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Biomedical subjects

H Wang

Publications and source records attributed to H Wang.

At least 469 records · Page 26Linked to original sources
PubMed2001

Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats.

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+ were evaluated. In conscious young (5-6 wk old) and adult (10-11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2-0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 microl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular alpha2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus "ouabain" significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain "ouabain" is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.

Adrenergic alpha-Agonists↗
PubMed2001

Nitric oxide decreases lung liquid production via guanosine 3',5'-cyclic monophosphate.

We studied the role of cGMP in nitric oxide (NO)-induced changes in lung liquid production (J(v)) in chronically instrumented fetal sheep. Forty-five studies were done in which J(v) was measured by a tracer dilution technique. Left pulmonary arterial flow (Q(lpa)) was measured by a Doppler flow probe. There were two series of experiments. In the first, we gave 8-bromo-cGMP, a cGMP analog, by either the pulmonary vascular or intraluminal route; in the second, we used agents to inhibit or enhance endogenous cGMP activity. When infused directly into the pulmonary circulation, 8-bromo-cGMP significantly increased Q(lpa) but had no effect on J(v). Conversely, when instilled into the lung liquid, 8-bromo-cGMP had no effect on Q(lpa) but significantly reduced J(v). Inhibition of guanylate cyclase activity with methylene blue totally blocked, whereas phosphodiesterase inhibition with Zaprinast significantly enhanced, the effect of instilled NO on J(v). Thus the reduction in lung liquid caused by NO appears to be mediated by cGMP, perhaps through a direct effect on the pulmonary epithelium.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Nystatin and valinomycin induce tubuloglomerular feedback.

The macula densa expresses a luminal Na(+)-K(+)-2Cl(-) cotransporter and a basolateral Cl(-) conductance. Although it is known that cotransport of Na(+), K(+), and Cl(-) is the first step in tubuloglomerular feedback (TGF), subsequent steps are unclear. We hypothesized that Na(+)-K(+)-2Cl(-) entry via the luminal Na(+)-K(+)-2Cl(-) cotransporter elevates intracellular Cl(-), increases electrogenic Cl(-) efflux across the basolateral membrane, and depolarizes the macula densa, initiating TGF. We perfused afferent arterioles with macula densa attached. The macula densa was perfused with solutions containing either 5 mM Na(+) and 3 mM Cl(-) (low NaCl) or 80 mM Na(+) and 77 mM Cl(-) (high NaCl). When the macula densa perfusate was changed from low to high NaCl, afferent arteriole diameter decreased from 15.8 +/- 0.8 to 13.1 +/- 0.7 mm (P < 0.05). Adding 10 microM furosemide to the macula densa lumen blocked TGF. When nystatin, a group I cation ionophore, was added to the macula densa lumen together with furosemide in the presence of low NaCl, it induced TGF (from 18.0 +/- 1.5 to 15.6 +/- 1.6 mm; P = 0.003). When valinomycin, a K(+)-selective ionophore, was added to the macula densa lumen together with furosemide in the presence of low NaCl containing 5 mM K(+), it did not induce TGF. Subsequent addition of 50 mM KCl to the macula densa perfusate induced TGF (from 21.7 +/- 0.8 to 17.5 +/- 1.3 mm; P = 0.0047; n = 6). Adding 50 mM KCl without valinomycin did not induce TGF. When 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 1 microM), a Cl(-) channel blocker, was added to the bath, it blocked TGF induced by high NaCl, but did not block TGF induced by valinomycin plus 50 mM KCl. NPPB did not alter afferent arteriole constriction induced by norepinephrine. We concluded that increased NaCl in the lumen of the macula densa leads to influx of Cl(-) via the Na(+)-K(+)-2Cl(-) cotransporter. The accelerated transport increases intracellular Cl(-). The subsequent exit of Cl(-) across the basolateral membrane via Cl( -) channels in turn leads to depolarization of the macula densa and thereby induces TGF.

Animals↗
PubMed2001

Pre-Bötzinger neurons with preinspiratory discharges "in vivo" express NK1 receptors in the rat.

Substance P stimulates respiration, in part by a direct action on the pre-Bötzinger complex (preBötC). This region of the medulla oblongata contains neurons that are strongly immunoreactive for the neurokinin-1 receptor (NK1R-ir), and a recent theory has postulated that these cells might be the adult form of excitatory interneurons that are essential for respiratory rhythmogenesis in neonates. Here we sought to determine whether preBötC respiratory neurons are indeed NK1R-ir in the adult rat. Preinspiratory (pre-I) neurons were recorded in the preBötC region of halothane-anesthetized rats. Most pre-I cells could be antidromically activated from the contralateral side of the medulla (7 of 10; latency 1.3 +/- 0.2 ms), suggesting that most of them were propriomedullary neurons rather than respiratory motoneurons or bulbospinal cells. Thirty-two pre-I neurons including seven cells with contralateral projection were labeled with biotinamide using the juxtacellular method. Eleven cells (34.4%) were NK1R-ir, including three of the seven pre-I cells that were antidromically activated from the contralateral side. In 3 control rats we labeled 20 preBötC neurons with patterns of discharge other than pre-I and found that none were detectably NK1R-ir. In conclusion, some of the intensely NK1R-ir neurons of the adult preBötC region are indeed respiratory interneurons as suggested by Gray et al. The subtype of NK1R identified by the antibody is detectable only in a small minority of preBötC respiratory cells, most notably in pre-I interneurons. Given prior anatomical evidence, these NK1R-ir pre-I interneurons are most likely glutamatergic. The data are consistent with the possibility that the NK1R-ir pre-I interneurons of the adult preBötC could be the adult form of a class of inspiratory neurons that are rhythmogenic in the neonate (either the pacemakers and/or an excitatory subtype of follower neurons).

Animals↗
PubMed2001

Inhibition of ryanodine binding to sarcoplasmic reticulum vesicles of cardiac muscle by Zn(2+) ions.

Using the assay of [(3)H]ryanodine binding to the sarcoplasmic reticulum, the effect of Zn(2+) on ryanodine receptors (RyRs) of cardiac muscle was investigated. There was no obvious change in the binding at [Zn(2+)](f) of less than 0.2 microM. However, a decrease of the binding became significant with raising [Zn(2+)](f) to 0.5 microM. The inhibitory effect of Zn(2+) was [Zn(2+)](f)-dependent, with IC(50/ZnI) of 2.1+/-0.4 microM (mean+/-S.D.). Scatchard analysis indicates that both an increase of K(d) and a decrease of B(max) were responsible for Zn(2+)-induced decrease of the binding. The Hill coefficient for this inhibitory effect of Zn(2+) was between 0.8 and 1.2. The interactions of the effects of Zn(2+) and various modulators of RyR indicate that the inhibitory effect of Zn(2+) was mostly mediated through inhibiting Ca(2+) activation sites (CaA) on RyR. Since the [Zn(2+)](f) dependence was not clearly changed by [Ca(2+)](f), the inhibitory effect of Zn(2+) may not be due to competition of Zn(2+) with Ca(2+) for CaA and probably is indirect. The inhibitory effect of Zn(2+) could not be antagonized by 2 mM dithiothreitol, a thiol-reducing agent, suggesting that the binding of Zn(2+) ions to RyRs of cardiac muscle is not accompanied by obvious change of redox state of the RyRs. In comparison with that seen in skeletal muscle [3], the effects of Zn(2+) on ryanodine binding to the sarcoplasmic reticulum of cardiac muscle show several distinct differences. It is indicated that the effect of Zn(2+) on RyRs may be isoform-dependent. The physiological significance of the effects of Zn(2+) is discussed.

Animals↗
PubMed2001

Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats.

BACKGROUND AND PURPOSE: CD44 is a transmembrane glycoprotein involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. The present report describes the discovery of upregulated CD44 gene expression and its spatial and temporal distribution in the brain after focal stroke. METHODS: Rats were subjected to permanent occlusion of the middle cerebral artery (MCAO). Suppression subtractive hybridization (SSH) strategy was used to identify differentially expressed genes. Northern blotting and real-time polymerase chain reaction were used to evaluate the expression of CD44 and hyaluronan synthase 2 (HAS-2) mRNA. Western blotting and immunohistochemistry were used to examine CD44 expression and cellular distribution. RESULTS: CD44 upregulation after focal stroke was discovered by the SSH approach and confirmed by DNA sequencing. Northern blot using a pooled poly(A)+ RNA revealed 3 splice variants of CD44 mRNA, and their inducible expression started at 6 hours (5.3-fold increase over sham operation), peaked at 24 hours (28.6-fold increase), and persisted up to 72 hours (17.8-fold increase) after MCAO. A parallel induction profile of HAS-2 mRNA was observed in the ischemic brain tissue. The levels of CD44 were markedly elevated at 6 hours (1.8-fold increase over sham; n=3), 24 hours (2.9-fold, peak induction; P<0.01), and 72 hours (2.4-fold increase; P<0.05) after MCAO by means of Western analysis. Immunohistochemical and confocal microscopy confirmed that constitutive expression of CD44 is limited to microvessels in normal brain but is strongly induced after ischemia, where the immunoreactive signal mainly resided in endothelial cells and monocytes. Double-labeling immunohistochemistry demonstrated that a marked induction of CD44 in the ischemic lesion is dominantly located in microglia and a subset of macrophages. CONCLUSIONS: The discovery of concomitant induction of CD44 and HAS-2 mRNA expression and the localization of CD44 in the microglia, macrophages, and microvessels of the ischemic brain tissue suggest that an active interaction between CD44 and hyaluronan may occur and play a role in the known inflammatory response and tissue remodeling after stroke.

Alternative Splicing↗
PubMed2001

Human gamma/delta T-cell lines derived from airway biopsies.

gamma/delta T cells have been postulated to play an important role in the immune response at epithelial boundaries, but have not been well described in human lung tissue. We have identified and characterized gamma/delta T-cell lines from human airway biopsies and compared them with T-cell lines from paired peripheral blood samples. Airway-derived T-cell lines stimulated with tetanus toxoid (TT) contained a greater proportion of gamma/delta T cells compared with T-cell lines stimulated with mitogens, other antigens, or without antigen. TT-stimulated airway T cells expressed different T-cell receptors (TCRs) than did blood- derived T cells, and used predominantly variable region (V)gamma I family genes rather than V gamma II family genes. Airway-derived gamma/delta T cells produced high levels of interferon-gamma and were associated with T helper 1--like cytokine profiles. This study describes the presence and antigen-dependent proliferation of gamma/delta T cells from human airway tissue, and demonstrates differences in lung-derived gamma/delta TCRs compared with gamma/delta T cells derived from peripheral blood. The data suggest that gamma/delta T cells may be functionally enriched in human airways relative to peripheral blood.

Biopsy↗
PubMed2001

Cytokine inhibition of fibroblast-induced gel contraction is mediated by PGE(2) and NO acting through separate parallel pathways.

Contraction of three-dimensional collagen gels is a model of the contraction that characterizes normal healing and remodeling after injury. In the current study, we evaluated the hypothesis that a number of inflammatory factors, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and interferon (IFN)-gamma, modulate this process by induction of prostaglandin (PG) E(2) and nitric oxide (NO) production and that these secondary mediators function in an autocrine or paracrine manner to modulate contraction. Human fetal lung fibroblasts (HFL) were cultured in type I collagen gels and floated in medium containing TNF-alpha, IL-1 beta, or IFN-gamma alone or in combination (cytomix). All cytokines inhibited the contraction significantly. The potency order was IL-1 beta, TNF-alpha, IFN-gamma. The cytomix was no more potent than was IL-1 beta alone. PGE(2) production was increased by TNF-alpha (5.0 versus 0.16 ng/ml, P < 0.01), IL-1 beta (5.3 versus 0.16 ng/ml, P < 0.01), and cytomix (5.9 versus 0.16 ng/ml, P < 0.01), and was completely inhibited by indomethacin. Indomethacin (P < 0.05) and L-NG-monomethyl arginine citrate (L-NMMA) (P < 0.05) alone both partially attenuated the inhibition of contraction caused by cytokines alone or by cytomix. Indomethacin and L-NMMA together attenuated inhibition more than either alone (P < 0.05). Exogenous PGE(2) and exogenous NO donors (DETA nononate and 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride) inhibited the contraction significantly. The protein kinase A inhibitor KT5270 and the protein kinase G inhibitor Rp-pCPT-cGMPS attenuated the inhibition induced by PGE(2) and NO, respectively. In summary, PGE(2) and NO appear to function in parallel as autocrine/paracrine mediators of cytokine-driven fibroblast inhibition of the contraction of collagen gels and may contribute to remodeling during repair and inflammation in lung disorders.

Animals↗
PubMed2001

Retinoic acid attenuates cytokine-driven fibroblast degradation of extracellular matrix in three-dimensional culture.

Proteolytic degradation of extracellular matrix is thought to play an important role both in emphysema and in tissue development and repair. Retinoic acid has been suggested to modify tissue injury, and in an animal model of emphysema may induce alveolar repair. Since cytokines can induce matrix metalloproteinase (MMP) production in fibroblasts and neutrophil elastase (NE) can activate MMPs, we hypothesized that retinoic acid could attenuate collagen degradation by modifying MMP production and activation. To evaluate this, human lung fibroblasts were cast into native type I collagen gels and floated in medium containing cytomix (TNF-alpha, IL-1beta, and IFN-gamma) alone or in combination with NE in the presence and absence of retinoic acid (1 microM). After 5 d, cytomix with elastase induced significant degradation of the collagen gels assessed by quantifying total hydroxyproline (41.6 +/- 1.6 microg versus 3.3 +/- 1.5 microg, P < 0.01). Retinoic acid significantly inhibited this degradation (23.3 +/- 1.5 microg versus 3.3 +/- 1.5 microg, P < 0.01). Gelatin zymography and Western blot revealed that MMP-1, MMP-3, and MMP-9 were induced by cytomix and that co-exposure to NE resulted in increased production of activated forms of these enzymes. Retinoic acid attenuated the induction and activation of MMP-1 and MMP-3. The current study, therefore, suggests that in addition to stimulating anabolic effects, retinoic acid may modulate proteolytic processes thought to contribute to tissue destruction in emphysema.

Animals↗
PubMed2001

Cigarette smoke inhibits human bronchial epithelial cell repair processes.

By interfering with the ability of airway epithelial cells to support repair processes, cigarette smoke could contribute to alterations of airway structures and functions that characterize chronic obstructive pulmonary disease (COPD). The current study assessed the ability of cigarette smoke extract (CSE) to alter human airway epithelial cell chemotaxis, proliferation, and contraction of three-dimensional collagen gels, a model of extracellular matrix remodeling. The volatile components contained in cigarette smoke, acetaldehyde and acrolein, were able to inhibit all three processes. Nonvolatile components contained within lyophilized CSE also inhibited chemotaxis but displayed no activity in the other two bioassays. CSE also inhibited the ability of airway epithelial cells to release transforming growth factor (TGF)-beta and fibronectin. Exogenous fibronectin was unable to restore epithelial cell contraction of collagen gels. Exogenous TGF-beta partially restored the ability of airway epithelial cells to contract collagen gels and to produce fibronectin. This supports a role for inhibition of TGF-beta release in mediating the inhibitory effects of cigarette smoke. Taken together, the results of the current study suggest that epithelial cells present in the airways of smokers may be altered in their ability to support repair responses, which may contribute to architectural disruptions present in the airways in COPD associated with cigarette smoking.

Acetaldehyde↗
PubMed2001

Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34(-)/low, c-Kit(+), Sca-1(+)) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and alpha-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.

Animals↗
PubMed2001

The novel gene locus for agenesis of permanent teeth (He-Zhao deficiency) maps to chromosome 10q11.2.

He-Zhao deficiency has been recently characterized with a distinct form of agenesis of permanent teeth that is different from other previously reported disorders of tooth agenesis. This inherited abnormality suggests that some gene(s) associated with the development of permanent teeth may mutate. In this study, we map the gene locus to chromosome 10q11.2. The DNA pooling method combined with two-point and multi-point linkage analysis has been successfully applied. The maximum LOD (Zmax) scores for two-point and multi-point analyses are 13.29 (on marker D10S196) at recombination fraction (theta) = 0 and 18.09 (between markers D10S1772 and D10S1766), respectively. Haplotype analysis confined the locus within an interval of 5.5 cM flanked by markers D10S604 and D10S568. This study has demonstrated a novel gene locus responsible for He-Zhao deficiency and provides a good likelihood for the discovery of one of the genes determining permanent tooth formation and development.

Alleles↗
PubMed2001

Dual roles for HMGB1: DNA binding and cytokine.

Effective therapies against overwhelming Gram-negative bacteremia, or sepsis, have eluded successful development. The discovery that tumor necrosis factor (TNF), a host-derived inflammatory mediator, was both necessary and sufficient to recapitulate Gram-negative sepsis raised cautious optimism for developing a targeted therapeutic. However, the rapid kinetics of the TNF response to infection defined an extremely narrow window of opportunity during which anti-TNF therapeutics could be successfully administered. HMGB1 was previously studied as a DNA-binding protein involved in DNA replication, repair, and transcription; and as a membrane-associated protein that mediates neurite outgrowth. A decade-long search has culminated in our identification of HMGB1 as a late mediator of endotoxemia. HMGB1 is released by macrophages upon exposure to endotoxin, activates many other pro-inflammatory mediators, and is lethal to otherwise healthy animals. Elevated levels of HMGB1 are observed in the serum of patients with sepsis, and the highest levels were found in those patients that died. The delayed kinetics of HMGB1 release indicate that it may be useful to target this toxic cytokine in the development of future therapies.

Animals↗
PubMed2001

Interstimulus interval effect on event-related potential N270 in a color matching task.

Event-related brain potentials were recorded in a matching task, in which subjects were asked to discriminate if the color of the second stimulus (S2) was the same as the first stimulus (S1). The interstimulus interval between the two stimuli of a pair was of three levels (150 ms, 500 ms and 1000 ms). A negative component about 270 ms after the presentation of S2 was elicited when the color of the two stimuli was not identical for the interstimulus interval of 500 ms and 1000 ms, but not for the interval of 150 ms. This may suggest that N270 represented the response of the brain to conflicting information between different cortical levels.

Adult↗
PubMed2001

Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice.

The present study investigates the physiological significance of dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, androstenedione (Delta(4)), dihydrotestosterone (DHT), estrone (E1), and E2 on recombinant human FSH- (rhFSH) resistant type 4 follicles obtained from immature mice. Type 4 follicles of a diameter of 100-120 microm with one or two granulosa cell layers around the oocyte and an intact basal lamina with theca cells were isolated from the ovaries of 11-d-old BDF-1 mice and cultured with medium alone (control) or with dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, Delta(4), DHT, E1, or E2 at concentrations ranging from 1 x 10(-11) to 1 x 10(-7) M for 4 d. We examined the mean diameters of type 4 follicles, levels of immunoreactive (IR)-inhibin, and E2 and progesterone in the culture media on day 4. In addition, we evaluated follicular cell proliferation by immunofluorescence staining with 5-bromo-2'-deoxyuridine. All tested androgens significantly increased the diameter of type 4 follicles in a dose-dependent manner without the production of IR-inhibin and E2. The nuclei of granulosa cells in type 4 follicles cultured with all tested androgens exhibited intense 5-bromo-2'-deoxyuridine-positive staining, compared with those of controls. In contrast, neither E1 nor E2 had any stimulatory effects. The stimulatory effects of T, Delta(4), or DHT were inhibited by an AR antagonist in a dose-related fashion but not by an aromatase inhibitor. Furthermore, all tested androgens had a synergistic effect with rhFSH on follicular growth and the production of IR-inhibin and E2. These results demonstrated that neither adrenal nor ovarian androgens are arteriogenic but that they stimulate type 4 follicles unresponsive to rhFSH and augment the responsiveness of these follicles to rhFSH.

Adrenal Glands↗
PubMed2001

Beta-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1 alpha induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice.

Mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) cause maturity-onset diabetes of the young 3, a severe form of diabetes characterized by pancreatic beta-cell dysfunction. We have used targeted expression of a dominant-negative mutant of HNF-1 alpha to specifically suppress HNF-1 alpha function in beta-cells of transgenic mice. We show that males expressing the mutant protein became overtly diabetic within 6 wk of age, whereas females displayed glucose intolerance. Transgenic males exhibited impaired glucose-stimulated insulin secretion, detected both in vivo and in the perfused pancreas. Pancreatic insulin content was markedly decreased in diabetic animals, whereas the glucagon content was increased. Postnatal islet development was altered, with an increased alpha-cell to beta-cell ratio. beta-Cell ultrastructure showed signs of severe beta-cell damage, including mitochondrial swelling. This animal model of maturity-onset diabetes of the young 3 should be useful for the further elucidation of the mechanism by which HNF-1 alpha deficiency causes beta-cell dysfunction in this disease.

Animals↗
PubMed2001

Elevated androgens and prolactin in aromatase-deficient mice cause enlargement, but not malignancy, of the prostate gland.

Although androgens are the main steroids controlling the growth of the mammalian prostate, increasing evidence demonstrates that estrogens also regulate prostate development and growth. This study describes the effects of estrogen deficiency using aromatase knockout mice (ArKO) with targeted disruption of the cyp19 gene. Serum and tissue testosterone and 5alpha-dihydrotestosterone as well as serum PRL levels are significantly (P < 0.05) elevated in mature male ArKO mice. Histological, stereological, and immunohistochemical studies demonstrated enlargement of the ventral, anterior, and dorsolateral lobes of the prostate in young and older ArKO mice. Hyperplasia of the epithelial, interstitial, and luminal compartments was identified and associated with up-regulation of androgen receptors. There was no evidence of malignancy as the animals aged (up to 56 weeks). The changes observed in the prostates of ArKO mice were unaffected by maintaining mice on regular or soy-free diets. It is concluded in ArKO mice that, despite the long-term elevation of androgens and PRL, the absence of estrogen in these animals does not result in induction of malignancy in the prostate gland.

Androgens↗