observation that the viral DNA isolated from S. shibatae is relaxed, suggest that regions of free DNA in the S. shibatae genome, if present, are highly positively supercoiled.

Acids↗

PubMed1998

Differential expression of Nur77 family members in human T-lymphotropic virus type 1-infected cells: transactivation of the TR3/nur77 gene by Tax protein.

We analyzed the differential expression and regulation of three members of the Nur77 transcription factor family by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein. We have demonstrated that in both HTLV-1-infected cells and Tax-expressing JPX-9 cells, TR3/nur77 is highly expressed, whereas neither NOR-1 nor NOT expression is detectable. Transient transfection analysis further confirmed the Tax transactivation of the TR3/nur77 promoter but not the NOR-1 promoter in different cell types. Furthermore, expression of a luciferase reporter gene driven by the NGFI-B (rat homolog of TR3/Nur77) response element (NBRE) provided evidence that Tax-mediated transactivation resulted in the induction of a functional protein. Cotransfection assays with the TR3/nur77 promoter sequence or the NBRE binding motif together with a series of Tax mutants have shown that Tax-induced TR3/nur77 expression is mediated by CREB/ATF-related transcription factors.

Activating Transcription Factor 1↗

PubMed1998

DDB, a putative DNA repair protein, can function as a transcriptional partner of E2F1.

The transcription factor E2F1 is believed to be involved in the regulated expression of the DNA replication genes. To gain insights into the transcriptional activation function of E2F1, we looked for proteins in HeLa nuclear extracts that bind to the activation domain of E2F1. Here we show that DDB, a putative DNA repair protein, associates with the activation domain of E2F1. DDB was identified as a heterodimeric protein (48 and 127 kDa) that binds to UV-damaged DNA. We show that the UV-damaged-DNA binding activity from HeLa nuclear extracts can associate with the activation domain of E2F1. Moreover, the 48-kDa subunit of DDB, synthesized in vitro, binds to a fusion protein of E2F1 depending on the C-terminal activation domain. The interaction between DDB and E2F1 can also be detected by coimmunoprecipitation experiments. Immunoprecipitation of an epitope-tagged DDB from cell extracts resulted in the coprecipitation of E2F1. In a reciprocal experiment, immunoprecipitates of E2F1 were found to contain DDB. Fractionation of HeLa nuclear extracts also revealed a significant overlap in the elution profiles of E2F1 and DDB. For instance, DDB, which does not bind to the E2F sites, was enriched in the high-salt fractions containing E2F1 during chromatography through an E2F-specific DNA affinity column. We also observed evidence for a functional interaction between DDB and E2F1 in living cells. For instance, expression of DDB specifically stimulated E2F1-activated transcription. In addition, the transcriptional activation function of a heterologous transcription factor containing the activation domain of E2F1 was stimulated by coexpression of DDB. Moreover, DDB expression could overcome the retinoblastoma protein (Rb)-mediated inhibition of E2F1-activated transcription. The results suggest that this damaged-DNA binding protein can function as a transcriptional partner of E2F1. We speculate that the damaged-DNA binding function of DDB, besides repair, might serve as a negative regulator of E2F1-activated transcription, as damaged DNA will sequester DDB and make it unavailable for E2F1. Furthermore, the binding of DDB to damaged DNA might be involved in downregulating the replication genes during growth arrest induced by damaged DNA.

Base Sequence↗

PubMed1998

Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication.

It has been proposed that the functions of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27Kip1 are limited to cell cycle control at the G1/S-phase transition and in the maintenance of cellular quiescence. To test the validity of this hypothesis, p21 was expressed in a diverse panel of cell lines, thus isolating the effects of p21 activity from the pleiotropic effects of upstream signaling pathways that normally induce p21 expression. The data show that at physiological levels of accumulation, p21, in addition to its role in negatively regulating the G1/S transition, contributes to regulation of the G2/M transition. Both G1- and G2-arrested cells were observed in all cell types, with different preponderances. Preponderant G1 arrest in response to p21 expression correlated with the presence of functional pRb. G2 arrest was more prominent in pRb-negative cells. The arrest distribution did not correlate with the p53 status, and proliferating-cell nuclear antigen (PCNA) binding activity of p21 did not appear to be involved, since p27, which lacks a PCNA binding domain, produced similar arrest distributions [corrected], DNA endoreduplication occurred in pRb-negative but not in pRb-positive cells, suggesting that functional pRb is necessary to prevent DNA replication in p21 G2-arrested cells. These results suggest that the primary target of the Cip/Kip family of inhibitors leading to efficient G1 arrest as well as to blockade of DNA replication from either G1 or G2 phase is the pRb regulatory system. Finally, the tendency of Rb-negative cells to undergo endoreduplication cycles when p21 is expressed may have negative implications in the therapy of Rb-negative cancers with genotoxic agents that activate the p53/p21 pathway.

Cyclin-Dependent Kinase Inhibitor p21↗

PubMed1998

Lasp-1 is a regulated phosphoprotein within the cAMP signaling pathway in the gastric parietal cell.

Activation of the cAMP signaling pathway is correlated with increased secretory-related events in a wide variety of cell types including the gastric parietal cell. Within this pathway, as well as in other intracellular signaling pathways, protein phosphorylation serves as a major downstream regulatory mechanism. However, although agonist and cAMP-dependent activation of cAMP-dependent protein kinase (PKA) has been demonstrated, little is currently known about the downstream in vivo phosphoprotein substrates of this enzyme. Here we report the isolation, microsequencing, and cloning of a LIM and SH3 domain-containing, cAMP-responsive, 40-kDa phosphoprotein (pp40) from rabbit gastric parietal cells. The deduced amino acid sequence for pp40 is 93.5%, homologous with the putative protein product of the human gene lasp-1, which was recently identified based on its overexpression in some breast carcinomas. In addition to LIM and SH3 domains, the rabbit homolog contains two highly conserved PKA consensus sequences as well as two conserved SH2 binding motifs and several other putative protein kinase phosphorylation sites, including two for tyrosine kinase(s). Combined Northern and Western blot analyses indicate that pp40/lasp-1 is widely expressed (through a single 3.3-kb message) not only in epithelial tissues but also in muscle and brain. Furthermore, stimulation of isolated parietal cells, distal colonic crypts, and pancreatic cells with the adenylyl cyclase activator forskolin leads to the appearance of a higher molecular weight form of pp40/lasp-1, a finding which is consistent with an increase in protein phosphorylation. Thus pp40/lasp-1 appears to be regulated within the cAMP signaling pathway in a wide range of epithelial cell types. Because the cAMP-dependent increase in pp40 phosphorylation is correlated with secretory responses in the parietal cell and because pp40 appears to be widely distributed among various secretory tissues, this newly defined signaling protein may play an important role in modulating ionic transport or other secretory-related activities in many different cell types.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Stimulatory effect of lithium on glucose transport in rat adipocytes is not mediated by elevation of IP1.

Lithium has been shown to increase glucose uptake in skeletal muscle and adipose tissues. The therapeutic effect of lithium on bipolar disease is thought to be mediated by its inhibitory effect on myo-inositol-1-monophosphatase (IMPase). We tested the hypothesis that the stimulatory effect of lithium on glucose uptake results from inhibition of IMPase and the resultant accumulation of inositol monophosphates (IP1) by comparing the effects of lithium and a selective IMPase inhibitor, L-690,488, on isolated rat adipocytes. Insulin produced a concentration-dependent stimulation of 2-deoxy-D-[14C]glucose (2-DG) transport (10 microU/ml caused half-maximal activation). Acute exposure to lithium stimulated basal glucose transport activity in a concentration-dependent manner, with a threefold stimulation at 30 mM lithium. Lithium also potentiated insulin-stimulated 2-DG transport. Lithium produced a concomitant increase in IP1 accumulation. In contrast, L-690,488 increased IP1 to levels comparable to those of lithium without stimulatory effects on 2-DG transport. These results demonstrate that stimulatory effects of lithium on glucose transport are not mediated by the inhibition of IMPase and subsequent accumulation of IP1 in rat adipocytes.

Adipocytes↗

PubMed1998

Direct evidence for the role of neuropeptide Y in sympathetic nerve stimulation-induced vasoconstriction.

Neuropeptide Y (NPY) is a vasoconstrictor peptide and a cotransmitter with norepinephrine (NE) in sympathetic nerve terminals and is thought to be involved in sympathetic nerve stimulation (SNS)-induced vasoconstriction. Using BIBP-3226, a Y1 receptor selective antagonist, we examined this hypothesis in the isolated and perfused mesenteric vascular bed. SNS produced a frequency-dependent increase in perfusion pressure and concomitant overflow of NPY immunoreactivity in the perfusate. [Leu31,Pro34]NPY potentiated NE-induced and ATP-induced vasoconstriction, indicating the presence and biological action of Y1 receptors in this vascular bed. The potentiation effect of [Leu31,Pro34]NPY of the increase in perfusion pressure by NE, ATP, or SNS was prevented by BIBP-3226. In addition, SNS-induced vasoconstriction at both high and low frequencies was significantly attenuated by BIBP-3226 at a concentration that completely blocked the [Leu31,Pro34]NPY-induced potentiation of the NE- or ATP-induced vasoconstrictor effect. These results suggest that approximately 30% of vasoconstriction produced by SNS depends on NPY in the mesenteric vascular bed.

Animals↗

PubMed1998

Cloning and expression of rat lung acidic Ca(2+)-independent PLA2 and its organ distribution.

A clone for a rat acidic Ca(2+)-independent phospholipase A2 (aiPLA2) was isolated from a cDNA library prepared from rat granular pneumocytes with a probe based on the human aiPLA2 sequence (T.S. Kim, C.S. Sundaresh, S. I. Feinstein, C. Dodia, W. R. Skach, M. K. Jain, T. Nagase, N. Seki, K. Ishikawa, N. Nomura, and A. B. Fisher. J. Biol. Chem. 272: 2542-2550, 1997). In addition, a consensus sequence for mouse aiPLA2 was constructed from several mouse cDNA clones in the GenBank and dbEST databases. Each sequence codes for a 224-amino acid protein with 88% identity of the amino acids among the three species and conservation of a putative lipase motif (GDSWG). Translation of mRNA produced from the rat clone in a wheat germ system resulted in expression of PLA2 activity with properties similar to those of the human enzyme, i.e., acidic pH optimum and Ca2+ independence. The localization of aiPLA2 in rat tissues was studied with the human cDNA probe, polyclonal and monoclonal antibodies, and aiPLA2 activity. aiPLA2 is present in the lung as evidenced by high levels of mRNA and protein expression and by enzymatic activity that is inhibited by anti-PLA2 antibody and by the transition state analog 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33). Immunocytochemistry showed the presence of aiPLA2 in alveolar type II cells, alveolar macrophages, and bronchiolar epithelium. In the brain, heart, liver, kidney, spleen, and intestine, aiPLA2 mRNA content was < 50% of that in the lung, immunoreactive protein was not detectable, and enzymatic activity was not inhibited by MJ33 or aiPLA2 antibody. These results show marked enrichment of aiPLA2 in the lung compared with the other organs and suggest translational control of aiPLA2 expression.

Amino Acid Sequence↗

PubMed1998

Release of a leukocyte activation inhibitor by staurosporine-treated pulmonary artery endothelial cells.

Bovine pulmonary arterial endothelial cells (BPAE) treated with the protein kinase C (PKC) inhibitor staurosporine inhibited O-2. generation by neutrophils exposed to phorbol myristate acetate (PMA) but did not affect O-2. generated enzymatically by xanthine/xanthine oxidase (X/XO). Similar results were obtained with conditioned medium from staurosporine-pretreated BPAE. The inhibitory effects of staurosporine-treated BPAE on O-2. generation were not altered by the superoxide dismutase inhibitor diethylcarbamazine. This BPAE-derived inhibitor was continuously released from staurosporine-pretreated BPAE for at least 5 h. The exact nature of the inhibitor remains unknown, but it appears to be a positively charged molecule with molecular weight <10,000. Treatment of either BPAE or neutrophils with staurosporine or conditioned medium from staurosporine-treated BPAE prevented the neutrophil-mediated decrease in endothelium-bound angiotensin-converting enzyme activity and cytotoxicity in BPAE. In contrast, staurosporine potentiated the H2O2- and X/XO-mediated endothelial cytotoxicity. These data suggest that staurosporine-treated endothelial cells release a soluble factor that inhibits neutrophil activation and protects endothelial cells from neutrophil-mediated injury.

Animals↗

PubMed1998

Interleukin-1beta fever in rats: gender difference and estrous cycle influence.

Evidence exists to support the concept of sex difference in immune system activation by pyrogenic cytokines. In this study, fever development was monitored to analyze the effect of peripheral administration of interleukin (IL)-1beta (1 microgram/kg) in adult male and cycling or ovariectomized female rats with or without ovarian hormonal replacement. In male and randomly cycling female rats, a similar increase in body temperature occurred after intraperitoneal IL-1beta injection. Two representative stages of estrus with higher and lower levels of ovarian hormones (proestrus and diestrus, respectively) were chosen for study of the febrile response induced by IL-1beta. The fever induced by IL-1beta was found to be significantly higher and more prolonged in females at proestrus than at diestrus. The differential fever response seems to be mainly linked to the ovarian hormonal levels because bilaterally ovariectomized females, supplemented with sequential injections of estradiol 17beta and progesterone, showed a significantly higher IL-1beta fever than did ovariectomized rats receiving estradiol 17beta only. These results indicate that gonadal hormones can influence fever development and raise the possibility of interaction between sex hormones and thermogenesis in females during the estrous cycle.

Animals↗

PubMed1998

The postnatal development of AMPA receptor subunits in the basal ganglia of the rat.

In situ hybridization and immunohistochemistry were used to characterize the expression pattern of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors during postnatal development in the rat basal ganglia. All subunit transcripts showed some degree of developmental regulation. GluR1 and GluR2 are expressed at high levels in the neonate with reduced expression in the adult. GluR3 and GluR4 are expressed at significantly lower levels in both neonates and adults and have much more modest degrees of reduced expression in adults as compared with GluR1 and GluR2. Analysis of the flip and flop transcript isoforms indicates that GluR1 flip and flop and GluR2 flip are the predominately expressed splice variants in adults. Observed changes in the expression of the AMPA receptor transcripts indicate that there are fundamental differences in the expression of these receptor subunits in adults and neonates. This phenomenon may play a significant role in the establishment of proper synaptic circuitry within the developing basal ganglia in early postnatal life as well as contributing to differences in susceptibility to injury and disease in the aging brain.

Animals↗

PubMed1998

Role of CD4+ and CD8+ T cells in regulating the chronic development of liver injury induced by delayed-type hypersensitivity to picryl chloride.

In this study we first investigated the cellular immune responses in mice with chronic liver injury induced by delayed-type hypersensitivity to picryl chloride (PCl). A continuous reduction, after week 3 of liver injury, was observed in the level of PCl-induced contact sensitivity but not in sheep red blood cell-induced footpad reaction, suggesting the presence of PCl-specific suppression. When spleen cells from mice whose liver had been injured for 1 week were systemically transferred into syngeneic recipients with the liver injury, the elevation in serum lactic dehydrogenase and the decrease in alkaline phosphatase and albumin levels in recipient mice were significantly exacerbated. However, when the liver damage in the donor mouse was allowed to proceed for 3, 5 or 7 weeks, biochemical changes in recipients were reduced to near normal levels. A flow-cytometric assay demonstrated that the number of CD4+ T cells in both spleen cells and liver nonparenchymal cells decreased dramatically during the late phase of liver injury, while CD8+ counts did not. These findings suggest that CD4+ and CD8+ T lymphocytes may contribute to the positive and negative regulation, respectively, of the early and late phases in the chronic development of liver injury.

Animals↗

PubMed1998

Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke.

BACKGROUND AND PURPOSE: Although the cause of stroke among patients with patent foramen ovale (PFO) may be due to paradoxical cerebral embolism (PCE), this mechanism is often difficult to prove. The aim of our study was to evaluate the association between brain imaging findings suggestive of embolism and PFO among ischemic stroke patients. METHODS: As part of the Northern Manhattan Stroke Study, 95 patients with first ischemic stroke over age 39 underwent transesophageal echocardiography (TEE) for evaluation of a cardiac source of embolism. The stroke subtype was determined by modified NINDS Stroke Data Bank criteria. Stroke subtype and MRI/CT imaging data were evaluated blind to the presence of a PFO. These findings were compared between two groups: patients with medium to large PFO (> or =2 mm) and small (<2 mm) or no PFO. RESULTS: Of the 95 patients who underwent TEE, 31 (33%) had a PFO. The frequency of PFO was significantly greater among patients with cryptogenic infarcts (19 of 42; 45%) compared with patients with determined cause of stroke (12 of 53, 23%; P=0.02). Medium to large PFOs were found more often among cryptogenic strokes than among infarcts of determined cause (26% versus 6%; P=0.04). Superficial infarcts occurred more often in the group with larger PFOs than in the group with small or no PFOs (50% versus 21%; P=0.02). Patients with medium or large PFOs more frequently had occipital and infratentorial strokes (57% versus 27%; P=0.02). CONCLUSIONS: Stroke patients with larger PFOs show more brain imaging features of embolic infarcts than those with small PFOs. Larger PFOs may be more likely to cause paradoxical embolization and may help explain the stroke mechanism among patients with no other definite cause.

Aged↗

PubMed1998

Chicken (Gallus domesticus) inner ear afferents.

Neurons from the vestibular (VG) and the statoacoustic (SAG) ganglion of the chick (Gallus domesticus) were evaluated histologically and morphometrically. Embryos at stages 34 (E8 days), 39 (E13 days) and 44 (E18 days) were sacrificed and temporal bones microdissected. Specimens were embedded in JB-4 methacrylate plastic, and stained with a mixture of 0.2% toluidine blue (TB) and 0.1% basic Fuschin in 25% ethanol or with a mixture of 2% TB and 1% paraphenylenediamine (PDA) for axon and myelin measurement study. Images of the VIIIth nerve were produced by a V150 (R) color imaging system and the contour of 200-300 neuronal bodies (perikarya) was traced directly on a video screen with a mouse in real time. The cross-sectional area of VG perikarya was 67.29 micrometers2 at stage 34 (E8), 128.46 micrometers2 at stage 39 (E13) and 275.85 micrometers2 at stage 44 (E18). The cross-sectional area of SAG perikarya was 62.44 micrometers2 at stage 34 (E8), 102.05 micrometers2 at stage 39 (E13) and 165.02 micrometers2 at stage 44 (E18). A significant cross-sectional area increase of the VG perikarya between stage 39 (E13) and stage 44 (E18) was determined. We randomly measured the cross-sectional area of myelin and axoplasm of hatchling afferent nerves, and found a correspondence between axoplasmic and myelin cross-sectional area in the utricular, saccular and semicircular canal nerve branches of the nerve. The results suggest that the period between stage 34 (E8) and 39 (E13) is a critical period for afferent neuronal development. Physiological and behavioral vestibular properties of developing and maturing hatchlings may change accordingly. The results compliment previous work by other investigators and provide valuable anatomical measures useful to correlate physiological data obtained from stimulation of the whole nerve or its parts.

Animals↗

PubMed1998

Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis.

Annexin I is a 36 kilodalton (kD) calcium-dependent phospholipid-binding protein which may have anti-inflammatory properties. Previous investigations which sampled lower respiratory tract epithelial lining fluid (ELF) via bronchoalveolar lavage (BAL) have demonstrated that annexin I can be degraded in inflammatory lung disease. We analyzed BAL fluid from patients with cystic fibrosis (CF) to determine the effects of lung inflammation on the structure and activity of annexin I. Intact annexin I was absent in 17 out of 20 BAL fluid samples from patients with CF, due largely to degradation to a 33 kD protein. The three CF BAL fluids in which annexin I was detectable had very little or no unopposed neutrophil elastase activity in contrast to the 17 in which no annexin I was detectable. Annexin I was present in all BAL fluid samples from 10 normal volunteer (NV) subjects and 12 patients with interstitial lung disease (ILD). The 33 kD annexin I breakdown product was not detectable in samples from NV, but was detectable only in ILD patients with relatively high percentages of neutrophils on BAL differential cell counts. Annexin I appeared to be cleaved by neutrophil elastase at the N-terminal portion between Val-36 and Ser-37 to yield the 33 kD protein. Cleavage of the N-terminal portion of annexin I was accompanied by a marked change in the annexin I isoelectric point (pI) value (from 6.0 to 8.5-9.0) and greatly diminished annexin I functional activity. Our findings demonstrate that annexin I degradation in epithelial lining fluid is closely related to lung inflammation.

Amino Acid Sequence↗

PubMed1998

Free fatty acids and insulin resistance during pregnancy.

The purpose of this study was to determine whether elevation of plasma free fatty acids (FFA) in early pregnancy would cause alterations in insulin-stimulated glucose disposal similar to those occurring in late gestation. Seven glucose-tolerant women underwent 4-h euglycemic hyperinsulinemic (1 mU/kg.min) clamping during the early second trimester of pregnancy (14-17 weeks) on 2 consecutive days, receiving either lipid (Liposyn II; 1.5 mL/min) and heparin (0.4 U/kg.min; L/H) or saline/glycerol (2.25 g/h; S/G) infusions. Rates of total body glucose disposal (6,6-2H2 glucose) and of carbohydrate and fat oxidation (indirect calorimetry) were determined at hourly intervals. Blood glucose was clamped at about 85 mg/dL. Plasma FFA increased from 290 +/- 50 to 1000 +/- 139 mumol/L during L/H infusion and decreased from 351 +/- 60 to 35 +/- 11 mumol/L during S/G infusion. L/H infusion inhibited insulin stimulation of total body glucose disposal by 28% compared with S/G infusion (from 6.7 +/- 0.7 to 4.9 +/- 0.6 mg/kg.min; P < 0.01). L/H infusion increased fat oxidation from 0.73 +/- 0.04 to 1.26 +/- 0.2 mg/kg.min (P < 0.05) and decreased carbohydrate oxidation from 2.0 +/- 0.2 to 1.6 +/- 0.2 mg/kg.min (P < 0.05). Endogenous glucose production decreased equally by approximately 70% during L/H and S/G infusions. These data showed that elevating plasma FFA levels during early pregnancy inhibits total body glucose uptake and oxidation. We conclude that elevation of plasma FFA can contribute to the peripheral insulin resistance commonly observed during late pregnancy.

Adult↗