Prostate cancer is the second most common malignancy and the sixth leading cause of cancer-related death in men worldwide. Radical prostatectomy (RP) is the standard treatment for localized prostate cancer, but the procedure often results in postoperative erectile dysfunction (ED). The poor efficacy of phosphodiesterase 5 inhibitors after surgery highlights the need to develop new therapies to enhance cavernous nerve regeneration and improve the erectile function of these patients. In the present study, we aimed to examine the potential of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in preserving erectile function in cavernous nerve injury (CNI) mice. We found that HB-EGF expression was reduced significantly on the 1 st day after CNI in penile tissue. Ex vivo and in vitro studies showed that HB-EGF promotes major pelvic ganglion neurite sprouting and neuro-2a (N2a) cell migration. In vivo studies showed that exogenous HB-EGF treatment significantly restored the erectile function of CNI mice to 86.9% of sham levels. Immunofluorescence staining showed that mural and neuronal cells were preserved by inducing cell proliferation and reducing apoptosis and reactive oxygen species production. Western blot analysis showed that HB-EGF upregulated protein kinase B and extracellular signal-regulated kinase activation and neurotrophic factor expression. Overall, HB-EGF is a major promising therapeutic agent for treating ED in postoperative RP.
Animals ; Male ; Heparin-binding EGF-like Growth Factor/therapeutic use* ; Erectile Dysfunction/etiology* ; Mice ; Penis/drug effects* ; Nerve Regeneration/drug effects* ; Penile Erection/drug effects* ; Peripheral Nerve Injuries/drug therapy* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Cell Movement/drug effects* ; Prostatectomy/adverse effects* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism*

OBJECTIVE: Cellular, animal, and human epidemiological studies suggested that benzodiazepines increase the risk of cancer and cancer mortality. Obesity is also clearly linked to carcinogenesis. However, no human studies have examined benzodiazepine-associated carcinogenesis as assessed by changes in cancer biomarkers. METHODS: A total of 19 patients were recruited, and received a 6-week treatment of 0.5 mg lorazepam. The measured cancer biomarkers were angiopoietin-2 (ANG-2), soluble CD40 ligand, epidermal growth factor, endoglin, soluble Fas ligand (sFASL), heparin-binding EGF-like growth factor (HB-EGF), insulin-like growth factor binding protein, interleukin (IL)-6, IL-8, IL-18, plasminogen activator inhibitor (PLGF), placental growth factor, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)-α, urokinase-type plasminogen (uPA), vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D. RESULTS: Six cancer biomarkers were significantly increased in all patients as a whole. The subgroup analysis revealed a distinct pattern of change. Overweight patients showed a significant increase in 11 cancer biomarkers, including ANG-2, sFASL, HB-EGF, IL-8, PLGF, TGF-α, TNF-α, uPA, VEGF-A, VEGF-C, and VEGF-D. However, normal-weight patients did not show any changes in cancer biomarkers. CONCLUSION: Adiposity may have primed the carcinogenic potential, leading to lorazepam-associated carcinogenesis in overweight patients. Epidemiological studies addressing this issue should consider the potential modulator contributing to benzodiazepine-associated carcinogenesis.
Adiposity ; Angiopoietin-2 ; Animals ; Benzodiazepines ; Biomarkers, Tumor ; Carcinogenesis* ; Carrier Proteins ; CD40 Ligand ; Epidemiologic Studies ; Epidermal Growth Factor ; Fas Ligand Protein ; Heparin-binding EGF-like Growth Factor ; Humans ; Interleukin-18 ; Interleukin-8 ; Interleukins ; Lorazepam ; Mortality ; Obesity ; Overweight* ; Plasminogen ; Plasminogen Activators ; Transforming Growth Factors ; Tumor Necrosis Factor-alpha ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor C ; Vascular Endothelial Growth Factor D

PURPOSE: To determine whether levels of nerve growth factor (NGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) can be used to objectively assess overactive bladder syndrome (OAB) treatment outcome and to evaluate the effects of fixed-dose fesoterodine on OAB symptoms. MATERIALS AND METHODS: This study included 124 participants (62 patients with OAB and 62 controls) in Severance Hospital between 2010 and 2012. In patients with OAB, 4 mg fesoterodine was administered once daily. Repeated evaluations of putative biomarker levels, urine creatinine (Cr) levels, and questionnaire responses, including the Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire (OAB q), were performed from baseline to 16 weeks. RESULTS: Urinary levels of NGF/Cr (OAB: 1.13+/-0.9 pg/mg; control: 0.5+/-0.29 pg/mg) and HB-EGF/Cr (OAB: 8.73+/-6.55 pg/mg; control: 4.45+/-2.93 pg/mg) were significantly higher in subjects with OAB than in controls (p<0.001). After 16 weeks of fixed-dose fesoterodine treatment, urinary NGF/Cr levels (baseline: 1.13+/-0.08 pg/mg; 16 weeks: 0.60+/-0.4 pg/mg; p=0.02) and HB-EGF/Cr levels significantly decreased (baseline: 8.73+/-6.55 pg/mg; 16 weeks: 4.72+/-2.69 pg/mg; p=0.03, respectively). Both the OABSS and OAB q scores improved (p<0.001). However, there were no a statistically significant correlations between these urinary markers and symptomatic scores. CONCLUSION: Urinary levels of NGF and HB-EGF may be potential biomarkers for evaluating outcome of OAB treatment. Fixed-dose fesoterodine improved OAB symptoms. Future studies are needed to further examine the significance of urinary NGF and HB-EGF levels as therapeutic markers for OAB.
Adult ; Benzhydryl Compounds/pharmacology/*therapeutic use ; Biological Markers/urine ; Case-Control Studies ; Creatinine/urine ; Female ; Heparin-binding EGF-like Growth Factor/*urine ; Humans ; Male ; Middle Aged ; Nerve Growth Factor/*urine ; Questionnaires ; Treatment Outcome ; Urinary Bladder, Overactive/*drug therapy/physiopathology/*urine ; Urodynamics

OBJECTIVEBased on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC.

DATA SOURCESThe studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis".

STUDY SELECTIONMainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected.

RESULTSImmature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis.

CONCLUSIONIntestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC.

Endothelin-1 ; physiology ; Endothelium, Vascular ; physiopathology ; Enterocolitis, Necrotizing ; drug therapy ; etiology ; pathology ; Heparin-binding EGF-like Growth Factor ; Humans ; Infant, Newborn ; Intercellular Signaling Peptides and Proteins ; therapeutic use ; Intestines ; blood supply ; Ischemia ; complications ; Microcirculation ; physiology ; Nitric Oxide ; physiology ; Splanchnic Circulation

In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.
Adult ; Aged ; Amphiregulin ; Betacellulin ; EGF Family of Proteins ; Epidermal Growth Factor ; metabolism ; Epiregulin ; Female ; Gene Expression Profiling ; Glycoproteins ; metabolism ; Heparin ; metabolism ; Heparin-binding EGF-like Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Keratinocytes ; metabolism ; Leukoplakia, Oral ; metabolism ; Lichen Planus, Oral ; metabolism ; Ligands ; Male ; Middle Aged ; Mouth Mucosa ; metabolism ; Nerve Growth Factors ; Neuregulins ; metabolism ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism ; Receptor, ErbB-4 ; Receptors, Cell Surface ; metabolism ; Transforming Growth Factor alpha ; metabolism ; Up-Regulation ; physiology

The sigma-1 receptor is a molecular chaperone protein highly enriched in the brain. Recent studies linked it to many diseases, such as drug addition, Alzheimer's disease, stroke, depression, and even cancer. Sigma-1 receptor is enriched in lipid rafts, which are membrane microdomains essential in signaling processes. One of those signaling processes is ADAM17- and ADAM10-dependent ectodomain shedding. By using an alkaline phosphatase tagged substrate reporter system, we have shown that ADAM10-dependent BTC shedding was very sensitive to both membrane lipid component change and sigma-1 receptor agonist DHEAS treatment while ADAM17-dependent HB-EGF shedding was not; and overexpression of sigma-1 receptor diminished ADAM17- and ADAM10-dependent shedding. Our results indicate that sigma-1 receptor plays an important role in modifying the function of transmembrane proteases.
ADAM Proteins ; metabolism ; ADAM10 Protein ; ADAM17 Protein ; Amyloid Precursor Protein Secretases ; metabolism ; Animals ; Betacellulin ; COS Cells ; Cercopithecus aethiops ; Gene Expression ; HEK293 Cells ; Heparin-binding EGF-like Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Membrane Microdomains ; metabolism ; Membrane Proteins ; metabolism ; Receptors, sigma ; agonists ; metabolism

OBJECTIVETo explore the relationship of airway remodeling with epidermal growth factor receptor (EGFR) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) levels in asthmatic mice and the effect of EGFR tyrosine kinase inhibitor (AG1478) on airway remodeling.

METHODSTwenty-four male BALB/c mice were randomly divided into three groups: normal control, asthma, AG1478-treated. Mice were sensitized and challenged with ovalbumin (OVA) and a mouse mode1 of asthma was prepared. Collagen deposition was determined in Masson-stained lung sections. Periodic acid Schiff (PAS) staining was used to observe the proliferation of goblet cells. Immunohistochemistry was used to determine the protein expression of HB-EGF. RT-PCR was used to determine the mRNA expression of HB-EGF and EGFR.

RESULTSThe characteristic changes of airway remodeling occurred in the asthma group. The expression of HB-EGF and EGFR in the epithelial cells of bronchi in the asthma group was significantly higher than that in the normal control group. Compared with the asthma group, the AG1478-treated group had decreased inflammation reactions, decreased collagen deposition and proliferation of goblet cells and lower expression of EGFR and HB-EGF.

CONCLUSIONSEGFR tyrosine kinase inhibitor (AG1478) ameliorates the progression of airway remodeling in mice with asthma by inhibitions of EGFR and HB-EGF expression and EGFR signal pathway.

Airway Remodeling ; Animals ; Asthma ; drug therapy ; pathology ; Heparin-binding EGF-like Growth Factor ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins ; analysis ; genetics ; Male ; Mice ; Quinazolines ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; genetics ; physiology ; Tyrphostins ; therapeutic use

OBJECTIVETo investigate the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in patients with gastric carcinoma in different stages.

METHODSThe expressions of HB-EGF protein and mRNA in normal gastric tissues, metaplasic intestinal mucosa, early-stage gastric cancer and advanced-stage gastric cancer tissues were detected by immunohistochemistry and in situ hybridization.

RESULTSHB-EGF expression was only detected in the parietal cells of the gastric fundic glands and in gastrin cells of the pyloric glands in normal gastric tissues. Weak HB-EGF expression was detected in the epithelial cells of the gastric mucosa in intestinal metaplasic mucosa, and the expression increased in all layers of the gastric mucosa in early-stage gastric cancer. Intense HB-EGF expression was observed in advanced gastric cancer.

CONCLUSIONIncreased HB-EGF expression may be implicated in the pathogenesis and development of gastric carcinoma.

Adenocarcinoma ; metabolism ; pathology ; Adult ; Aged ; Female ; Gastric Mucosa ; metabolism ; Heparin-binding EGF-like Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; genetics ; metabolism ; Male ; Middle Aged ; RNA, Messenger ; genetics ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Tumor Cells, Cultured