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At least 667 records · Page 37Linked to original sources
PubMed2002

Recipient hypertension potentiates chronic functional and structural injury of rat renal allografts.

BACKGROUND: Systemic hypertension affects many allograft recipients, is an important risk factor for chronic graft dysfunction, and is linked to reduced graft survival. The condition may up-regulate the expression of inflammatory host cells and their products. These, in turn, may significantly injure vascular endothelium and other components of allografted kidneys. METHODS: Lewis rats received orthotopic F344 renal allografts, a standard model of chronic rejection. Renovascular hypertension was produced by placing a silver clip (0.25 mm) on the renal artery of the retained contralateral native kidney 4 weeks after transplantation. Sham-clipped rats served as normotensive controls. Four recipient groups (Gp) were studied: Gp 1, rats with an allograft plus a clipped native kidney; Gp 2, those with an allograft and a sham-clipped native kidney; Gp 3, isografted animals with a clipped native kidney; and Gp 4, those bearing an isograft and a sham-clipped native kidney. Systolic blood pressure and proteinuria were measured every 2 weeks for 24 weeks. Grafts were assessed serially for morphologic and immunohistologic changes. RESULTS: Systemic blood pressure rose to hypertensive levels in Gps 1 and 3 within a week of clipping but never increased in Gps 2 and 4. Proteinuria developed in hypertensive animals but remained at baseline in normotensive controls. Intimal thickening of allograft arteries progressed to luminal obliteration with extensive perivascular and interstitial fibrosis by 24 weeks. In contrast, vascular changes in isografts of hypertensive hosts were restricted to medial hypertrophy. Tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, platelet derived growth factor (PDGF), endothelin, Il-6, major histocompatibility complex (MHC) class II, and B7 were up-regulated in allografts in hypertensive hosts. Vascular deposition of immunoglobulin (IgG) was increased. These changes were markedly less pronounced in Gp 3 isografts and minimal in the kidneys of the normotensive animals of Gps 2 and 4. CONCLUSIONS: An experimental model is presented that examines the influence of recipient hypertension in the pathogenesis of chronic dysfunction and injury developing in rat renal allografts over time.

Animals↗
PubMed1998

HLA-G polymorphisms: ethnic differences and implications for potential molecule function.

PROBLEM: Human leukocyte antigen (HLA)-G is uniquely expressed on extravillous cytotrophoblasts of the placenta and is postulated to be a mediator of maternal immune tolerance. Although it was originally considered to be nonpolymorphic, variations of the HLA-G DNA sequence have been reported, and a limited number of HLA-G alleles been defined. METHOD OF STUDY: The HLA-G wild-type sequence was compared with HLA-A2 with regard to the conservation of functionally essential parts of classical HLA-I molecules. HLA-G polymorphisms were analyzed under the aspect of ethnic differences, site, and consequences for postulated molecule functions. RESULTS: HLA-G exhibits a high degree of conservation relative to HLA-A2 in functionally relevant sites of HLA-class I molecules. However, polymorphic sites in HLA-G and classical HLA loci are not congruent. CONCLUSION: The type and localization of HLA-G polymorphisms suggest that different parts of HLA-G molecule underlie different selective constraints.

Ethnicity↗
PubMed2002

Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase.

Antigen-presenting cells (APCs) can induce tolerance or immunity. We describe a subset of human APCs that express indoleamine 2,3-dioxygenase (IDO) and inhibit T cell proliferation in vitro. IDO-positive APCs constituted a discrete subset identified by coexpression of the cell-surface markers CD123 and CCR6. In the dendritic cell (DC) lineage, IDO-mediated suppressor activity was present in fully mature as well as immature CD123+ DCs. IDO+ DCs could also be readily detected in vivo, which suggests that these cells may represent a regulatory subset of APCs in humans.

Antigen-Presenting Cells↗
PubMed1998

Potential Alu function: regulation of the activity of double-stranded RNA-activated kinase PKR.

Cell stress, viral infection, and translational inhibition increase the abundance of human Alu RNA, suggesting that the level of these transcripts is sensitive to the translational state of the cell. To determine whether Alu RNA functions in translational homeostasis, we investigated its role in the regulation of double-stranded RNA-activated kinase PKR. We found that overexpression of Alu RNA by cotransient transfection increased the expression of a reporter construct, which is consistent with an inhibitory effect on PKR. Alu RNA formed stable, discrete complexes with PKR in vitro, bound PKR in vivo, and antagonized PKR activation both in vitro and in vivo. Alu RNAs produced by either overexpression or exposure of cells to heat shock bound PKR, whereas transiently overexpressed Alu RNA antagonized virus-induced activation of PKR in vivo. Cycloheximide treatment of cells decreased PKR activity, coincident with an increase in Alu RNA. These observations suggest that the increased levels of Alu RNAs caused by cellular exposure to different stresses regulate protein synthesis by antagonizing PKR activation. This provides a functional role for mammalian short interspersed elements, prototypical junk DNA.

Cell Line↗
PubMed2000

The leg depressor and levator muscles in the squat lobster Munida quadrispina (Galatheidae) and the crayfish Procambarus clarkii (Astacidae) have multiple heads with potentially different functions.

The proximal leg muscles of decapod crustaceans, controlling movements at the first two joints, are anatomically more complex than the better-studied distal leg muscles. Despite extensive research on their involvement in diverse behaviors, no complete descriptions of the anatomy and innervation of these muscles for any species have been published. We describe the anatomy and innervation of the depressor muscle in the second leg of the squat lobster Munida quadrispina and compare its anatomy with that of its homologue in the crayfish Procambarus clarkii and its antagonist, the levator, in both species. Of the six anatomically distinct heads comprising M. quadrispina's depressor muscle, one arises in the coxa (coxal head) and five are bi-articular (cross two joints), arising from widely dispersed sites on the thoracic endophragmal skeleton (dorsal, sternal, caudal, ventral-rostral, ventral-caudal heads). The heads' widely divergent force vectors are accommodated by the depressor apodeme's bifurcation at a thin flexible point. In total, eighteen neurons with central somata were backfilled from nerve branches to the heads. The common inhibitor and at least one neuron of unknown function with rostro-lateral soma and extremely sparse neurites innervate all heads. The sixteen excitatory motoneurons' somata are clustered in two locations, five rostral and eleven caudal to the neuropil. Rostral motoneurons innervate the two ventral heads (rostral and caudal). Their integrating segments lie rostral to those of the caudal group motoneurons and are straight or 'Y'-shaped, the latter longer and larger in diameter. Both morphological types have one prominent medial neurite that crosses the midline and could allow direct interaction between bilateral pairs of rostral motoneurons. The caudal motoneurons provide partially shared innervation to the remaining four heads. Six provide exclusive innervation, one to the caudal head, two to the sternal head, and three to the bi-articular dorsal head and uni-articular coxal head which share innervation. Of the remaining five caudal motoneurons, two are shared by the caudal head and the dorsal-coxal pair of heads and three are shared by the caudal and sternal heads. P. clarkii has two depressor muscles; the rostral depressor has a single head morphologically similar to the ventral rostral head in M. quadrispina; the caudal depressor muscle has four heads (dorsal, coxal, caudal, sternal) that insert on the large caudal depressor apodeme. The overall organization of depressor muscle heads in P. clarkii and M. quadrispina is similar, taking into consideration the different internal and external thoracic anatomies and the different resting stances, horizontal and tilted, respectively. As in other species, M. quadrispina and P. clarkii have two levator muscles, each with an apodeme of complex structure attributable to the levators' role in leg autotomy. The caudal levator arises in the coxa; it has two heads in M. quadrispina, but only one in P. clarkii. In both species the rostral levator has three heads all arising within the thorax. Divergent force vectors and partially independent innervation of different heads composing complex musculature at single joints constitute an anatomical level of organization that neural mechanisms must accommodate to produce adaptive movements.

Animals↗
PubMed2002

Myocardial gene transfer and overexpression of beta2-adrenergic receptors potentiates the functional recovery of unloaded failing hearts.

BACKGROUND: Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of beta-adrenergic receptor (betaAR) inotropic reserve. We tested whether prolonged LV unloading of failing rabbit hearts by use of a heterotopic transplantation technique could lead to recovery and whether adenoviral gene transfer of a beta2AR transgene (Adv-beta2AR) could alter this process. METHODS AND RESULTS: Heart failure was induced by coronary artery ligation in adult New Zealand White rabbits. After 4 weeks, failing hearts were heterotopically transplanted into recipient rabbits, allowing normal coronary perfusion but complete LV unloading. We also placed an LV latex balloon for remote access and in vivo physiological analysis. We found that there was reversal of signaling and functional abnormalities after 30 days of unloading. In another set of failing hearts, we randomly delivered, at the time of transplantation, either 2x10(11) viral particles of Adv-beta2AR or saline via the coronary arteries. Sham-operated animals with nonfailing hearts served as controls. After 5 days of unloading, in vivo LV contractility (LV dP/dt(max)) and relaxation (LV dP/dt(min)) were significantly decreased in saline-treated failing hearts compared with control nonfailing hearts (P<0.05). In failing hearts treated with Adv-beta2AR, however, LV dP/dt(max) and LV dP/dt(min) were improved in response to higher preloads (P<0.05) and betaAR stimulation (P<0.01). CONCLUSIONS: Heterotopic transplantation in the rabbit does allow recovery of the failing heart, and beta2AR overexpression acutely enhances this functional improvement. Accordingly, genetic manipulation of betaAR signaling may represent a novel molecular adjunct to mechanical assistance to facilitate functional myocardial recovery.

Adenoviridae↗
PubMed1993

Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease.

Thromboembolism is a prominent but poorly understood feature of eosinophilic, or Loeffler's endocarditis. Eosinophil (EO) specific granule proteins, in particular major basic protein (MBP), accumulate on endocardial surfaces in the course of this disease. We hypothesized that these unusually cationic proteins promote thrombosis by binding to the anionic endothelial protein thrombomodulin (TM) and impairing its anticoagulant activities. We find that MBP potently (IC50 of 1-2 microM) inhibits the capacity of endothelial cell surface TM to generate the natural anticoagulant activated protein C (APC). MBP also inhibits APC generation by purified soluble rabbit TM with an IC50 of 100 nM without altering its apparent Kd for thrombin or Km for protein C. This inhibition is reversed by polyanions such as chondroitin sulfate E and heparin. A TM polypeptide fragment comprising the extracellular domain that includes its naturally occurring anionic glycosaminoglycan (GAG) moiety (TMD-105) is strongly inhibited by MBP, whereas its counterpart lacking the GAG moiety (TMD-75) is not. MBP also curtails the capacity of TMD-105 but not TMD-75 to prolong the thrombin clotting time. Thus, EO cationic proteins potently inhibit anticoagulant activities of the glycosylated form of TM, thereby suggesting a potential mechanism for thromboembolism in hypereosinophilic heart disease.

Aged↗
PubMed1996

Site-directed mutagenesis of amino acids 33-44 of the common alpha-subunit reveals different structural requirements for heterodimer expression among the glycoprotein hormones and suggests that cyclic adenosine 3',5'-monophosphate production and growth promotion are potentially dissociable functions of human thyrotropin.

Amino acid residues 33-44 of the common alpha-subunit of the glycoprotein hormones have been implicated in heterodimerization as well as high affinity receptor binding of human (h) CG. In the present study, we compared the role of specific amino acids within this region for glycoprotein hormone heterodimer formation, using a transient transfection system to coexpress different mutant alpha-subunit constructs with the beta-subunit of either hTSH, hCG, or hFSH. Our results identified a crucial role for alpha Pro38 in the heterodimer expression of hTSH as well as hFSH, similiar to what had been described for hCG. In contrast, alpha Ala38, which had been critical for hCG, was not essential for hTSH heterodimer expression and less important for hFSH, whereas alpha Phe33 and alpha Arg35 appeared uniquely important for hFSH. Furthermore, we assessed the role of these residues for bioactivity and receptor binding of hTSH. Mutation of the surface-exposed residues alpha Arg42-Ser43-Lys44, which form part of a unique alpha-helical structure, to Ala42-Ala43-Ala44, decreased TSH receptor binding using porcine thyroid membranes as well as rat FRTL-5 cells. Residues alpha Phe33 and alpha Arg35, in contrast, were not important for high affinity binding of hTSH. In the signal transduction of hTSH, alpha Ala36 was necessary for efficient growth induction in FRTL-5 cells but not for cAMP production in either FRTL-5 cells or Chinese hamster ovary cells expressing the human TSH receptor (JP09). Similarly, residues alpha Arg42-Ser43-Lys44 were more important for hTSH-mediated induction of cell growth than cAMP production. Mutating alpha Arg35 to Ala reduced cAMP induction but not receptor binding of hTSH. In summary, using site-directed mutagenesis, we identified a domain, residues 33-44 of the common alpha-subunit, important in heterodimer expression, receptor binding, and activation of hTSH. The comparison of the relative roles of specific amino acids within this region in hTSH with hCG and hFSH highlights previously unrecognized differences in the structural requirements for heterodimer expression among the members of the glycoprotein hormone family. Moreover, our findings revealed a novel role for residues alpha 33-44 in triggering different postreceptor events, suggesting that cAMP production and growth promotion may, at least in part, be dissociable functions of hTSH.

Amino Acid Sequence↗
PubMed2005

Members of TALE and WUS subfamilies of homeodomain proteins with potentially important functions in development form dimers within each subfamily in rice.

Transacting factors often form homo- and heterodimers and regulate various targets, the type of regulation depending on the dimeric combination. The WUS and TALE subfamilies are two atypical homeodomains in plants. A homeodomain mediates sequence-specific binding to its target DNA and usually consists of 60 amino acid residues, whereas atypical homeodomains have extra amino acid residues in the well-conserved region. The genes OsWUS and OsPRS, which encode atypical homeodomain proteins from the WUS subfamily, and OsBEL and OSH15, which encode those from the TALE subfamily, were isolated from rice and tested for their interactions by yeast two-hybrid analysis. OsWUS and OsPRS formed homodimers and formed heterodimers with each other but did not form dimers with the TALE family homeodomain proteins OSH15 or OsBEL. Likewise, OSH15 and OsBEL formed homodimers and heterodimers but did not form dimers with the WUS family homeodomain proteins OsWUS and OsPRS. These findings suggest that the combinations of dimers are well correlated with the classification of these proteins on the basis of sequence similarity. RT-PCR analysis revealed that expression of OsWUS and OsPRS was detected in the same organs, namely floral buds, roots, and suspension cells. Therefore, it is possible that the proteins encoded by both of these genes function as homo- and heterodimers in planta. These results suggest that, during the evolution of these subfamilies, various combinations of dimers within proteins encoded by paralogous genes were formed and generated independent regulatory networks that enabled complex patterns of plant development.

Base Sequence↗
PubMed1986

Inhibition of mast cell chymase by eglin c and antileukoprotease (HUSI-I). Indications for potential biological functions of these inhibitors.

Recombinant eglin c (originally isolated from the medical leech) and antileukoprotease (HUSI-I from human seminal plasma) were examined for their ability to inhibit the mastcell protease chymase. Both inhibitors react rapidly with the enzyme: when about equimolar concentrations (in the range of 10(-8) M) of chymase and HUSI-I or eglin c were incubated the complex formation was apparently at equilibrium after 1 or 5 min respectively. When a constant amount of chymase (approximately 3 X 10(-8) M) was incubated with increasing concentrations of inhibitor a concentration of HUSI-I of 7 X 10(-7) M was necessary to cause 50% inhibition of the initial enzyme activity, whereas 8 X 10(-8) M eglin c was sufficient. The dissociation constant of the chymase-eglin c complex was calculated to be 4.4 X 10(-8) M. These results are discussed with respect to the possible in vivo function of antileukoprotease as an inhibitor of mast cell chymase.

Animals↗