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PubMed1996

Physical and functional association of Fc mu receptor on human natural killer cells with the zeta- and Fc epsilon RI gamma-chains and with src family protein tyrosine kinases.

We recently reported that Fc mu R on NK cells is a signal transducing protein that stimulates a rapid increase in the level of cytoplasmic free calcium upon binding of IgM. This study was designed to examine signal transduction via the Fc mu R on NK cells and to characterize intracellular second messengers activated by IgM. Immunoprecipitation of IgM-bound Fc mu R by IgM-specific Ab coimmunoprecipitated the zeta- and Fc epsilon RI gamma-chains. Furthermore, engagement and clustering of Fc mu R by polyclonal IgM induced tyrosine phosphorylation of the zeta- and Fc epsilon RI gamma-chains, indicating their functional association with the Fc mu R-induced signal transduction cascade. Ligand-induced clustering of the Fc mu R also induced activity of src family kinases, Lck, Fyn, Lyn, and Src, as well as their physical interaction with the receptor. Triggering via Fc mu R also induced the activity of Syk and Zap-70, tyrosine kinases demonstrated to associate with zeta and Lck. Phospholipase C-gamma 1 and phosphatidylinositol 3-kinase were identified as substrates phosphorylated on tyrosine, as down-stream components of the signaling pathway activated in NK cells by polyclonal IgM. Although the Fc mu R on NK cells has not yet been biochemically characterized, our results suggest that the zeta- and Fc epsilon RI gamma-chains are functional subunits of this as well as other important cell surface receptors and that the Fc mu R is coupled either directly or indirectly to nonreceptor tyrosine kinases, which phosphorylate and thereby activate regulatory enzymes such as phospholipase C-gamma 1 and phosphatidylinositol 3-kinase.

Calcium↗

PubMed2005

Selective activation of the MEK-ERK pathway is regulated by mechanical stimuli in forming joints and promotes pericellular matrix formation.

It is well established that local modification of extracellular matrix (ECM) hyaluronan composition is vital in the regulation of cell behavior. Indeed, the formation of articulating chick joint cavities, which requires mechanical stimuli derived from skeletal movement, is dependent upon the accumulation of an ECM rich in hyaluronan (HA). However, the mechanisms responsible for such precise mechano-dependent regulation of cell behavior and the formation of a HA-rich ECM remain undefined. Here we show that extracellular-regulated kinase 1/2 (ERK1/2) is selectively activated in cells at sites of cavity formation and activity diminished by in ovo immobilization that induces cartilaginous fusion across presumptive joint interzones. In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK-dependent activation of ERK1/2. In addition, our direct regulation of ERK1/2 phosphorylation status via modulation of its up-stream "classical cascade" activator either pharmacologically or by transfection with dominant negative or constitutively active Mek confirms the essential role for ERK1/2 activation in the elaboration of HA-rich pericellular matrices. Together, our findings demonstrate that the MEK-ERK pathway, regulated by mechanical stimuli, controls HA-rich matrix assembly. The precision of ERK1/2 activation selectively distinguishing cells at the joint line suggests that it directly contributes to the loss of tissue cohesion essential for generating HA-rich cavities between joint elements during their development.

Animals↗

PubMed1989

Vessel invasion by tumour cells. An ultrastructural study.

The present electron microscopic investigation explored the mechanism through which the cells of an experimental fibrosarcoma implanted in the liver of syngeneic mice broke through the continuous (unperforated) endothelium of peri-tumour veins to enter the blood stream, as well as the immediate reaction of blood cells to the tumour breakthrough. It was found that at their point of contact with the endothelial tube of the peri-tumour vein, the tumour cells caused the endothelial basement membrane to disappear and they entered the vein lumen either by inducing an opening of interendothelial junctions, or by causing intensive vacuolation and disintegration of individual endothelial cells--and thus producing gaps for their passage into the lumen. Both mechanisms of entry were sometimes observed in the same tumour. At their point of breakthrough into the vein lumen, many neoplastic cells were immediately covered by a dense platelet aggregate or they were surrounded by numerous polymorph leucocytes (neutrophils more often than eosinophils) that stuck to their surfaces and sometimes caused a focal disappearance of the tumour cell plasma membrane at the site of polymorph-tumour cell contact. Occasionally polymorph lysosomal granules migrated to such contact areas, and the plasma membrane of the contacting polymorph disappeared as well. Finally, some polymorphs apparently plunged into the cytoplasm of vessel-invading tumour cells, while others were seemingly phagocytised by the latter.

Animals↗

PubMed2006

C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1alpha gene define HIF-1alpha protein expression in non-small cell lung cancer.

OBJECTIVES: In this study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the patterns of HIF-1alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1alpha down-stream proteins. METHODS: Specific HIF-1alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number , which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number , which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. RESULTS: A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1alpha expression was noted. HIF-1alpha polymorphism did not relate to the expression of the HIF-1alpha downstream proteins analysed, but significant association of HIF-1alpha expression with LDH-5 was confirmed (p=0.008). CONCLUSIONS: HIF-1alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function.

Aged↗

PubMedDate not supplied

Quantitative immuno-electron microscopic analysis of nuclear respiratory factor 2 alpha and beta subunits: Normal distribution and activity-dependent regulation in mammalian visual cortex.

The macaque visual cortex is exquisitely organized into columns, modules, and streams, much of which can be correlated with its metabolic organization revealed by cytochrome oxidase (CO). Plasticity in the adult primate visual system has also been documented by changes in CO activity. Yet, the molecular mechanism of regulating this enzyme remains not well understood. Being one of only four bigenomic enzymes in mammalian cells, the transcriptional regulation of this enzyme necessitates a potential bigenomic coordinator. Nuclear respiratory factor 2 (NRF-2) or GA-binding protein is a transcription factor that may serve such a critical role. The goal of the present study was to determine if the two major subunits of NRF-2, 2alpha and 2beta, had distinct subcellular distribution in neurons of the rat and monkey visual cortex, if major metabolic neuronal types in the macaque exhibited different levels of the two subunits, and if they would respond differently to monocular impulse blockade. Quantitative immuno-electron microscopy was used. In both rats and monkeys, nuclear labeling of alpha and beta subunits was mainly over euchromatin rather than heterochromatin, consistent with their active participation in transcriptional activity. Cytoplasmic labeling was over free ribosomes, the Golgi apparatus, and occasionally the nuclear envelope, signifying sites of synthesis and possible posttranslational modifications. The density of both subunits was much higher in the nucleus than in the cytoplasm for all neurons examined, again indicating that their major sites of cellular action is in the nucleus.

Animals↗

PubMed1995

Quantitative evaluation of leukocyte dynamics in retinal microcirculation.

PURPOSE: Leukocyte rheology may play a key role in microcirculation because leukocytes have unique properties, such as large cell volume, high cytoplasmic rigidity, and low deformability. However, only a few methods are available to study the dynamic behavior of leukocytes in retinal microcirculation. The authors developed a new method to analyze directly movements of leukocytes in the retinal vessels of primates. METHODS: Acridine orange, which has been used as a nuclear stain in histochemistry and cytochemistry, was injected intravenously into cynomolgus monkeys for a vital staining of leukocytes. The fundus image was generated with the argon blue laser and a scanning laser ophthalmoscope. The images were recorded on a magnetic tape and evaluated with a personal computer-based image analysis system. RESULTS: Each leukocyte was recognized as a single fluorescent dot moving in the retinal vessels. It was possible to analyze the spatial and temporal dynamics of individual leukocytes in the capillaries. Some leukocytes passed through the capillaries, plugging transiently under the physiological condition. Leukocytes that stayed in the same position for a few minutes may have stuck to the endothelium as a result of leukocyte-endothelial interactions. In the postcapillary vessels, leukocytes tended to be displaced from the center stream toward the vessel walls. The mean flow velocity of leukocytes in the perifoveal capillary was 0.92 +/- 0.32 mm/sec. CONCLUSIONS: This study clearly demonstrated that rheologic behaviors of leukocytes in the retinal microcirculation can be studied through the vital staining with acridine orange in vivo. The authors' results suggest a potential role of leukocytes in retinal vascular flow disturbances. This study may open the door to the investigation of leukocyte hemodynamics in the retinal microcirculation in vivo.

Acridine Orange↗

PubMed1976

[Changes in the ultrastructure of the anterior lobe of the pituitary after subjecting animals to cooling].

Stress reactions caused by extreme factors have a common nonspecific main component-a release of ACTH into the blood stream and increased functional activity of corticotropic cells of the anterior lobe of the hypophysis. Qualitative properties of the acting agents depending on their nature determine other adaptive changes of hormonal and metabolic processes in the organism after the interference. The study of the dynamics of the ultrastructure of glandular cells of the rat's hypophysis anterior lobe after a single severe cooling has revealed a sharply pronounced early mobilization of thyreotrops. The increased thyreotropic activity is an additional specific component of stressor reaction which is caused by cooling. The electron microscopic study of the structure and topography of glandular elements has revealed a cycle of functional-morphological changes completed within a day after the exposure.

Animals↗

PubMed1979

Hepatic glucose-6-phosphatase activities and correlated ultrastructural alterations in hepatocytes of diabetic rats.

Cell fractionation, enzyme analysis, and electron microscopy were used to study the effects of streptozotocin-induced diabetes and insulin replacement on liver structure and function. In liver homogenates from diabetic rats, glucose-6-phosphatase (G-6-Pase) activity was stimulated about 2 1/2-fold over that found in normal animals. Analyses of isolated rough and smooth microsomes from diabetic rats for G-6-Pase activity showed a fourfold increase in the smooth microsomes and a small increase in enzyme activity in rough microsomes when compared with these fractions from control animals. Associated with the increased enzyme activity was a reduction in liver glycogen. Insulin treatment of the diabetic rats caused a fall in homogenate G-6-Pase levels to approximately normal values and stimulated the accumulation of hepatic glycogen. Administration of insulin to these animals also caused a decrease in G-6-Pase activity, which was most pronounced in the smooth microsomes. Studies with the electron microscope revealed ultrastructural alterations in livers of the diabetic rats, which were most striking in the periportal region of the lobule. Periportal hepatocytes from diabetic rats displayed dispersed particles of glycogen separated by cytoplasm rich in SER rather than dense masses of glycogen with little SER, as is characteristic of these cells in normal animals. Centrilobular cells from the diabetic animals displayed some disorganization of the RER and a dispersed pattern of glycogen with abundant SER, similar to the pattern found in these cells from normal animals. After insulin treatment the periportal cells appeared normal morphologically, whereas the centrilobular hepatocytes displayed regions of both dense masses and dispersed glycogen. In the glycogen masses, little SER was found; however, in the areas of dispersed glycogen particles, an abundance of this organelle was evident. We conclude from these studies that diabetes causes an increase in amount of hepatic smooth endoplasmic reticulum (SER), especially within periportal hepatocytes. The results of cell fractionation indicate that membranes of the smooth endoplasmic reticulum are enriched in G-6-pase. We interpret these results to indicate that diabetes causes hepatocytes to form additional smooth endoplasmic reticulum with specialized membranes, at least with respect to G-6-Pase. It is suggested that this cellular specialization is a response of the hepatocyte to the diabetic state, namely, a demand for increased hepatic glucose production and release into the blood stream, thus contributing to the hyperglycemia characteristic of this disease. Insulin administration to the diabetic animals reverses the above alterations.

Animals↗

PubMed1979

Neutrophil function and host resistance.

The part played by the phagocytic cells against invading pathogens has been known since the work of Metchnikoff nearly a century ago. This review deals primarily with the role of the neutrophilic polymorphonuclear leukocyte in host defense against microbial infections. The overall function of these cells in protection from infection is dependent on a number of steps. First, an adequate number of functionally mature neutrophils have to be produced and released into the circulation by the bone marrow. Cells must circulate normally and be capable of adhering to capillary and venule walls overlying inflammatory sites. The next step involves the exit of phagocytes from the blood stream through the capillary wall and emigration into the tissues to establish contact with the invading pathogens. This process is accomplished by the locomotive characteristics of these cells and chemotaxis. Most organisms must then be phagocytized to be killed. Two discrete phases are involved in phagocytosis; the "recognition" and attachment phase followed by the ingestion phase. After phagocytosis a series of coordinated morphologic and biochemical events are set into motion which leads to eventual death and lysis of the ingested microbes. A variety of antimicrobial mechanisms are involved in this final step and indicate that these cells have an appreciable reserve capacity if one mechanism is impaired. Recent evidence which clarifies mechanisms involved in all these stages is discussed.

Animals↗

PubMed1994

Ordered binding of retinoic acid and retinoid-X receptors to asymmetric response elements involves determinants adjacent to the DNA-binding domain.

Retinoic acid, a pleiotropic regulator of development and homeostasis, controls the expression of specific gene networks via direct interactions with nuclear receptors. The retinoic acid receptor (RAR), as a heterodimer with the retinoid-x receptor (RXR), binds to DNA recognition sites, referred to as retinoic acid response elements (RAREs), that are generally composed of a direct repeat of the half-site core motif PuGGTCA spaced by 2 (DR-2) or 5 (DR-5) basepairs. The asymmetric nature of direct repeat RAREs suggests that RAR and RXR bind preferentially to one of the two half-site core motifs. Here we show that RXR occupies the 5'-up-stream half-site, and RAR the 3'-down-stream half-site of the direct repeat in both DR-2 and DR-5 RAREs. We also demonstrate that a region adjacent to the zinc finger region of RAR and RXR is essential for specific and cooperative binding of DNA-binding domain peptides to RAREs. However, differential utilization of these determinants mediate RAR-RXR heterodimer binding to DR-2 and DR-5 RAREs. The demonstration of ordered but nonequivalent binding of RAR-RXR complexes to DR-2 and DR-5 RAREs sets a precedent for the generation of sequence specificities in heterodimeric DNA-binding proteins.

Amino Acid Sequence↗

PubMed1999

Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice.

Stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), a member of the MAP kinase (MAPK) superfamily, plays a key role in a variety of cellular processes. It is well established that SAPK/JNK activation is controlled by SEK1/MKK4, an up-stream MAP kinase kinase. To gain insight into the role of SEK1 during embryonic development and in adult life, we examined the temporal and spatial patterns of sek1 expression in mice by using in situ hybridization and immunohistochemical study. Dynamic changes of sek1 expression were observed during embryogenesis. Strong sek1 expression was detected in most of the central nervous system and in liver and thymus during early stages of development. While the sek1 expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of the sek1 expression in the central nervous system was persisted throughout postnatal development and remained at a stable level in adult brain. These observations provide an anatomical basis for the vital role(s) of SEK1 in development, for example, in hepatogenesis and/or neurogenesis. Although SEK1 was widely expressed in adult brain, more strong expression of the sek1 was observed at layers 2 and 6 in cerebral cortex, in Purkinje cells of cerebellum, and also in hypothalamic nuclei. The strongest expression of the sek1 was found in the CA3 region of hippocampus, the region being highly vulnerable to exitotoxicity-induced apoptosis in kainate-treated animal models. Interestingly, SEK1 was localized not only in cytoplasm but in dendrites and/or in nucleus of neurons depending on the regions of adult mouse brain. Taken together, these results suggest multiple roles of the SEK1 during embryogenesis and in adult brain.

Age Factors↗

PubMed1999

Evidence for the presence of a functional pregnane X receptor response element in the CYP3A7 promoter gene.

Pregnane X Receptor (PXR) has been recently shown to regulate the inducible expression of CYP3A genes in response to xenobiotics and steroids. PXR forms a heterodimer with the retinoic acid receptor (RXR) and this complex binds to and transactivates an 18bp region containing two everted repeats TGA(A/C)CT separated by 6 nucleotides (ER6) and located at approximately -150 in the CYP3A4 promoter. In this work we have isolated and sequenced the proximal 5'-flanking region of CYP3A7 from two different human genomic libraries. In contrast to a previously reported sequence (Itoh et al., 1992), we did not observe any mutation in the 3'-half of the CYP3A7 ER6 element. Using electrophoretic mobility shift assays and cotransfection experiments we show that this element is able to bind the PXR:RXR complex and transactivates the expression of a down stream promoter in response to rifampicin, clotrimazole, and RU-486, three compounds known to specifically activate the human PXR. This is consistent with the fact that CYP3A7 mRNA is inducible in several primary cultures of human hepatocytes from different patients, as well as in two hepatocarcinoma cell lines HuH7 and HepG2, in response to these compounds. In contrast to a previous report (Blumberg et al., 1998), based on the sequence published by Itoh et al., we conclude that CYP3A7, like CYP3A4, is inducible in response to xenobiotics and presumably in a large proportion of the population.

Adult↗

PubMed1976

[The histogenesis of Kaposi sarcoma: a histochemical and electronmicroscopical study (author's transl)].

UNLABELLED: 1. Histologically, Morbus Kaposi is primarily characterized by a proliferation of streams composed of spindle-shaped cells, by vascular slits lined by cells, and by a minor cellular inflammatory reaction. 2. The cells lining the vascular slits resemble endothelial cells and exhibit strong alkaline phosphatase activity and a clear leucinaminopeptidase activity. They contain Weibel-Palade bodies. 3. The ultrastructural analysis of the tumor cells shows a proliferative formation resembling capillary sprouts with and without lumina. The lumina are composed primarily of poorly differentiated endothelial cells. A second typical cellular component are fibroblast-like tumor cells possibly derived from perithelial cells. 4. Indicative of M.K. are also extravasation and phagocytosis of erythrocytes with intracytoplasmic decomposition, and storage of myelinlike structures somewhat resembling Schwannian-cells. 5. CONCLUSION: M.K. is characterized by a multifocal neoplasia of capillary like structures and by a progressive sarcomatous development.

Aged↗

PubMed2000

Growth and paracrine factors regulating follicular formation and cellular function.

The purpose of this paper is to review, using fetal sheep as the animal model, aspects of ovarian development related to follicular formation and to report on the identity of growth and paracrine factors which might be involved in this process. Before follicular formation there is a massive and sustained colonisation of the fetal ovary by mesonephric cells, which become a precursor source of follicular cells. From within the ovarian medulla, somatic 'cell-streams' branch into the cortex around nests of oogonia and oocytes. These 'cell-streams', which contain elongated cells with either flattened or cuboidal shaped nuclei, express steroidogenic factor-1 (SF-1), steroid acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), cytochrome P450(scc), and P450(aromatase) mRNA and/or protein. Follicles form from the association of an oocyte with the 'cell-stream' with either a single layer of flattened cells (i.e. type 1 follicle) or with a mixture of flattened and cuboidal cells (i.e. type 1a follicle). These newly-formed follicles have between 3 and 57 somatic cells (i.e. granulosa cells) and contain oocytes which vary in diameter between 23 and 52 microm. Newly formed and early growing follicles have been identified with growth factors or growth factor receptors in either the oocytes or granulosa cells. Many of the growth factors are from the TGFbeta superfamily and are expressed in a cell- and stage-specific manner.

Animals↗

PubMed1993

[A study of goblet cells in the rat nasal septum by quantitative histological techniques].

The number and area of goblet cells in the normal rat septum were examined quantitatively using a whole-mount method and image analysis. With this approach, the number of goblet cells can easily be counted and quantitative analysis of secretory granules under different conditions can be determined histologically. When the whole mucosa of the nasal septum was divided from anterior to posterior into 8 equal sections, the third and fourth sections contained many large goblet cells. This finding may reflect the physiological role of the nasal mucosa, which warms and humidifies nasal air streams. The distribution of goblet cells in the nasal septum seems to be complementary with that of glandular orifices, which may serve the purpose maintaining the mucous blanket in the nasal cavity. ACh perfusion demonstrated an area of alcian-blue-positive secretory granules in goblet cells which decreased immediately afterwards, but recovered in 10 minutes. These results strongly suggest that ACh initially increases secretion in goblet cells and then enhances the production of secretory granules in these cells approximately 10 minutes later. IPR perfusion, on the other hand, showed an area of alcian-blue-positive secretory granules in goblet cells which decreased 30 minutes after treatment. Furthermore, there was variety in the area of each goblet cell. These results strongly suggest the possibility that IPR may slowly elevate secretion from goblet cells. It seems most likely that goblet cells have the same secretory reaction characteristics to autonomic nerve agents as glandular secretory cells.

Animals↗

PubMed1991

Light and dark active phosphodiesterase regulation in salamander rods.

We studied the activation of 3',5'-cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) by using a cell-permeant enzyme inhibitor. Rods of Ambystoma tigrinum held in a suction electrode were jumped into a stream of 3-isobutyl-1-methylxanthine (IBMX), 0.01-1 mM. Initial transient light-sensitive currents fit the notion that dark and light-activated forms of PDE contributed independently to metabolic activity and were equivalently inhibited by IBMX (apparent Ki 30 microns). Inhibition developed within 50 ms, producing a step decrease of enzyme velocity, which could be offset by activation with flashes or steps of light. The dark PDE activity was equivalent to light activation of enzyme by 1,000 isomerization rod-1s-1, sufficient to hydrolyze the free cGMP pool (1/e) in 0.6 s. Steady light activated PDE in linear proportion to isomerization rate, the range from darkness to current saturation amounting to a 10-fold increase. The conditions for simultaneous onset of inhibitor and illumination to produce no net change of membrane current defined the apparent lifetime of light-activated PDE, TPDE* = 0.9 s, which was independent of both background illumination and current over the range 0-3 x 10(5) isomerization s-1, from 50 to 0 pA. Adaptation was a function of current rather than isomerization: jumps with different proportions of IBMX concentration to steady light intensity produced equal currents, and followed the same course of adaptation in maintained light, despite a 10-fold difference of illumination. Judged from the delay between IBMX- and light-induced currents, the dominant feedback regulatory site comes after PDE on the signal path. The dark active PDE affects the hydrolytic flux and cytoplasmic diffusion of cGMP, as well as the proportional range of the cGMP activity signal in response to light.

1-Methyl-3-isobutylxanthine↗

PubMed1996

Histopathological changes in the islets of Langerhans in hamsters infected with the 139H strain of scrapie: semi-thin section study.

Using histopathological analysis of semi-thin sections stained with toluidine blue, we observed profound pathological changes in the islets of Langerhans of hamsters infected with the scrapie agent (strain 139H). These included cytoplasmic vesicles, nuclear swelling, and vacuolization in the islet cells. Two types of vacuolization were seen. "Localized vacuolization" (LV) has a distinct edge and is restricted or confined within the cell. "Diffuse vacuolization" (DV) has no distinct edge and is scattered within tissues either inside or outside of cells. DV may span intracellular and extracellular regions of the islet tissues. There were abnormal structures which we termed blood vessel cores (BVCs) in the islets of 139H-infected hamsters. BVC is a hollow space filled up with blood cells. Immunocytochemical staining for insulin antibody suggested that BVC was surrounded by the B cells of the islet. In the present study, we observed that many inflammatory cells passed through the blood-tissue barriers using pathways between cell-junction in the lumen of BVC. We also observed many necklace-like hollow spaces between islet cells. They are the pockets of extracellular space. A novel concept of "the accordion effect" was described to explain a function of the extracellular space. Under normal physiological conditions, as the synthesis of insulin increase in B cells, the volume of the B cells will increase while the volume of the extracellular space will decrease. After a synchronized secretory response from the stimulated B cells, the secretory product would move from the intracellular space into the extracellular space, the volume of the B cells would be decreased and the volume of the extracellular space would be increased. Most of the secretory product might be released into the blood stream immediately, causing an insulin releasing peak in the blood stream, whereas the rest would remain in the enlarged extracellular space. As the cycle repeat, the increasing volume of the B cells will squeeze the remaining insulin into the blood stream gradually. Thus, the expandable extracellular space would serve as buffer system and a reservoir to collect and store some secretory products for future use. We refer to this concept as "the accordion effect". The concept of "the accordion effect" may also be true in other endocrine organs such as pituitary gland and adrenal gland.

Animals↗

PubMed2005

Circulating osteoprotegerin and soluble RANKL: do they have a future in clinical practice?

The discovery of the signalling system consisting of receptor activator of nuclear factor-KB ligand (RANKL), its receptor RANKL and its decoy receptor osteoprotegerin (OPG) has been a key step in the understanding of pathophysiology of the bone microenvironment and has provided pharmacological targets for new anti-resorptive drugs. The system is central to the interactions among bone, vascular and immune cells. OPG and a soluble form of RANKL (sRANKL) are present in the blood stream. The measurement of their concentrations offers insights into the regulatory mechanisms of the system and the possibility of using new markers in a number of diseases. Besides bone metabolic disorders, the list includes malignancies, rheumatic and cardiovascular diseases. However, apparent discrepancies in the outcome of studies point to a number of caveats: lack of control of pre-analytical and analytical variables; paucity of data on the metabolic removal of the molecules; the cross sectional design of most studies comparing patients with healthy subjects. Finally, circulating OPG and sRANKL derive from several sources, and their concentrations may be alterated by different coexisting pathological processes. In the absence of tissue-specific isoforms, diagnostic or prognostic significance may be suggested from data obtained in large cohorts, but is still of limited usefulness in single patients.

Biomarkers↗