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PubMed1993

Tissue-specific gene expression as an indicator of epididymis-specific functional status in the boar, bull and stallion.

cDNA probes derived from genes expressed specifically in the human epididymis were used to examine gene expression in the epididymides of boar, bull and stallion by Northern hybridization. Two probes for the HE1 and HE4 gene products were found to recognize tissue-specific transcripts in all three species, with a regionally differential distribution within the epididymis. Additionally, antibodies recognizing the HE4 protein were shown to react specifically in the epididymis of the boar and bull. An extensive study of the boar showed that, whereas mRNA for the HE1-homologue was up-regulated markedly only at puberty, the HE4-homologue was already present at moderate levels prepubertally. The distribution of the HE1-homologue changed at sexual maturity from a maximum in the cauda epididymis in the 3-4-week-old pig, to a maximum in the corpus/caput region in the adult, while the shift was in the opposite direction for the HE4-homologue. Evidently, gene expression is not fixed regionally through epididymal development in this species. The abdominal epididymis of a hemicryptorchid pig also showed a differential change in expression for the two gene products by comparison with the scrotal testis from the same animal. The results suggest that the HE1 and HE4 gene homologues may be sensitive markers for physiological changes within the mammalian epididymis, and that the boar could prove a useful model to examine the regulation of these human epididymal transcripts.

Animals↗
PubMedDate not supplied

Function of human epididymal proteins in sperm maturation.

Human post-testicular proteins were cloned by subtractive screening of epididymal cDNA libraries, employing testis as the primary negative control. This method identified six human epididymal cDNAs, named HE1-HE6, which are derived from abundant epididymal mRNAs. With the exception of HE5, which turned out to be identical to the lymphocyte surface antigen CD52, they represented completely novel human gene products. To date, there is little information on their function and the mechanism of their deposition on the sperm surface. Unlike the sperm coating antigens, CD52 binds firmly to the sperm membrane via its GPI anchor during epididymal passage. Its synthesis is carefully regulated by the epididymal epithelium. From the results of both in vivo and in vitro studies it was concluded that androgen and temperature are principal factors synergistically modulating epididymal CD52 expression. The human counterparts of two well-known major rodent epididymal proteins, secretory epididymal glutathione peroxidase (sGPX) and acidic epididymal glycoprotein (AEG = Protein DE), were not cloned by the subtractive screening approach, but by RT-PCR amplification.

Antigens, CD↗
PubMed2003

Keratinocyte expression of human beta defensin 2 following bacterial infection: role in cutaneous host defense.

Human beta defensin 2 (hbetaD-2) is thought to play an important role in cutaneous immune defense. We hypothesized that (i) keratinocyte expression of hbetaD-2, measured by reverse transcription-PCR, would be upregulated in response to challenge with pathogenic bacteria, particularly highly adherent strains of Streptococcus pyogenes and Staphylococcus aureus, and (ii) hbetaD-2 would have potent antimicrobial activity against pathogenic but not commensal organisms. Expression of hbetaD-2 was induced consistently by S. aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa, whereas strains of S. pyogenes were poor and variable inducers of hbetaD-2. No correlation was found between levels of bacterial adherence and keratinocyte expression of hbetaD-2. S. pyogenes was significantly more sensitive to killing by hbetaD-2 than S. epidermidis. We conclude that the ability to induce hbetaD-2 expression in combination with sensitivity to its antimicrobial effects may contribute to the rarity of skin infections with the gram-negative bacterial organisms, whereas lack of stimulation of hbetaD-2 expression by S. pyogenes may be important in its ability to evade innate defenses and cause skin disease. Induction of expression of hbetaD-2 but relative tolerance to it may enable S. epidermidis to survive on the skin surface and modulate hbetaD-2 expression when the stratum corneum barrier is disrupted.

Bacterial Adhesion↗
PubMed2001

Expression of natural peptide antibiotics in human articular cartilage and synovial membrane.

In view of frequent present use of invasive procedures on limb joints, it is astonishing that articular joint inflammation is a rare event. We questioned whether antimicrobial peptides play a role in protecting human articular cartilage and synovial membrane against inflammatory agents. Our results implicate defensins in the protection of human articular joints against pathogens.

Anti-Bacterial Agents↗
PubMed1994

Killing of Giardia lamblia by cryptdins and cationic neutrophil peptides.

Antimicrobial polypeptides such as the defensins kill a wide range of organisms, including bacteria, fungi, viruses, and tumor cells. Because of the recent finding that intestinal defensins, also known as cryptdins, are synthesized by the Paneth cells of the small intestinal crypts and released into the lumen, we asked whether defensins and other small cationic antimicrobial peptides could kill the trophozoites of Giardia lamblia, which colonize the small intestine. Four mouse cryptdins, two neutrophil defensins (HNP-1 [human] and NP-2 [rabbit]), and the unique tryptophan-rich bovine neutrophil polypeptide indolicidin each had some antigiardial activity against trophozoites in vitro. Cryptdins 2 and 3, indolicidin, and NP-2 each reduced viability by more than 3 log units in 2 h, and killing by all peptides was dose and time dependent. Exposure of trophozoites to peptides frequently resulted in cell aggregation and dramatic changes in morphology. The mechanism of binding and lysis appeared to involve charge interactions, since 150 mM NaCl as well as millimolar levels of Ca2+ and Mg2+ inhibited killing by most of the peptides. Our studies show that G. lamblia is sensitive to defensins and indolicidin and suggest that these small polypeptides could play a role in nonimmune host defenses.

Amino Acid Sequence↗
PubMed2002

Characterization of the mouse beta defensin 1, Defb1, mutant mouse model.

Beta defensins are small cationic antimicrobial peptides present in the respiratory system which have been proposed to be dysfunctional in the environment of the cystic fibrosis lung. Defb1, a murine homologue to the human beta defensins, has also been found to be expressed in the respiratory system and, in order to examine the function of beta defensins in vivo, gene targeting was used to generate Defb1-deficient (Defb1(tm1Hgu)/Defb1(tm1Hgu) [Defb1(-/-)]) mice. The Defb1 synthetic peptide was shown to have a salt-sensitive antimicrobial activity that was stronger against Staphylococcus aureus than against Escherichia coli or Pseudomonas aeruginosa. Defb1(-/-) mice were found, however, to be effective in the clearance of the cystic fibrosis relevant pathogen S. aureus from the airways after nebulization. Although no overt deleterious phenotype was evident in the Defb1(-/-) mice, the number of mutant mice found to harbor bacteria of the Staphylococcus species in the bladder was significantly higher (P = 0.008) than that of controls, suggesting a role for these peptides in resistance to urinary tract infection.

Animals↗
PubMed2003

Defensin pattern in chronic gastritis: HBD-2 is differentially expressed with respect to Helicobacter pylori status.

BACKGROUND/AIMS: Recent reports have suggested that Helicobacter pylori infection induces the mucosal antibiotic peptide human beta defensin 2 (HBD-2). Therefore, the present study investigated mRNA and peptide expression of four different defensins in the upper gastrointestinal tract in patients with H pylori positive and negative chronic gastritis. MATERIALS/METHODS: Biopsies from the oesophagus to the duodenum were taken during routine gastroscopy in 71 individuals. Total RNA was extracted and the reverse transcription polymerase chain reaction was performed with primers for human defensins 5 and 6 (HD-5/6) or HBD-1 and HBD-2. Paraffin wax embedded tissue from gastric resections was tested for HD-5, HBD-1, and HBD-2 by immunohistochemistry. RESULTS: Helicobacter pylori colonisation was associated with an increased percentage of positive biopsies with respect to HBD-2 in the corpus (p < 0.05). Helicobacter pylori had no impact on the gastric expression of HD-5 and HBD-1, whereas HD-6 was increased in the fundus. The abundant expression of alpha defensins in the duodenum and beta defensins in the oesophagus served as a positive control in each individual. Immunohistochemical analysis confirmed the presence of the HD-5, HBD-1, and HBD-2 peptides in gastric resection specimens. CONCLUSIONS: The recently described induction of HBD-2 upon H pylori infection was confirmed in a clinical setting of chronic gastritis. This phenomenon may be mediated by components of the pathogen itself or may occur secondary to immune events in chronic inflammation.

Adult↗
PubMed2002

Expression of human beta defensin (HBD-1 and HBD-2) mRNA in nasal epithelia of adult cystic fibrosis patients, healthy individuals, and individuals with acute cold.

BACKGROUND: Lack or inactivation of defensins may facilitate chronic bacterial colonization in the cystic fibrosis (CF) lung. CF nasal epithelium exhibits typical biochemical abnormalities and can be used to study defensin expression in CF. OBJECTIVES: To evaluate the expression of beta defensin (HBD-1 and HBD-2) mRNA and the presence of inflammatory markers (percentage of neutrophils and IL-8 mRNA expression) in CF and non-CF nasal mucosa. METHODS: Case-control study. Nasal brushing samples were obtained from 22 stable adult CF patients and 32 non-CF controls (25 healthy individuals and 7 individuals with acute cold). Samples were subjected to analysis involving mRNA expression (semiquantitative RT-PCR) and differential cell counting. RESULTS: Defensins and inflammatory markers were expressed at low levels in healthy individuals and at high levels in subjects with acute cold. In non-CF controls, defensin expression correlated significantly with inflammatory parameters (p < 0.001). In CF, defensin mRNA expression was comparable to healthy individuals (p = 0.2). In contrast to non-CF controls, in CF patients high levels of inflammatory markers did not correlate with defensin mRNA levels. CONCLUSIONS: Defensin expression is not upregulated in CF epithelium in response to inflammatory stimuli. Further studies are necessary to elucidate whether this is a consequence of the CF gene mutation.

Acute Disease↗
PubMed2002

Cutaneous eccrine glands of the foot pads of the rock hyrax (Procavia capensis, Hyracoidea, Mammalia).

In order to find correlations between skin gland morphology and specific ethological features, the cutaneous glands of the foot pads of Procavia capensis were studied by histological and various histochemical methods and by electron microscopy. In the foot pads, abundant specific eccrine skin glands occur, which consist of coiled tubular secretory portions and coiled ducts. The wall of the secretory part is composed of cuboidal glandular cells and myoepithelial cells. Among the glandular cells two types occur: clear and dark cells. Clear cells have numerous mitochondria and form a basal labyrinth, indicating fluid transport. Dark cells, which stain strongly with periodic acid-Schiff, contain a highly developed perinuclear Golgi apparatus, large amounts of rough endoplasmic reticulum and many secretory granules indicating production of glycoproteins. Cytokeratin (CK) 19 was found in secretory compartments and ducts, CK14 only in duct cells. Single cells of the secretory coils and ducts may be stained with antibodies against antimicrobial peptides. Some glandular cells contain proliferating cell nuclear antigen-positive nuclei especially in the ducts indicating an increased cell proliferation. Terminal transferase (TdT)-mediated d-UTP nick-end labeling-positive nuclei can be detected predominantly in the secretory coils and rarely in the transitional portions between ducts and end pieces. We suppose that proliferating cells migrate from the ducts to the secretory coils. The secretory product of the eccrine cutaneous glands seems to improve the traction between the foot pads of these animals and the steep and smooth rock formations among which they live.

Adrenomedullin↗
PubMed1998

Antibacterial peptides in bronchoalveolar lavage fluid.

Defensins and other antimicrobial peptides act in the innate host defense of epithelial surfaces. Human beta defensin 1 (hBD-1) has recently been shown to be expressed in airway epithelial cells and so has been implicated as a primary component of antibacterial activity in human lung. We attempted to purify these molecules from bronchoalveolar lavage fluid (BALF). Extraction of BALF on SepPak C-18 cartridges, followed by continuous acid-urea polyacrylamide gel electrophoresis and reverse-phase high-performance liquid chromatography yielded one fraction with antibacterial activity associated with factors of < 6.5 kD. N-terminal amino acid sequencing identified these peptides as human neutrophil defensins (HD) 1 through 3. No hBD-1 was detected. Together with lysozyme, it appears that HD-1 through -3 are the most prominent antimicrobial factors in BALF. The contribution of epithelial defensins such as hBD-1 to antibacterial defense of human airway in vivo remains to be elucidated.

Anti-Bacterial Agents↗
PubMed2001

Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid.

The link between the genetic defect in cystic fibrosis (CF) and the recently described breach in pulmonary host defense has focused on the role of salt and water metabolism in the airways. Using a human bronchial xenograft model we demonstrate a salt-independent abnormality in bacterial killing in CF airway surface fluid (ASF). Biochemical characterization implicates the absence or dysfunction of a molecule critical to the constitution of normal bacterial killing. Our study suggests that CF transmembrane conductance regulator (CFTR) deficiency causes a primary abnormality in the composition of ASF that leads to a salt-independent defect in host defense. Importantly, this defect is corrected by adenovirus-mediated gene transfer of CFTR.

Adolescent↗
PubMed2000

Human antimicrobial peptides: analysis and application.

Antimicrobial peptides are innate host defense molecules that have a direct effect on bacteria, fungi and enveloped viruses. They are found in evolutionarily diverse species ranging from prokaryotes and plants to invertebrate and vertebrate animals. Humans express several families of antimicrobial peptides in myeloid cells and on various epithelial surfaces where they are poised to defend against pathogens. Recently, antimicrobial peptides from animals and plants have served as templates for the design of new therapeutic antibiotics. This review provides an introduction to the biology of human antimicrobial peptides, followed by a more detailed discussion of their isolation from tissues and biological fluids, their purification by gel electrophoresis and chromatography and assays of their antimicrobial activities.

Anti-Bacterial Agents↗
PubMed2002

Antimicrobial peptides initiate IL-1 beta posttranslational processing: a novel role beyond innate immunity.

Human monocytes stimulated with LPS produce large quantities of prointerleukin-1beta, but little of this cytokine product is released extracellularly as the mature biologically active species. To demonstrate efficient proteolytic cleavage and export, cytokine-producing cells require a secondary effector stimulus. In an attempt to identify agents that may serve as initiators of IL-1beta posttranslational processing in vivo, LPS-activated human monocytes were treated with several individual antimicrobial peptides. Two peptides derived from porcine neutrophils, protegrin (PTG)-1 and PTG-3, promoted rapid and efficient release of mature IL-1beta. The PTG-mediated response engaged a mechanism similar to that initiated by extracellular ATP acting via the P2X(7) receptor. Thus, both processes were disrupted by a caspase inhibitor, both were sensitive to ethacrynic acid and CP-424,174, two pharmacological agents that suppress posttranslational processing, and both were negated by elevation of extracellular potassium. Moreover, the PTGs, like ATP, promoted a dramatic change in monocyte morphology and a loss of membrane latency. The PTG response was concentration dependent and was influenced profoundly by components within the culture medium. In contrast, porcine neutrophil antimicrobial peptides PR-26 and PR-39 did not initiate IL-1beta posttranslational processing. The human defensin HNP-1 and the frog peptide magainin 1 elicited export of 17-kDa IL-1beta, but these agents were less efficient than PTGs. As a result of this ability to promote release of potent proinflammatory cytokines such as IL-1beta, select antimicrobial peptides may possess important immunomodulatory functions that extend beyond innate immunity.

Adenosine Triphosphate↗
PubMed2002

A newly discovered function of palatine tonsils in immune defence: the expression of defensins.

The palatine tonsils have an undoubted role in the immune defence system. After antigen contact an effective adaptive immune response by B- and T-cell lymphocytes will be released. In addition the palatine tonsils seem to exert influence to the defence by the innate immune system. Therefore, we studied the ability of palatine tonsils to express different alpha and beta defensins and to find out any distinctions in chronic inflamed tonsils. Total RNA of 49 specimens of hyperplastic tonsils and chronic tonsillitis with pathological provided evidence of Actinomyces israelii was isolated using TRIzol protocol, reverse transcribed and the HNP-1, HNP-4, HBD-1 and HBD-2 gene expression densitometric determined, standardised in relation to glycerinaldehyd-3-phosphatdehydrogenase gene expression, after a semiquantitative polymerase chain reaction was performed. mRNA of HNP-1, HNP-4, HBD-1 and HBD-2 was detected in tissue samples, but their amount differed within the two defensin families and tissue of origins. HBD-1 was detected in all 49 tissues of hyperplastic tonsils and chronic tonsillitis. Only in chronic inflamed tonsils the amount of HBD-2 mRNA expression was significant increased. In these specimens also mean relative expression rate of all defensins was observed to be manifestly increased. Palatine tonsils express mRNA for different alpha and beta defensins and this expression suggest a newly supposed function in immune defence: the participation in the innate, non-adaptive immune system. Thus, palatine tonsils have a potentially influence in the growth and control of the physiological mouth bacteria by their bactericidal activity.

Actinomyces↗
PubMed2003

Antibacterial activity of synthetic human B defensin-2 against periodontal bacteria.

The oral epithelium is continuously exposed to a variety of microbial challenges that can cause infectious diseases such as periodontal disease. Human B Defensin-2 (hBD-2) is a cationic antimicrobial peptide with low molecular weight, which is inducible from oral epithelial cells upon either bacterial infection or stimulation with inflammatory cytokines. This peptide has a broad antimicrobial spectrum that includes gram-positive bacteria, gram-negative bacteria, and fungi. Therefore, it is thought that hBD-2 plays an important role as one of natural immunities to bacterial infection. However, its activity is inhibited by body fluids such as serum. The aim of this study was to assess the antibacterial activity of synthetic hBD-2 against oral bacteria in the presence of saliva or serum. The antibacterial activity of synthetic hBD-2 was tested against Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Streptococcus mutans, and Escherichia coli. Antibacterial broth assay and diffusion assay were performed in vitro. The antibacterial activity of hBD-2 was approximately equal to that of minocycline at equimolar concentrations. Furthermore, the activity of hBD-2 remained at 60% in the presence of 80% saliva, whereas no activity remained in the presence of 20% serum. Our results suggest the possibility that synthetic hBD-2 could be useful to prevent infection by periodontal bacteria.

Aggregatibacter actinomycetemcomitans↗