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PubMed2000

Energy, water balance and the roost microenvironment in three Australian cave-dwelling bats (Microchiroptera).

The ghost bat, Macroderma gigas, and the orange leaf-nosed bat, Rhinonycteris aurantius, occupy similar ranges across northern Australia and are often found in the same roost caves. Both species are considered rare and vulnerable to further population decline. A third small species, the large bent-wing bat, Miniopterus schreibersii, has a similar body mass to R. aurantius, but has one of the largest ranges of any Australian mammal. In the present study we examine the effect and sensitivity of the animals' roosting microclimates on their energy and water balance. M. schreibersii exhibits a basal metabolic rate about 40% greater than other bats of similar body mass, whereas the other two species are close to predicted levels. R. aurantius shows a decrease in body temperatures below thermoneutrality. R. aurantius has levels of pulmocutaneous water loss among the highest seen for a mammal, and calculations based on nasal tip temperatures suggest that most of this loss is across the skin. Calculated ambient temperatures at which metabolic water production is equal to pulmocutaneous water loss in dry air are -14.7 degrees C for R. aurantius, 9.8 degrees C for M. schreibersii and -0.3 degrees C for M. gigas. Exposing the animals to relative humidities of between 80% and 90% shifted these calculated temperatures to 5.6 degrees C, 25.2 degrees C, and 2.9 degrees C, respectively. For each species the ratio of metabolic water production to evaporative water loss has been treated as a joint function of humidity and ambient temperature. The resulting surface plot shows that under known roosting conditions in caves R. aurantius and M. schreibersii remain in positive water balance, whereas M. gigas does not.

Animals↗
PubMed2006

Toll-like receptors 2, 3 and 4 (TLR-2, TLR-3 and TLR-4) are expressed in the microenvironment of human acquired cholesteatoma.

Human toll-like receptors (TLR 1-10) are crucial in the induction and activation of innate immunity in the course of an infection. They are expressed mainly on the cells of the immune system, and also on some epithelia and endothelia. Their ligands so called pathogen associated molecular patterns are abundant on invading microbes. TLR-ligand binding results in cell signal transduction and subsequent production of various proinflammatory cytokines such as IL-1 and TNF-alpha. Acquired cholesteatoma is formed during chronic otitis media in the proportion of cases. It has adverse effects on ear structures, resulting in osteolysis and bone resorption. Its formation and pathogenesis are not fully understood. The current study attempted to search the possible role of TLRs in this somewhat awkward pathological condition. Surgical specimens of human acquired cholesteatoma (n=15) and normal external auditory canal skin (n=5, control tissues) were tested by immunohistochemistry for the presence of TLRs. Three TLRs were examined: TLR-2, TLR-3 and TLR-4. All TLRs tested were demonstrated in matrix (layer of keratinizing epithelium) and perimatrix (granulation tissue) of this inflammatory tumour. Expression of particular TLRs within the keratinizing epithelium was distinct and uneven. In the perimatrix, numerous T (CD3+) cells were seen and relatively few macrophages (CD11c+, HLA-DR+). There was a weak expression of all TLRs on normal (non-inflammatory) skin. Expression of TLR-3 both on the epithelium and some cells within the perimatrix and the presence of T cells may suggest that apart from innate immune responses, mechanisms of adaptive immunity also operate in cholesteatoma. Weak expression of these receptors on normal skin may also suggest the important role of TLRs in the etiopathogenesis of cholesteatoma.

Adolescent↗
PubMed1998

Microenvironment of Gyrodactylus derjavini on rainbow trout Oncorhynchus mykiss: association between mucous cell density in skin and site selection.

Microhabitat selection of Gyrodactylus derjavini on the body surface of rainbow trout changed markedly during a 6-week experimental infection period. Pectoral fins, pelvic fins and anal fins were the most important sites (expressed in terms of parasite density) during the initial part of the infection. In the later stages of infection, the corneal surface and tail fin became increasingly more heavily infested. Factors responsible for this dynamic site selection were investigated. The density of superficial mucous cells in the epithelium of fins and skin was weakly correlated (r = 0.23) with parasite density in the first part of the infection. This association changed into a significant negative correlation (r = -0.92) as the infection progressed and the parasite population increased. These results strongly indicate that mucous cell contents play a decisive role in gyrodactylid site selection. Lysozyme, protease, immunoglobulin (Ig), complement factor C3, enzymes, lectinbinding carbohydrates and peptides adrenocorticotropic hormone, interleukin (IL-1) and somastatin) were detected in mucus and some of these (Ig, C3, IL-1, carbohydrates) are suggested to influence the infection dynamics. Thus, some molecules in mucus are liable first to attract the gyrodactylids, but subsequently reactive substances present in increasing amounts will counteract the performance of parasites in mucous-cell-rich microhabitats. The mechanisms involved in this process are discussed.

Animals↗
PubMed2004

Bone marrow subendosteal microenvironment harbours functionally distinct haemosupportive stromal cell populations.

In adult animals, bone marrow is the major site of blood cell production, which is controlled by interactions between the local stroma and blood cell progenitors. The endosteal/subendosteal environment comprises bone-lining and adjacent reticular cells and sustains haemopoietic stem cell (HSC) self-renewal, proliferation and differentiation. We have questioned the specific role of each of these stroma cells in controlling HSC fate. We have isolated two distinct stroma-cell populations containing subendosteal reticulocytes (F-RET) and osteoblasts (F-OST) from periosteum-free fragments of murine femurs by a two-step collagenase-digestion procedure. Both populations produce similar extracellular matrix (collagen I, laminin, fibronectin, decorin), except for collagen IV, which is low in F-OST. They also express osteogenic markers: osteopontin, osteonectin, bone sialoprotein and alkaline phosphatase (ALP). The quantity and activity of ALP are however higher in F-OST. When co-cultured with bone marrow mononuclear cells or lineage-negative haemopoietic progenitors, F-OST stroma induces low proliferation and high maintenance of early haemopoietic progenitors, whereas F-RET stroma induces high short-term proliferation and differentiation. Analysis by reverse transcription/polymerase chain reaction has revealed higher levels of Jagged-1 expression by F-OST cells than by the F-RET population. Thus, two adjacent stroma cells (subendosteal and endosteal) play distinct roles in controlling the stem-cell capacity and fate of HSC and probably contribute distinctly to HSC niche formation.

Alkaline Phosphatase↗
PubMed1998

Ontogeny of NADPH-d expression in the thymic microenvironment of the chick embryo.

Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry was used to demonstrate the presence of nitric oxide in the developing chicken thymus. NADPH-d was first expressed in the epithelial cells located at the corticomedullary junction of the thymic rudiment on day 13 of incubation. The number of labelled cells gradually increased from day 13 to day 21. Ultrastructural evidence showed that the labelling was localized in a heterogeneous population of cells in the medulla near the corticomedullary junction, comprising the cystic, undifferentiated, myoid, lymphoid and epithelial reticular cells. At this age, the vascular endothelium was NADPH-d positive. Labelling was also detected in some macrophages. The reaction product primarily labelled profiles of rough endoplasmic reticulum and to a lesser extent the outer membranes of mitochondria, portions of the nuclear envelope and the Golgi apparatus. By day 18/19, NADPH-d-labelled nerve fibres were occasionally observed in the interlobular connective tissue. By day 21, these fibres formed perivascular plexuses. Labelled nerve fibres were occasionally observed in the medullary parenchyma. Possible functions of nitric oxide in the embryonic thymus are discussed.

Animals↗
PubMed2004

Reduction of solar UV-B mediates changes in the Sphagnum capitulum microenvironment and the peatland microfungal community.

The influence of near-ambient and reduced solar UV-B radiation on a peatland microfungal community was assessed by exposing experimental plots to UV-selective filtration. Replicate plots were covered with special plastic films to effect treatments of near-ambient and attenuated solar UV-B. The microfungal community from the top 1 cm of Sphagnum capitulum in a Tierra del Fuego peatland was censused throughout three growing seasons, between 1999 and 2002. Sphagnum capitula under near-ambient UV-B were more compressed and held more water than capitula under reduced UV-B. This water had a greater conductivity and was more acidic under near-ambient UV-B, as would be expected with increased leaching from the Sphagnum leaves. Nine regularly occurring hyphal fungi from the peatland were identified, at least to genus. Over three field seasons, no treatment effect on total fungal colony abundance was recorded, but individual species abundance was increased (Mortierella alpina), decreased (Penicillium frequentans), or was unaffected (P. thomii, Aureobasidium) by near-ambient UV-B. Species richness was also slightly lower under near-ambient UV-B. These treatment differences were smaller than seasonal or inter-annual fluctuations in abundance and species richness. In a growth chamber experiment, lamp UV-B treatments indicated that realistic fluxes of UV-B can inhibit fungal growth in some species. In addition to this direct UV-B effect, we suggest that changes in the peatland fungal community under near-ambient solar UV-B may also result from increased nutrient and moisture availability in the Sphagnum capitulum. The subtle nature of the responses of peatland fungi to solar UV-B suggests that most fungal species we encountered are well adapted to current solar UV-B fluxes in Tierra del Fuego.

Biomass↗
PubMed2002

Impact of laparoscopic gases on peritoneal microenvironment and essential parameters of cell function.

UNLABELLED: Several experimental studies confirm the hypotheses that laparoscopic gases influence the development of tumor metastases [12, 14, 23]. The mechanism for this alteration of malignant tumor growth is still unknown. One reason might be an influence of the in sufflation gas on essential cell function regulating parameters. To investigate the changes of the intra- and extracellular milieu, four parameters--extra- and intracellular pH, intracellular free calcium levels, and tissue oxygen partial pressure--were measured during insufflation with carbon dioxide (CO2), helium (He), or a nonhypoxic gas mixture consistent of 80% CO2 and 20% O2. STUDY DESIGN: (In vitro experiments) Intracellular calcium and pH levels were measured in DHD/K12/TRb colon adenocarcinoma cells using fluorescence imaging microscopy. (In vivo experiments) Tissue oxygen partial pressure was measured using a flexible micro catheter (Licox CMP) implanted in the abdominal wall of rats. After establishing the pneumoperitoneum an optical system and an aspirator were inserted to control the position of the micro catheter and to aspirate wound exudates for pH measurements of the wound fluid. RESULTS: Creating of pneumoperitoneum with both CO2 and helium caused a decrease in partial pressure of oxygen in the abdominal wall to about 5 mm Hg whereas insufflation with a nonhypoxic gas mixture (80% CO2 and 20% O2) induced no significant changes. The intra- and extra cellular pH values dramatically decreased during CO2 insufflation (7.4 to 6.2) in vitro. Helium caused a pH increase up to 7.6. Free intracellular calcium was enhanced during CO2 insufflation, whereas helium insufflation did not cause any changes in [Ca2+]i. Nevertheless, a significant decrease of [Ca2+]i was observed during reoxygenation following helium-induced hypoxia. CONCLUSION: Our study demonstrates that insufflation with either CO2 or He causes significant changes of intra- and extracellular parameters regulating essential cell functions such as oxidative phosphorylation to produce ATP, cell proliferation, or onset of apoptosis.

Acidosis↗
PubMed2006

Does the tumor microenvironment influence radiation-induced apoptosis?

UNLABELLED: Cytotoxic anti-cancer agents induce apoptosis in tumor and normal tissues. Therefore, it is important to investigate which factors determine these apoptotic processes and hence their likely impact on therapeutic gain. Radiation-induced apoptosis in tumors may be inhibited due to mutations of apoptotic elements or to tumor microenvironmental conditions arising from vascular insufficiency. Tumors typically contain regions of hypoxia, low glucose and acidosis. Hypoxic cells compromise treatment partly because of reduced fixation of damage during radiotherapy and partly because they promote a more malignant phenotype. There is also evidence that hypoxia may inhibit apoptosis. For some cell types, concurrent hypoxia may modulate radiation-induced apoptosis while, for others, post-irradiation hypoxia may be required. This may reflect the activity of different apoptotic pathways. Pathways involving mitochondrial components as well as regulation of SAPK and Fas have been implicated. In addition, several key stages in apoptosis are sensitive to depletion of cellular energy reserves, which results from hypoxia and low glucose conditions. There is also evidence that low pH in tumors can interfere with radiation-induced apoptosis, partly through cell cycle arrest and other undefined mechanisms. CONCLUSIONS: Hypoxia, low glucose and acidosis influence radiation-induced apoptosis and thus may be detrimental to radiotherapy.

Animals↗
PubMed2005

Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment.

Integrins play an important role in cellular matrix interactions requisite for cancer cell adhesion, growth, migration and invasion. In this study, we have investigated the expression of integrin subunits alpha3, alpha6, alphav and beta1 in normal ovaries, benign ovarian tumors and ovarian carcinomas of different pathological grades. The expression of these integrins in ovarian cancer cell lines was also investigated, and their role in sustaining proliferation, adhesion, migration and invasion in cohort with the activation of signaling pathways in response to extracellular matrices (ECM) was evaluated. We demonstrate a differential expression pattern of alpha3, alpha6, alphav and beta1 integrin subunits in ovarian carcinomas compared to normal ovaries and benign ovarian tumors. Ovarian cancer cell lines (Hey, Ovcar3 and Peo.36) demonstrated significantly high expression of alpha3, alpha6, alphav and beta1 integrin subunits. A significant increase in proliferation and adhesion (P<0.05) in response to collagen 1 (Coll) and laminin (LM), ligands for integrin receptor alpha3beta1 and alpha6beta1 was observed in ovarian cancer cell lines. On the other hand, fibronectin (FN), a receptor for alphavbeta1 integrin, increased proliferation in all ovarian cancer cell lines studied but only enhanced adhesion in Hey cell line (P<0.05). Neutralizing antibodies against alpha3, alpha6, alphav and beta1 integrin subunits inhibited ECM-induced proliferation, but increased adhesion to ECM was inhibited by beta1 integrin subunit antibody. No suppression of Coll, LM and FN-induced (Hey cells only) adhesion was observed in the presence of alpha3 or alphav subunit antibodies but LM-induced adhesion was inhibited by blocking alpha6 subunit functions. LM, FN and Coll enhanced chemotactic migration in Hey cells, but direct invasion across ECM was observed only in the presence of LM and Coll. Blocking antibodies against alpha3, alpha6 and beta1 integrin subunits inhibited both chemotactic migration and invasion of Hey cells in response to respective ECM. Adhesion of ovarian cancer cells to FN, Coll and LM activated Ras, Erk and Akt pathways. Neutralizing alphav and beta1 functions did not inhibit FN-induced activation of Ras and Erk pathways but inhibited the Akt pathway. On the other hand, antibodies against alpha6 and beta1 subunits, but not alpha3 subunit, inhibited LM-induced activation of Ras but did not inhibit the downstream Akt pathway. Neutralizing beta1 subunit function however, inhibited LM-induced Erk activation. Coll-induced activation of Ras, Erk and Akt pathways was inhibited by alpha3 and beta1 integrin subunit antibodies. These results indicate that alpha3beta1, alphavbeta1 and alpha6beta1 integrin mediate proliferation, adhesion, migration and invasion of ovarian cancer cells in response to ECM and targeting these integrins to modulate integrin-ECM interactions in tumor cells may be a promising tool to reduce the dissemination of ovarian carcinoma in vivo.

Carcinoma↗
PubMed2006

Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas.

TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. The aim of this study was to assess the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. Immunohistochemical analysis two hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens. Currently, NGR-TNF is being tested in clinical studies.

Animals↗
PubMed1989

Stopped-flow chemical modification with N-bromosuccinimide: a good probe for changes in the microenvironment of the Trp 62 residue of chicken egg white lysozyme.

The stopped-flow chemical modification with N-bromosuccinimide (NBS) of Trp 62 of hen (chicken) egg white lysozyme (EC 3.2.1.17) was found to depend greatly on pH: it was not observed at pH's above 7, but it was observed at pH's lower than 6. In addition, at pH's between 6 and 7 the NBS modification showed a delta epsilon pH profile similar to a "titration curve," giving a pK (congruent to 6.5) nearly equal to the pK (congruent to 6.2) of a catalytic residue, Glu 35. The stopped-flow chemical (NBS) modification of N-acetyl-L-tryptophan ethyl ester, a model compound of Trp 62, does not depend on pH at the pH's examined, approximately 3.5-8.5. These experimental results suggest that a change in the state of Trp 62 at Subsite C is induced by protonation-deprotonation of an ionizable residue, which could be Glu 35 (catalytic site), indicating that stopped-flow NBS modification is a good probe for detection of changes in the micorenvironment around the tryptophan residue(s) of enzymes.

Binding Sites↗
PubMed1994

Changes of protein structure, nucleotide microenvironment, and Ca(2+)-binding states in the catalytic cycle of sarcoplasmic reticulum Ca(2+)-ATPase: investigation of nucleotide binding, phosphorylation and phosphoenzyme conversion by FTIR difference spectroscopy.

Changes of infrared absorbance of sarcoplasmic reticulum Ca(2+)-ATPase (EC 3.6.1.38) associated with partial reactions of its catalytic cycle were investigated in the region from 1800 to 950 cm-1 in H2O and 2H2O. Starting from Ca2E1, 3 reaction steps were induced in the infrared cuvette via photolytic release of ATP and ADP: (a) nucleotide binding, (b) formation of the ADP-sensitive phosphoenzyme (Ca2E1P) and (c) formation of the ADP-insensitive phosphoenzyme (E2P). All reaction steps caused distinct changes of the infrared spectrum which were characteristic for each reaction step but comparable for all steps in the number and magnitude of the changes. Most pronounced were absorbance changes in the amide I spectral region sensitive to protein secondary structure. However, they were small--less than 1% of the total protein absorbance--indicating that the reaction steps are associated with small and local conformational changes of the polypeptide backbone instead of a large conformational rearrangement. Especially, there is no outstanding conformational change associated with the phosphoenzyme conversion Ca2E1P-->E2P. ADP-binding induces conformational changes in the ATPase polypeptide backbone with alpha-helical structures and presumably beta-sheet or beta-turn structures involved. Phosphorylation is accompanied by the appearance of a keto group vibration that can tentatively be assigned to the phosphorylated residue Asp351. Phosphoenzyme conversion and Ca(2+)-release produce difference signals which can be explained by the release of Ca2+ from carboxylate groups and a change of hydrogen bonding or protonation state of carboxyl groups.

Adenosine Diphosphate↗