ABSTRACT
Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.
ABSTRACT
INTRODUCTION AND HYPOTHESIS: The objective of this study was to compare the impact of different modes of delivery, especially forceps delivery (FD), on pelvic floor muscles (PFMs) through vaginal surface electromyography (sEMG) in primiparous women at early (6-8 weeks) postpartum. METHODS: A total of 1259 primiparous women with full-term singleton births were included in this cross-sectional study. Of these, 98 were delivered by forceps, 865 underwent spontaneous vaginal delivery (SD) and 296 underwent elective cesarean delivery (CD). Clinical demographic characteristics and vaginal sEMG variables of parturients 6-8 weeks after birth were collected and analyzed using SPSS software. One-way ANOVA with Bonferroni correction, Chi-square test or Student's t-test was used according to the variable type. Spearman correlation and binary logistic regression analyses were also used. P/α ≤ 0.05 was considered statistically significant. RESULTS: Amplitude of fast and sustained contractions on sEMG in the FD group was significantly lower compared with the CD and SD groups. The sEMG amplitude of all contractions was significantly higher in the CD group compared with the FD and SD groups (P < 0.01). According to binary logistic regression analysis, mode of delivery was a major influencing factor in sEMG. CONCLUSIONS: An early postpartum sEMG test appears to be helpful for the assessment of PFM activity. Mode of delivery was a major influencing factor on sEMG. Forceps delivery significantly inversely influenced PFM activity.
Subject(s)
Pelvic Floor Disorders , Pelvic Floor , Cross-Sectional Studies , Electromyography , Female , Humans , Muscle Contraction/physiology , Pelvic Floor/physiology , Pelvic Floor Disorders/diagnosis , Pelvic Floor Disorders/etiology , PregnancyABSTRACT
BACKGROUND: Hypospadias, as a congenital disorder of the urethra, is the second most common birth abnormality of the male reproductive system. This study primarily investigates the effects of microRNA-494 (miR-494) on the transforming growth factor-ß1 (TGF-ß1)/Smads signaling pathway and on the development of hypospadias by binding to neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4L). METHODS: We induced a mouse model of hypospadias through di-(2-ethylhexyl) phthalate treatment. The underlying regulatory mechanisms of miR-494 in this model were analyzed upon treatment of miR-494 mimic, miR-494 inhibitor, or small interfering RNA against Nedd4L in urethral epithelial cells isolated from mice with hypospadias. We then verified the binding site between miR-494 and Nedd4L and applied a gain- and loss-of-function approach to determine the effects of miR-494 on cell proliferation, cycle distribution, and apoptosis. RESULTS: Male mice with hypospadias exhibited significantly higher miR-494 expression and lower Nedd4L expression in urethral tissues than normal male mice. Nedd4L was verified as a target gene of miR-494. Treatment with miR-494 inhibitor suppressed the activation of the TGF-ß1/Smads signaling pathway, whereas down-regulation of miR-494 exerted protective effects on urethral epithelial cells by impeding cell proliferation and inducing cell apoptosis. CONCLUSIONS: The study indicates that downregulation of miR-494 inhibits the TGF-ß1/Smads signaling pathway and prevents the development of hypospadias through upregulating Nedd4L.
Subject(s)
Down-Regulation/genetics , Hypospadias/genetics , Hypospadias/prevention & control , MicroRNAs/genetics , Nedd4 Ubiquitin Protein Ligases/genetics , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta1/metabolism , Up-Regulation/genetics , Animals , Apoptosis/genetics , Base Sequence , Cell Cycle/genetics , Cell Proliferation/genetics , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Hypospadias/pathology , Male , Mice , MicroRNAs/metabolism , Nedd4 Ubiquitin Protein Ligases/metabolism , Urethra/pathologyABSTRACT
OBJECTIVE: To observe the clinical effect of priligy (dapoxetine hydrochloride) combined with behavioral therapy and psychological counseling in the treatment of primary premature ejaculation (PPE). METHODS: A total of 202 PPE patients diagnosed from 2017 to 2018 were randomized into a control (n = 100) and an experimental group (n = 102), the former treated with oral priligy at 30 mg 1ï¼3 hours before anticipated sexual activity, and the latter by the same medication combined with 30-minute behavioral therapy and psychological counseling once a month for two times. The therapeutic effects were evaluated according to the Premature Ejaculation Profile (PEP) scores of the patients at 1 and 2 months of treatment. RESULTS: After 1 month of treatment, both groups of the patients showed significant improvement, as compared with the baseline, in the PEP scores on personal distress related to ejaculation (P < 0 05), interpersonal difficulty related to ejaculation (P < 0.05) and satisfaction with sexual intercourse (P < 0.05) but not on perceived control over ejaculation (P > 0.05). At 2 months, however, the patients' scores on all the four PEP items were dramatically improved, even more significantly in the experimental than in the control group, as on perceived control over ejaculation (2.73 ± 0.95 vs 2.22 ± 0.68, P < 0.05), personal distress related to ejaculation (2.97 ± 1.07 vs 2.57 ± 0.69, P < 0.05), interpersonal difficulty related to ejaculation (3.19 ± 1.03 vs 2.77 ± 0.69, P < 0 05) and satisfaction with sexual intercourse (2.85 ± 0.99 vs 2.35 ± 0.63, P < 0.05). There was no statistically significant difference in the incidence rate of adverse events between the experimental and control groups (21.6% vs 20.0%, P > 0.05), and all the symptoms were relieved within 24 hours. CONCLUSIONS: Priligy combined with behavioral therapy and psychological counseling is more effective than priligy alone in improving the sexual function of PPE patients, raise their interest in sexual life and increase the intimacy between the partners, and can even achieve clinical cure in some patients.
Subject(s)
Benzylamines/therapeutic use , Cognitive Behavioral Therapy , Naphthalenes/therapeutic use , Premature Ejaculation , Psychotherapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Humans , Male , Premature Ejaculation/therapy , Treatment OutcomeABSTRACT
Uncontrollable vascular smooth cell proliferation is responsible for vascular remodeling during hypertension development. Glyoxalase 1 (GLO1), the major enzyme detoxifying methylglyoxal, has a critical role in regulating proliferation of several cell types. However, little is known whether GLO1 is involved in cerebrovascular remodeling and basilar smooth muscle cell (BASMC) proliferation during hypertension. Here we explored the role of GLO1 in angiotensin II (Ang II)-induced cerebrovascular remodeling and proliferation of BASMCs and the underlying mechanisms. The protein expression of GLO1 in basilar arteries from hypertensive mice was decreased, and GLO1 expression was negatively correlated with medial cross-sectional area and blood pressure in basilar arteries during hypertension. Knockdown of GLO1 promoted while overexpression of GLO1 prevented Ang II-induced cell proliferation and cell cycle transition in BASMCs. These results were related to the inhibitory effects of GLO1 on PI3K/AKT/CDK2 cascade activation upon Ang II treatment. In addition, in vivo study, GLO1 overexpression with adeno-associated virus harboring GLO1 cDNA improved cerebrovascular remodeling in basilar artery tissue during Ang II-induced hypertension development. These data indicate that GLO1 reduction mediates cerebrovascular modeling via PI3K/AKT/CDK2 cascade-dependent BASMC proliferation. GLO1 acts as a negative regulator of hypertension-induced cerebrovascular remodeling and targeting GLO1 may be a novel therapeutic strategy to prevent hypertension-associated cardiovascular complications such as stroke.
Subject(s)
Hypertension/pathology , Lactoylglutathione Lyase/metabolism , Myocytes, Smooth Muscle/pathology , Vascular Remodeling , Angiotensin II/metabolism , Animals , Brain/blood supply , Cell Proliferation , Cells, Cultured , Hypertension/metabolism , Male , Mice, Inbred C57BL , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Rats, Sprague-DawleyABSTRACT
The folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme involved in folate metabolism. Polymorphisms of MTHFR may change the level of homocysteine and affect DNA synthesis and methylation, leading to an increased oxidative stress and disturbed methylation reactions and consequently affecting reproductive function. This article presents an overview on MTHFR gene polymorphisms, proposing that multicentered, large-sample and long-term prospective studies are needed to reveal the relationship between MTHFR gene polymorphisms and infertility.
Subject(s)
Infertility/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Genetic , DNA/biosynthesis , DNA Methylation , DNA Repair , Folic Acid/metabolism , Homocysteine/metabolism , Humans , Infertility/enzymology , Prospective StudiesABSTRACT
OBJECTIVE: To investigate the protective effect of lycopene against cryopreservation injury of post-thawing human sperm and its mechanism. METHODS: Semen samples were collected from 25 volunteers, each sample equally divided into four parts to be cryopreserved with cryoprotectant only (Ly0 control) or cryoprotectant + lycopene at the concentrations of 2 (Ly2), 5 (Ly5), and 10 µmol/L (Ly10), respectively. Before and after thawing, the semen samples were subjected to computer-assisted semen analysis ( CASA) for sperm kinematics, flow cytometry for sperm apoptosis, thiobarbituric acid assay for malondialdehyde (MDA) concentration, and JC-1 fluorescent staining for the sperm mitochondrial membrane potential (MMP). RESULTS: After cryopreservation, sperm motility was markedly decreased in all the groups (P < 0.01). The rate of sperm apoptosis was significantly lower in the Ly5 group than in the Ly0 control ([25.68 ± 4.36]% vs [33.26 ± 4.78]%, P < 0.05), while sperm MMP remarkably higher in the former than in the latter ([66.18 ± 14.23]% vs [55.24 ± 12.31]%, P < 0.05). The Ly2, Ly5 and Ly10 groups showed no statistically significance differences in the MDA level from the Ly0 control (P > 0.05). CONCLUSION: Addition of lycopene at a proper concentration to cryoprotectant may reduce oxidative damage to sperm mitochondria in the freezing-thawing process, attenuate oxidative stress injury induced by reactive oxygen species to sperm plasma membrane, and improve the anti-apoptosis ability of sperm.
Subject(s)
Carotenoids/pharmacology , Cryopreservation , Semen Preservation/methods , Spermatozoa/drug effects , Apoptosis , Cryoprotective Agents/pharmacology , Flow Cytometry , Humans , Lycopene , Male , Malondialdehyde/analysis , Oxidative Stress , Reactive Oxygen Species , Semen Analysis , Semen Preservation/adverse effects , Sperm Motility , Spermatozoa/physiologyABSTRACT
OBJECTIVE: To study the expressions of differential proteins in the expressed prostatic secretion (EPS) of patients with III A chronic prostatitis and healthy men. METHODS: We collected EPS samples from 35 patients with III A chronic prostatitis and 18 age-matched healthy men, and detected the differentially expressed proteins in EPS by MALDI-TOF/MS. Based on the data obtained, we conducted a statistical analysis on the mass-to-charge (m/z) ratios of different proteins and a retrieval analysis on the relevant proteins using the protein database. RESULTS: In the comparative studies of the III A chronic prostatitis patients and healthy men, 5 proteins were detected as at least 2-fold differentially expressed, which were probably brevinin-2Eg, big endothelin-1, alpha-defensin 15, beta-defensin 134 and prostatic steroid-binding protein C2. The m/z ratios were significantly up-regulated in 3 372, 3 487, 425 and 5 325 Da proteins (P < 0.01) and down-regulated in 10631Da (P < 0.01). CONCLUSION: Proteins are differentially expressed in the EPS of III A chronic prostatitis patients and healthy men, and these proteins may be significantly correlated with the development and progression of III A chronic prostatitis.
Subject(s)
Body Fluids/metabolism , Prostate/metabolism , Prostatitis/metabolism , Adult , Case-Control Studies , Chronic Disease , Defensins/metabolism , Endothelin-1/metabolism , Humans , Male , Prostatitis/classification , Young AdultABSTRACT
Excessive apoptosis of placental trophoblast cells is considered a major cause of pre-eclampsia (PE) pathogenesis. Phosphorylation of the widely expressed cAMP response element binding protein (CREB) regulates apoptosis and may be involved in PE incidence. Low-dose aspirin (LDA) is an effective approach for preventing PE with unclear mechanisms. Thus we examined whether LDA protects against PE by inhibiting trophoblast cell apoptosis through CREB. The effects of LDA on human PE placenta, PE model rat placenta, and hydrogen peroxide (H2O2)-induced HTR-8/SVneo cell apoptosis were analyzed. TUNEL assay, immunohistochemistry, Cell Counting Assay Kit-8 (CCK-8) assay, western blot, and flow cytometry assay were performed. In the placenta of human PE and rat PE models, the TUNEL index increased and was partially corrected with LDA pre-treatment. Meanwhile, decreased Bcl-2 and increased Bax expression were significantly reversed by LDA pre-treatment. In HTR-8/SVneo cells, H2O2 decreased cell viability, promoted apoptosis, reduced the Bcl-2/Bax ratio, aggravated loss of mitochondrial membrane potential (MMP), increased cytoplasmic cytochrome c release, and simultaneously activated caspase-9 and caspase-3. These effects were effectively restored by LDA pre-treatment in the cells. Moreover, LDA promoted CREB phosphorylation in trophoblast cells. CREB interference further promoted apoptosis, reduced the Bcl-2/Bax ratio, and increased MMP loss. CREB interference also reversed the inhibitory effect of LDA on H2O2-induced apoptosis in HTR-8/SVneo cells. Thus, LDA was shown to inhibit trophoblast cell mitochondrial apoptosis by activating the CREB/Bcl-2 pathway, providing novel evidence for the protective mechanism of LDA in PE.Abbreviations; PE: Pre-eclampsia; LDA: low-dose aspirin; CREB: cAMP response element binding protein; ROS: reactive oxygen species; H2O2: hydrogen peroxide; PBS: Phosphate-buffered saline; Bcl-2: B-cell lymphoma-2; MMP: Mitochondrial membrane potential; Cyt-c: CytochromeC.
Subject(s)
Pre-Eclampsia , Trophoblasts , Animals , Apoptosis , Aspirin/metabolism , Aspirin/pharmacology , Caspase 3/metabolism , Caspase 9/metabolism , Cell Movement/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Cytochromes c/metabolism , Female , Humans , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/toxicity , Phosphates/metabolism , Phosphates/pharmacology , Placenta/metabolism , Pre-Eclampsia/pathology , Pregnancy , Rats , Reactive Oxygen Species/metabolism , Trophoblasts/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
BACKGROUND: Metastases from pancreas or ampullary malignancies are common, but the spread to testicle and paratesticular tissue is exceedingly rare. To the best of our knowledge, fewer than 30 cases have been reported in the literature. More rarely, metastasis to tunica vaginalis testis occurs without involvement of the testes and epididymis. CASE SUMMARY: A 65-year-old male who complained of painless swelling of the left scrotum for over 1 wk was referred to the Department of Urology. Scrotal ultrasound showed left testicular hydrocele with paratesticular masses. Chest computed tomography revealed lung metastasis and enlarged left supraclavicular lymph node.The blood tumor markersalpha-fetoprotein, human chorionic gonadotropin, and serum lactate dehydrogenase were withinnormal limits.The preoperative diagnosis was left testicular tumor with lung metastasis. Then radical orchidectomy of the left testicle and high ligation of the spermatic cord were performed, and postoperative histopathology suggested metastatic tumors that was confirmed by an abdominal computed tomographic scan. The positive computed tomography findings, in conjunction with the expression of cytokeratin 7 (CK7), CK20, CK5/6, and absence of expression of Wilms' tumor suppressor gene 1, calretinin, melanocyte, prostate-specific antigen, thyroid transcription factor-1, GATA binding protein 3, caudal type homeobox 2, and napsinA supported the diagnosis of pancreatic adenocarcinoma. The outcome of this patient was unsatisfactory, and he died 3 mo later. CONCLUSION: This case suggests that pancreatic metastatic carcinoma must be considered in the differential diagnosis of scrotal enlargement. The advanced age of the patient wassuggestive of a secondary testicular tumor.In addition, careful physical examination and ultrasonography as well as radiological examination have become a standard modality.
ABSTRACT
Patients suffering from depression most commonly present with symptoms associated with the autonomic nervous system. Despite the satisfactory results achieved following treatment with vagus nerve stimulation and drug treatment, recurrence is a common occurrence in many patients. As described in numerous studies, prolactin receptor (PRLR) has been identified as an anxiolytic and anti-depressant factor in depression. However, the effect of PRLR on chronic mild stress (CMS)-induced depression remains to be thoroughly demonstrated. Therefore, the present study was conducted on the effect of PRLR gene on brain derived neurotrophic factor (BDNF) expression and hippocampal neuron apoptosis through the establishment of CMS-induced depression mouse models, with aims of providing a new and effective therapeutic option for depression. Microarray-based analysis was initially used to retrieve depression-related expression dataset and PRLR-related signaling pathway. Lentiviral vectors overexpressing PRLR or expressing PRLR-specific shRNA were used to up- or down-regulated the expression of PRLR in mice. Subsequently, the effects of PRLR on hippocampal neurons and pyramidal cells in CA1 and CA3 regions, and ultrastructure in hippocampal region were evaluated. Serum BDNF level and the positive rate of cleaved-Caspase-3 in hippocampal CA3 region were determined. Next, the regulatory mechanism by which PRLR gene silencing influences hippocampal neuron apoptosis via the JAK2-STAT5 signaling pathway was detected. PRLR gene was assumed to participate in the development of depression by regulating the JAK-STAT signaling pathway. Our results found that the mice with CMS-induced depression exhibited locomotion activity and anhedonia. In addition, a decrease in the number of pyramidal cells was observed in the hippocampus while that of apoptotic cells was increased. In addition, serum BDNF level was increased, and the expression of Caspase-3 and Bax in hippocampal neurons and the JAK2-STAT5 signaling pathway was decreased in response to PRLR silencing, along with increased expression of BDNF and Bcl-2. From the aforementioned findings, we concluded that PRLR gene silencing results in the inhibition of hippocampal neuron apoptosis and alleviation of CMS-induced depression by inactivating the JAK2-STAT5 signaling pathway and elevating BDNF expression, providing a new insight for the treatment of depression.
Subject(s)
Apoptosis , Brain-Derived Neurotrophic Factor/metabolism , CA3 Region, Hippocampal/metabolism , Depression/metabolism , Janus Kinase 2/metabolism , Neurons/metabolism , Receptors, Prolactin/metabolism , Stress, Psychological/complications , Animals , CA3 Region, Hippocampal/ultrastructure , Depression/etiology , Disease Models, Animal , Male , Mice , Neurons/ultrastructure , RNA, Messenger/metabolism , Signal TransductionABSTRACT
Transient Receptor Potential Melastatin-2 (TRPM2) is a nonselective cation channel mediating Ca2+ influx in response to oxidative stress. Given that insulin resistance-related endothelial dysfunction in obesity attributes to fatty-acid-induced reactive oxygen species (ROS) overproduction, in this study, we addressed the possible role of TRPM2 in obesity-related endothelial insulin resistance and the underlying mechanisms. Whole-cell patch clamp technique, intracellular Ca2+ concentration measurement, western blot, vasorelaxation assay, and high-fat diet (HFD)-induced obese model were employed to assess the relationship between TRPM2 and endothelial insulin response. We found that both the expression and activity of TRPM2 were higher in endothelial cells of obese mice. Palmitate rose a cationic current in endothelial cells which was inhibited or enlarged by TRPM2 knockdown or overexpression. Silencing of TRPM2 remarkably improved insulin-induced endothelial Akt activation, nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production, while TRPM2 overexpression resulted in the opposite effects. Furthermore, TRPM2-mediated Ca2+ entry, CaMKII activation and the following activation of PERK/ATF4/TRB3 cascade were involved in the mechanism of obesity or palmitate-induced endothelial insulin resistance. Notably, in vivo study, knockdown of TRPM2 with adeno-associated virus harboring short-hairpin RNA (shRNA) against TRPM2 alleviated endothelial insulin resistance and ameliorated endothelium-dependent vasodilatation in obese mice. Thus, these results suggest that TRPM2-activated Ca2+ signaling is necessary to induce insulin resistance-related endothelial dysfunction in obesity. Downregulation or pharmacological inhibition of TRPM2 channels may lead to the development of effective drugs for treatment of endothelial dysfunction associated with oxidative stress state.
Subject(s)
Calcium/metabolism , Endothelium, Vascular/pathology , Fatty Acids, Nonesterified/toxicity , Hydrogen Peroxide/toxicity , Insulin Resistance , Obesity/physiopathology , TRPM Cation Channels/metabolism , Activating Transcription Factor 4/genetics , Activating Transcription Factor 4/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Oxidants/toxicity , Oxidative Stress , Phosphorylation , Reactive Oxygen Species/metabolism , Signal Transduction , TRPM Cation Channels/genetics , eIF-2 Kinase/genetics , eIF-2 Kinase/metabolismABSTRACT
Aspirin has been confirmed as an effective antitumor drug in various cancers. However, the relationship between aspirin and uterine leiomyoma is still underexplored. Here, we explored the effects of aspirin on human uterine leiomyoma cells and provide insights into the underlying mechanisms. Cell Counting Kit-8 (CCK-8) and flow cytometry analysis showed that aspirin treatment inhibited cell proliferation and promoted cell cycle arrest at G0/G1 phase in a dose- and timedependent manner of human uterine leiomyoma cells. Further studies revealed that aspirin blocked the interaction between K-Ras and p110α by co-immunoprecipitation and immunofluorescence. Western blotting demonstrated KRasp110α interaction was required for the effects of aspirininduced inhibition on cell growth and cell cycle transition via cell cycle regulators, including cyclin D1 and cyclin-dependent kinase 2 (CDK2). PI3K/Akt/caspase signaling pathway was involved in human uterine leiomyoma cell growth under aspirin treatment. Taken together, these results suggest that aspirin inhibited human uterine leiomyoma cell growth by regulating KRasp110α interaction. Aspirin which targeting on interaction between K-Ras and p110α may serve as a new therapeutic drug for uterine leiomyoma treatment.
Subject(s)
Aspirin/administration & dosage , Class I Phosphatidylinositol 3-Kinases/genetics , Leiomyoma/drug therapy , Proto-Oncogene Proteins p21(ras)/genetics , Apoptosis/drug effects , Caspases/genetics , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Cyclin D1/genetics , Cyclin-Dependent Kinase 2/genetics , Flow Cytometry , Humans , Leiomyoma/genetics , Leiomyoma/pathology , Signal Transduction/drug effectsABSTRACT
Ca2+-activated Cl- channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used. We found that TMEM16A was expressed abundantly and functioned as a Ca2+-activated Cl- channel in endothelial cells. Angiotensin II induced endothelial dysfunction with an increase in TMEM16A expression. The knockout of endothelial-specific TMEM16A significantly lowered the blood pressure and ameliorated endothelial dysfunction in angiotensin II-induced hypertension, whereas the overexpression of endothelial-specific TMEM16A resulted in the opposite effects. These results were related to the increased reactive oxygen species production, Nox2-containing NADPH oxidase activation, and Nox2 and p22phox protein expression that were facilitated by TMEM16A on angiotensin II-induced hypertensive challenge. Moreover, TMEM16A directly bound with Nox2 and reduced the degradation of Nox2 through the proteasome-dependent degradation pathway. Therefore, TMEM16A is a positive regulator of endothelial reactive oxygen species generation via Nox2-containing NADPH oxidase, which induces endothelial dysfunction and hypertension. Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated diseases.
Subject(s)
Chloride Channels/metabolism , Endothelium, Vascular/metabolism , Hypertension/metabolism , Membrane Glycoproteins/metabolism , NADPH Oxidases/metabolism , Reactive Oxygen Species/metabolism , Angiotensin II/pharmacology , Animals , Anoctamin-1 , Blood Pressure/drug effects , Blood Pressure/genetics , Chloride Channels/genetics , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium, Vascular/drug effects , Hypertension/genetics , Membrane Glycoproteins/genetics , Mice , Mice, Knockout , Mice, Transgenic , NADPH Oxidase 2 , NADPH Oxidases/genetics , Phosphorylation , Proteasome Endopeptidase Complex/metabolismABSTRACT
Germ cell tumors account for 98% of all testicular malignancies. Delays in seeking treatment are unfortunately common and may lead to metastatic spread. The present study reported a case of a 24-year-old man with a giant 12×10 cm left inguinal mass and a left neck mass that had grown rapidly during recent months. Computed tomography confirmed that the mass measured 12.1×9.4 cm and was a left undescended testicle malignancy, and also revealed widespread metastasis to the liver and a large retroperitoneal mass (12.6×8.2 cm). Immunohistochemical staining confirmed seminoma. The patient was treated with chemotherapy with the VIP protocol (cisplatin, etoposide and ifosfamide). Following courses of chemotherapy, the patient received complete clinical remission and was disease-free at the 6 month follow-up.
ABSTRACT
Paratesticular rhabdomyosarcoma (RMS) is an extremely rare malignancy in adults, accounting for 7% of all RMS cases and 6% of all non-germinal intrascrotal tumors. The clinical signs are similar to those of a hydrocele or testicular tumor, typically presenting as a unilateral, painless mass in the inguinal canal or scrotum. No specific serum markers are currently available for this tumor. RMS of the epididymis is extremely rare. Particularly when it is associated with epididymitis, this malignancy is usually overlooked. We herein present a case of epididymal embryonal RMS, manifesting an painful scrotal edema, misdiagnosed as epididymitis. The patient received 3 cycles of adjuvant chemotherapy postoperatively and remained disease-free after 4 years of follow-up.
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PURPOSE: To describe a case of free migration of intraocular glass in aphakia after glaucoma surgery. METHODS: We report the case of a 27-year-old man with a history of perforating injury to the right eye 10 years previously and glaucoma surgery 1 year previously presenting with 1 month of pain and frequent floaters in front of the right eye. On examination, the glass fragment was seen to lie free in the anterior chamber or migrate backwards through the pupil, remaining mobile on the inferior retinal surface when the patient was prone or supine, respectively. RESULTS: The fragment was surgically removed. CONCLUSION: Late migration of glass intraocular foreign bodies is a rare clinical entity, and the exact mechanism causing the migration of intraocular glass remains controversial. Early intervention must be weighed against the hazards of removal and the necessity of close follow-up.