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At least 55 records · Page 3Linked to original sources
PubMed1985

Homologous desensitization of the beta-adrenergic receptor. Functional integrity of the desensitized receptor from mammalian lung.

Previous work has demonstrated that injection of rats with isoproterenol is rapidly (10 min) followed by the development of a homologous form of desensitization of the beta-agonist-coupled adenylate cyclase in lung membranes. Half the receptor pool becomes sequestered in a light membrane fraction while the other half remains in the plasma membranes but becomes functionally uncoupled. In the present work we sought to assess whether "local sequestration" of the functionally intact receptor away from the effector adenylate cyclase in the plasma membrane contributes to the uncoupling of the beta-adrenergic receptor observed in the plasma membranes. We tested the functionality of the desensitized beta-adrenergic receptor in three different ways. We reconstituted the affinity chromatography purified control and "desensitized" receptors with pure Ns from human erythrocytes and assessed the ability to induce GTPase activity in Ns. Both control and desensitized beta-adrenergic receptors stimulate similar levels of GTPase activity in Ns (852 +/- 38 versus 738 +/- 49 fmol of Pi released/30 min (p greater than 0.05, n = 4). To further assess the relative ability of control and desensitized beta-adrenergic receptors to couple to another source of Ns we fused reconstituted beta-adrenergic receptors to Xenopus laevis erythrocytes, which contain Ns and adenylate cyclase but essentially no beta-adrenergic receptors. The functional interactions of control and desensitized beta-adrenergic receptor with the adenylate cyclase system of the acceptor cells was assessed by measuring the beta-agonist-stimulated adenylate cyclase activity and the agonist-induced formation of the high affinity state of the beta-adrenergic receptor (RH). Again both control and desensitized beta-adrenergic receptors appeared to interact with Ns to the same extent. To test if a local sequestration of the beta-adrenergic receptor away from Ns within the plasma membrane might contribute to the uncoupling of the beta-adrenergic receptors during desensitization, plasma membranes from control and desensitized lungs were treated with the fusogen polyethylene glycol to disrupt any compartmentalization of protein components within the plasma membrane. After polyethylene glycol treatment the previously uncoupled beta-adrenergic receptors could be recoupled to Ns as assessed by the formation of RH in agonist competition curves. These data suggest that in marked contrast to the heterologous type of desensitization, homologous desensitization may involve a local sequestration of a functionally intact beta-adrenergic receptor away from the adenylate cyclase effector system.

Adenylyl Cyclases↗
PubMed1985

Functional integrity of cytokineplasts: specific chemotactic and capping responses.

Cytokineplasts (CKP) are motile, membrane-bound, anucleate, granule-poor cytoplasmic fragments that are induced from human blood polymorphonuclear leukocytes (PMN) by the brief application of heat. We examined CKP with respect to specific chemotactic and capping responses, the presence of the N-formyl-peptide chemotactide receptor, and evidence of respiratory burst activity and compared them with CB-cytoplasts, which are fragments created by the centrifugation of cytochalasin B (CB)-treated PMN at high speeds. Under agarose, CKP responded chemotactically to both N-formyl-methionyl-leucyl-phenylalanine (fmlp) and zymosan-activated serum; CB-cytoplasts responded to neither chemoattractant. Despite the functional differences, both fragments retained N-formyl-peptide receptors as measured by affinity labeling with N-formyl-norleu-leu-phe-norleu-125I-tyr-lys and autoradiography of dried SDS-PAGE gels. For studies of capping we used a murine monoclonal antibody, PMN7C3, which binds a specific, widely distributed membrane component of intact PMN, and on warming, promptly induces capping of ligand-receptor complexes. Rhodamine-conjugated PMN7C3 at 4 degrees C labeled the surface of CKP homogeneously. As the CKP warmed to 37 degrees C, label became concentrated in small fluorescent caps at the rear of migrating fragments. Although CB-cytoplasts also bound the fluorochromed antibody homogeneously in the cold, on warming they were unable to concentrate the label normally. With respect to respiratory burst activity, the situation in the two fragments was reversed: CKP did not generate superoxide anion when stimulated either with phorbol myristate acetate or with fmlp after pretreatment with CB; CB-cytoplasts, as noted earlier by other investigators, did. These two types of cytoplasts with markedly different capabilities have complementary roles in the analysis of PMN function.

Chemotactic Factors↗
PubMed2026

Integrated functional, metabolomic, and biotransformation profiling of mycotoxin hepatotoxicity in 2D and 3D human hepatic models.

Mycotoxins pose a major risk to food safety and human health, yet their hepatotoxic mechanisms remain incompletely characterized due to limitations in conventional in vitro models. In this study, we systematically compared mycotoxin-induced hepatotoxicity and metabolomic profiling across two human hepatic models cultured under 2D monolayer and 3D spheroid conditions. The various mycotoxins (Aflatoxin B1, Citrinin, Deoxynivalenol, Ochratoxin A, Patulin, and Zearalenone) exhibit distinct metabolic signatures, thereby serving as an appropriate panel for comprehensively evaluating diverse hepatotoxic mechanisms. Mycotoxin exposure induced concentration-dependent hepatotoxicity accompanied by functional impairment and structural disruption in hepatic models. Metabolomic profiling revealed distinctive regulatory patterns between 2D and 3D hepatic models, with 3D spheroids showing consistent down-regulation across multiple intracellular metabolic pathways and altered extracellular metabolite release, whereas 2D monolayers predominantly exhibited global metabolic activation. In silico-assisted MS/MS analysis further demonstrated that Phase I biotransformation was largely conserved across models, whereas Phase II conjugation reactions were more frequently detected and exhibited greater model specificity in 3D spheroids. Overall, these findings indicate that 3D hepatic spheroids capture more integrated and coordinated hepatotoxic and metabolic responses to mycotoxins compared with 2D monolayer systems. These distinctive regulatory dynamics support their value as a physiologically relevant platform for toxicity assessment and mechanistic investigation.

3D hepatic spheroids↗
PubMed1991

Structural and functional integrity of ovarian tumor tissue obtained by ultrasonic aspiration.

For patients with ovarian epithelial cancer, survival increases when residual disease approaches zero after surgical removal of the tumor. A previous study using the Cavitron Ultrasonic Surgical Aspirator (CUSA) (Cavitron Lasersonic Corp., Stamford, CT) showed the successful removal of ovarian tumors from areas often considered unresectable: the diaphragm, spleen, stomach, and small bowel. However, the CUSA has not yet been approved by the Food and Drug Administration for gynecologic surgery except on an experimental basis. This study was designed to test whether ultrasonic irradiation produced by the CUSA caused alterations in cell structure or physiology of gynecologic tissue in adjacent areas. Paired tumor samples, unirradiated and irradiated, were obtained from ten patients, and portions were sent for pathologic structural evaluation and physiologic tissue culture evaluation. Histologic sections, stained with hematoxylin and eosin, showed that CUSA irradiation produced only minor tissue distortion as observed under the light microscope. A correct diagnosis would have been made in all cases had only tissue fragments obtained from the CUSA specimen trap been stained. For nine of ten patients, initial tumor cell viability was similar in the two specimen types. Flow cytometric DNA analysis confirmed that surgical methods produced matched samples. Cells that survived high-frequency ultrasound appeared functionally intact. For five of eight patients, the cells from the CUSA specimen traps survived and/or divided to a greater extent than those from the knife-dissected tumors. Cells from both surgical routes attained a similar number of passages in culture. It seems reasonable to extrapolate these in vitro observations with pelvic tumor tissues to normal surrounding tissue left in situ. Thus pelvic tissue is believed to be uninjured by CUSA ultrasonic irradiation.

Biopsy, Needle↗
PubMed1991

Microtubule disruption interferes with the structural and functional integrity of the apical pole in primary cultures of rat hepatocytes.

The effect of microtubule disruption on the development and maintenance of cell polarity was studied in rat hepatocytes cultured as primary monolayers in the presence of colchicine or nocodazole. Addition of colchicine immediately after plating did not inhibit the generation of bile canaliculi (the apical pole) after 1 day of culture, as judged by electron microscopic examination, and did not allow penetration of Ruthenium Red through the tight junctions. However, the bile canaliculi developed in the presence of colchicine or nocodazole were not fully normal since they were not able to concentrate fluorescein diacetate in their lumina, and did not enrich with proteins of the apical plasma membrane domain, as control cells did. When the drugs were added after 1 or 2 days of culture, the new bile canaliculi appeared to be unaffected when examined by electron microscopy, but many of them did not concentrate fluorescein and were not enriched with apical membrane proteins within 4 to 24 h after drug addition. Whenever the drugs were added, the proteins that would normally concentrate on the membrane of the bile canaliculi accumulated intracellularly in endocytic vesicles after 2 to 4 h of drug treatment, and in vacuoles resembling lysosomes when the drugs were maintained for 24 h or more. These results show that microtubule disruption does not inhibit the structural reconstitution of bile canaliculi, but impairs their normal function and the transport of proteins of the apical plasma membrane domain.

Animals↗
PubMed1989

Evaluation of the functional integrity of endothelium in perfused lungs.

Prostacyclin (PGI2) formation and the saturable uptake of 5-hydroxytryptamine (5HT) were studied as indices of endothelial integrity in isolated lungs. 5HT uptake was characterized by its kinetic parameters Km and Vmax. These were calculated from multiple indicator dilution data on the basis of an organ model of 5HT uptake. Perfused dog lung lobes were exposed to plasma activated with yeast (YAP) or zymosan (ZAP). YAP induced a transient elevation of Km. This increase probably reflects endothelial injury. Vmax remained unchanged, suggesting that the perfused endothelial surface remained stable. PGI2 biosynthesis was negligible in the control period, but started immediately after exposure to ZAP or YAP. It was proportional to the transient elevation of Km and to the pulmonary oedema. The data suggest that PGI2 might be a marker of severe endothelial distress.

Animals↗
PubMed1986

Integrated functioning of the chloroplast coupling factor.

This review is focused on some functional characteristics of the chloroplast coupling factor. The structure of the enzyme and the putative role of its subunits are recalled. An attempt is made to discriminate the driving force and the activator effects of the electrochemical proton gradient. Respective roles of delta pH, delta phi, external and internal pH are discussed with regard to mechanistic implications. The hypothesis of a functional switch of the enzyme between two states with better efficiency either in ATP synthesis or in ATP hydrolysis is also examined. A brief survey is made on some problems complicating quantitative studies of energy coupling, such as localized chemiosmosis, delta pH and delta phi computations, and scalar ATPases. The main data on the enzyme activation and the energy-dependent release of tightly bound nucleotides are summarized. The arguments for and against the catalytic competence of theses nucleotides are reviewed. Lastly, some prevailing models of the catalytic mechanism are presented. The relevance of nucleotides binding change events in this process is discussed.

Adenosine Diphosphate↗
PubMed1991

Requirement of innervation for maintenance of structural and functional integrity in the rat prostate.

The rat prostate is innervated by pelvic and hypogastric nerves through a single pelvic ganglion, removal of which would result in complete denervation of the prostatic complex. The present study was conducted to investigate the effect of denervation on the rat prostate. Adult Sprague-Dawley rats of 300 g in body weight were divided into two groups. Bilateral pelvic ganglion denervation was performed in one group of animals; the other group received a sham operation. Three weeks later, animals were killed; and the ventral prostates were removed, weighed, and subjected to routine procedures for light and electron microscopy. The average weight, total protein content, and total content of acid phosphatase of the ventral prostates in the denervated group were significantly less than those in the control group. Total DNA content per prostate, however, was not significantly different between the two groups. Results of histological examination indicated that the prostates from control animals showed normal morphology, whereas those from the denervated animals showed reduced cell height and enlarged vacuoles surrounding the nuclei. Inspection of electron micrographs revealed that the prostates from denervated animals, compared with those of controls, showed a reduced ratio of cell height:cell width, which is associated with a reduced number of microvilli and secretory granules. These results indicate that denervation in the prostate is associated with a lower prostatic weight, decreased cell height, and reduced secretory activity.

Acid Phosphatase↗
PubMed2025

The Annotated Blueprint: Integrated Functional Genomic Resources for a model Tetraploid Wheat Triticum turgidum cv. Kronos.

Triticum turgidum cv. Kronos is a tetraploid wheat cultivar that underpins one of the richest community platforms for functional genomics. Over the past decade, about 3,000 exome- and promoter-capture datasets, linked to mutagenized seed stocks, and transcriptomic and phenotypic resources have accumulated, yet the absence of a reference genome has constrained their impact. Here, we present a chromosome-scale reference genome of Kronos with high-confidence annotations, including manual curation of over 1,000 disease resistance (NLR) genes. This reference revealed previously hidden NLR diversity and clarified their genomic organization at chromosomal ends. Re-analysis of exome- and promoter-capture datasets enabled high-resolution mutation discovery in genes and regulatory regions that were previously inaccessible, uncovering the full standing variation present in Kronos mutant lines. We further re-curated transcriptomic and small RNA datasets, generating improved, genome-wide maps of microRNAs and phasiRNAs important for wheat development. Collectively, these resources elevate Kronos to reference quality and establish it as a versatile platform for functional and translational wheat research.

Journal Article↗